The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index; 44 of the 56 sources its claims cite were checked for support.
Hair-bearing human skin generated entirely from pluripotent stem cells
Open accessPublished version of a preprint
Abstract
The skin is a multilayered organ, equipped with appendages (that is, follicles and glands), that is critical for regulating body temperature and the retention of bodily fluids, guarding against external stresses and mediating the sensation of touch and pain 1,2. Reconstructing appendage-bearing skin in cultures and in bioengineered grafts is a biomedical challenge that has yet to be met 3-9. Here we report an organoid culture system that generates complex skin from human pluripotent stem cells. We use stepwise modulation of the transforming growth factor β (TGFβ) and fibroblast growth factor (FGF) signalling pathways to co-induce cranial epithelial cells and neural crest cells within a spherical cell aggregate. During an incubation period of 4-5 months, we observe the emergence of a cyst-like skin organoid composed of stratified epidermis, fat-rich dermis and pigmented hair follicles that are equipped with sebaceous glands. A network of sensory neurons and Schwann cells form nerve-like bundles that target Merkel cells in organoid hair follicles, mimicking the neural circuitry associated with human touch. Single-cell RNA sequencing and direct comparison to fetal specimens suggest that the skin organoids are equivalent to the facial skin of human fetuses in the second trimester of development. Moreover, we show that skin organoids form planar hair-bearing skin when grafted onto nude mice. Together, our results demonstrate that nearly complete skin can self-assemble in vitro and be used to reconstitute skin in vivo. We anticipate that our skin organoids will provide a foundation for future studies of human skin development, disease modelling and reconstructive surgery.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
A stepwise human pluripotent stem cell organoid culture using TGFβ/FGF pathway modulation self-assembles hair-bearing skin with stratified epidermis, fat-rich dermis, pigmented hair follicles, sebaceous glands, sensory neurons, and Merkel cells. Single-cell RNA-sequencing and foetal comparison suggest second-trimester facial skin identity, and grafted organoids form planar hair-bearing skin on nude mice.
Key findings
- Hair germs appeared at 70 ± 5 days for WA25 and 72 ± 4 days for DSP-GFP organoids; hair follicle production occurred in 87.4% of WA25, 87.2% of DSP-GFP, and 70.8% of WA01 organoids. Pigmented hair-bearing organoids formed in 53.5% of WA25 and 76.2% of DSP-GFP cultures (p=0.077).
- scRNA-seq identified 23,329 cells at day-6 and 18,190 cells at day-29; day-6 populations were epithelial ~59%, neuro-glial ~8%, mesenchymal ~8%, and cycling ~25%, while day-29 was dominated by mesenchymal cells ~70%, with epithelial ~17%, neuro-glial ~7%, and cycling ~6%.
- Organoids showed craniofacial identity, including first pharyngeal arch markers and lack of HOX gene expression, and were proposed as equivalent to human facial skin in the second trimester.
- In xenografts, 55% of grafts (15 of 27, 3 experiments) grew 2–5 mm hairs, 22% had in-grown hairs, and 22% failed; no grafts showed ulceration or uncontrolled tumour-like growth.
Methods
- hPSCs (WA25 hESC, DSP-GFP hiPSC, and WA01 validation) were aggregated at 3,500 cells per U-bottom well, differentiated with Matrigel, SB431542, FGF, and BMP-4, then LDN/FGF at day-3; organoids were matured in floating culture on an orbital shaker for up to ~150 days.
- scRNA-seq used 10x Genomics Chromium, CellRanger, and Seurat; day-6 organoids (n=10) and day-29 organoids (n=5) were pooled, and day-48 WA25 organoids (n=6) had tail structures removed before dissociation.
- Xenografts used day 113–145 hair-bearing WA25 organoids with tails removed, implanted into 1–2 mm incisions in back skin of 5–6-week-old female nude mice, then analysed by histology, immunostaining, and electron microscopy.
Limitations
- The paper states that sweat glands were absent, that additional molecular and physiological profiling is needed to determine whether other somatosensory neuron subtypes and nerve endings can be induced, and that long-term (>1 year) observation is needed to determine terminal hair fate or growth cycling.
- The paper notes that off-target cell lineages require additional control before clinical reconstitution, and that cell-line variability suggests further protocol optimization may be needed.
- The text also makes evident that no statistical test was used to predetermine sample size, investigators were not blinded to treatment groups, and experiments were generally not randomized; xenograft failures and in-grown hairs were attributed partly to technical issues.
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Claims the paper makes
53 Own result · 17 Partly supported · 13 Own interpretation · 11 Own method · 7 No full text of the sources · 5 Couldn’t confirm · 2 Supported · 1 Supported so far · 1 Not supported · 1 No basis given · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Within the neuro-glial group, PAX6+HES5+ neuroectoderm-like cells clustered near PLP1+SOX10+PAX3+ CNCC-like cells (Fig. 2d), suggesting that CNCC arise from a neuroectoderm intermediate11.”
What the sources say
- Disputedcites [11] Tchieu, J. et al. A modular platform for differentiation of human PSCs into all major ectodermal lineages. Cell Stem Cell 21, 399–410 (2017). sourceExperimental — accuracy not yet measured
In Results, “Expression analysis of purified cell types from the ectoderm” (page unavailable), the paper reports that neuroectoderm clustered near hESCs, whereas neural crest clustered near cranial placode—not neuroectoderm. It treats neuroectoderm and neural crest as distinct lineages and does not infer that cranial neural crest arises through a neuroectoderm intermediate. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Reconstruction of appendage-bearing skin in cultures and in bioengineered grafts remains an unmet biomedical challenge3–9.”
What the sources say
- Partly supportedcites [3] Yang, R. et al. Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells. Nat. Commun. 5, 3071 (2014). sourceExperimental — accuracy not yet measured
The Abstract and Introduction describe obtaining folliculogenic human epithelial stem cells for tissue engineering as a challenge. They do not specifically say that reconstructing appendage-bearing skin in culture remains unmet. The Results (Characterization of iPSCs-derived EpSCs in vivo; page unavailable) report hair follicles and epidermis forming in experimental grafts on mice, so the paper does not support an unqualified claim that reconstruction in grafts remains unmet. (LLM, conf=0.84)
- Supportedcites [4] Abaci, H. E. et al. Tissue engineering of human hair follicles using a biomimetic developmental approach. Nat. Commun. 9, 5301 (2018). source
The Introduction (page not provided) says that available human skin constructs lack appendages and that incorporating hair follicles into engineered constructs remains a major challenge. It also identifies poor long-term viability as a limitation of skin grafts, supporting the claim about cultured constructs and bioengineered grafts. (LLM, conf=0.91)
- Partly supportedcites [5] Gledhill, K. et al. Melanin transfer in human 3D skin equivalents generated exclusively from induced pluripotent stem cells. PLoS ONE 10, e0136713 (2015). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says current cultured human 3D skin equivalents lack appendages and that adding complex structures such as appendages remains a hurdle. The paper does not address whether reconstructing appendage-bearing skin in bioengineered grafts remains a challenge. (LLM, conf=0.88)
- Supportedcites [6] Itoh, M. et al. Generation of 3D skin equivalents fully reconstituted from human induced pluripotent stem cells (iPSCs). PLoS ONE 8, e77673 (2013). source
The Discussion reports that the authors’ in vitro 3D skin equivalent lacked appendages. The Results (Skin Reconstitution Using iPSC-Derived Fibroblasts) likewise report no hair follicles or glands in the grafted skin, supporting the statement that reconstructing appendage-bearing skin remained a challenge in both settings. (LLM, conf=0.86)
- Could not verifycites [7] Lei, M. et al. Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells. Proc. Natl Acad. Sci. USA 114, E7101–E7110 (2017). sourceExperimental — accuracy not yet measured
The Limitations and Waning Immunity passages discuss pertussis outbreaks, vaccine exemptions, and vaccine durability, not skin reconstruction. Searches for appendage-bearing skin, tissue-engineered grafts, hair follicles, and skin culture found no passage addressing the claim. (LLM, conf=0.78)
- Partly supportedcites [8] Heitman, N., Saxena, N. & Rendl, M. Advancing insights into stem cell niche complexities with next-generation technologies. Curr. Opin. Cell Biol. 55, 87–95 (2018). sourceExperimental — accuracy not yet measured
The Modeling complexity section says flat cultures lack tissue complexity and reports that older mouse skin clusters lost the ability to induce hair follicles, although this could be rescued. It also describes murine skin organoids that make hair and sebaceous glands. These passages support limitations in cultured skin reconstruction, but the paper does not address bioengineered skin grafts or characterize their reconstruction as an unmet challenge. (LLM, conf=0.78)
- Could not verifycites [9] Koehler, K. R. et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat. Biotechnol. 35, 583–589 (2017). sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) describes human inner ear organoids and briefly mentions keratinocyte-like cells, but does not address reconstruction of appendage-bearing skin or bioengineered skin grafts. Searches for skin appendages, grafts, and the claimed unmet challenge found no passage addressing that point. (LLM, conf=0.76)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TGFβ inhibition promotes ectoderm induction from pluripotent stem cells, whereas BMP activation promotes surface ectoderm (alternatively, non-neural ectoderm) induction and suppresses neuroectoderm induction9–12.”
What the sources say
- Supportedcites [9] Koehler, K. R. et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat. Biotechnol. 35, 583–589 (2017). source
The passage labeled Abstract reports that treatment with the TGFβ inhibitor SB-431542 induced surface ectoderm–like epithelium from human embryonic stem cells. It also reports ectodermal outcomes in treated human iPSCs, although the subtype varied by cell line. (LLM, conf=0.90)
- Partly supportedcites [10] Koehler, K. R., Mikosz, A. M., Molosh, A. I., Patel, D. & Hashino, E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500, 217–221 (2013). sourceExperimental — accuracy not yet measured
The paper’s concluding passage (Abstract; page unavailable) says TGFβ inhibition acts with BMP activation in the induction of non-neural ectoderm in vitro. It does not establish that TGFβ inhibition alone promotes ectoderm induction from pluripotent stem cells, as the cited clause could imply. (LLM, conf=0.84)
- Supportedcites [11] Tchieu, J. et al. A modular platform for differentiation of human PSCs into all major ectodermal lineages. Cell Stem Cell 21, 399–410 (2017). source
In the Results section on chemically defined differentiation (page unavailable), the paper reports that adding the TGFβ inhibitor SB431542 increased PAX6-positive neuroectoderm from about 40% to nearly 90% of cells. Neuroectoderm is an ectodermal lineage, so this supports the attributed statement that TGFβ inhibition promotes ectoderm induction from pluripotent stem cells. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [12] Wilson, P. A. & Hemmati-Brivanlou, A. Induction of epidermis and inhibition of neural fate by Bmp-4. Nature 376, 331–333 (1995). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Culture systems containing epidermal and dermal cells have been used to model human skin outside of the body for research or clinical uses for over 40 years7,8,10; however, growing functional skin appendages in these systems has been persistently difficult.”
What the sources say
- Could not verifycites [7] Lei, M. et al. Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells. Proc. Natl Acad. Sci. USA 114, E7101–E7110 (2017). sourceExperimental — accuracy not yet measured
The Discussion and Limitations sections address pertussis vaccination, outbreaks, and nonmedical vaccine exemptions, not skin culture systems. Searches for functional skin appendages, epidermal and dermal cells, and related terms found no passage addressing the claim. (LLM, conf=0.78)
- Partly supportedcites [8] Heitman, N., Saxena, N. & Rendl, M. Advancing insights into stem cell niche complexities with next-generation technologies. Curr. Opin. Cell Biol. 55, 87–95 (2018). sourceExperimental — accuracy not yet measured
In “Modeling complexity: 2D co-cultures and 3D tissue-recapitulating organoids” (page unavailable), the review says 3D epidermal–dermal clusters from old mouse skin lost the ability to induce hair follicles, although that ability could be rescued. This supports a difficulty in a particular culture system, but does not establish that growing functional skin appendages has been persistently difficult across the skin culture systems described in the claim; the review also describes murine organoids capable of making hair and sebaceous glands. (LLM, conf=0.78)
- Could not verifycites [10] Koehler, K. R., Mikosz, A. M., Molosh, A. I., Patel, D. & Hashino, E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500, 217–221 (2013). sourceExperimental — accuracy not yet measured
The paper’s Abstract describes generating inner-ear sensory epithelia and mechanosensitive hair cells from mouse embryonic stem cells. Searches for skin appendages and epidermal–dermal culture systems found no passage addressing whether functional skin appendages are difficult to grow in those systems. The paper’s inner-ear hair cells are not skin appendages. (LLM, conf=0.77)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The epithelial group contained three epidermal sub-clusters: CXCL14+ basal, KRT1+ intermediate, and KRT4+ peridermal keratinocytes (Fig. 2e, Extended Data Fig. 5)22.”
What the sources say
- Could not verifycites [22] Joost, S. et al. Single-cell transcriptomics reveals that differentiation and spatial signatures shape epidermal and hair follicle heterogeneity. Cell Syst. 3, 221–237 (2016). sourceExperimental — accuracy not yet measured
The Results sections on unbiased clustering and subclustering describe murine epidermal and hair-follicle populations, including basal cells marked by Krt14 and Krt5. The searched passages do not describe an epithelial group divided into CXCL14+ basal, KRT1+ intermediate, and KRT4+ peridermal sub-clusters. (LLM, conf=0.76)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The transcription factor SOX2 was expressed in every dermal papilla (DP) cell cluster examined (Fig. 1i–l, Supplementary Video 1, 2), consistent with human foetal HFs and mouse guard, awl, and auchene HFs17.”
What the sources say
- Partly supportedcites [17] Driskell, R. R., Giangreco, A., Jensen, K. B., Mulder, K. W. & Watt, F. M. Sox2-positive dermal papilla cells specify hair follicle type in mammalian epidermis. Development 136, 2815–2823 (2009). sourceExperimental — accuracy not yet measured
The citation supports the comparison with mouse guard, awl and auchene follicles: the section ‘Sox2 is expressed in guard/awl/auchene dermal papillae but not in zigzag dermal papillae’ reports Sox2 expression in those follicle types. Our copy does not report the claimed comparison with human foetal hair follicles. The statement that every cluster in the citing authors’ examination expressed SOX2 refers to their own observations, not a finding attributed to this source. (LLM, conf=0.85)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In particular, five VIM+ clusters contained cells expressing DPT, TWIST2 and LUM, as well as numerous collagen genes, such as COL1A1/2, COL3A1, COL5A3, COL6A3, COL12A1, and COL21A1 (Extended Data Fig. 6a–d, see Supplementary Data 7 for detailed analysis)24.”
What the sources say
- Partly supportedcites [24] Sennett, R. et al. An integrated transcriptome atlas of embryonic hair follicle progenitors, their niche, and the developing skin. Dev. Cell 34, 577–591 (2015). sourceExperimental — accuracy not yet measured
In Results, under “Isolation of HF Placode Progenitors, Dermal Condensate Niche Cells, and other Distinct Cell Types from Embryonic Skin” (page unavailable), the source identifies Col1a1 as a fibroblast marker. It does not report day-48 WA25 organoids, five VIM+ clusters, or the full list of genes attributed to those clusters; those are findings referenced to the citing paper’s own figure and supplementary data. (LLM, conf=0.84)
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In our inner ear culture system, we determined that a co-treatment of basic-FGF (FGF) and a BMP inhibitor, LDN-193189 (LDN) promotes induction of CNCC-like cells that can generate mesenchymal cells; however, we did not previously investigate dermal cell specification in the system9.”
What the sources say
- Partly supportedcites [9] Koehler, K. R. et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat. Biotechnol. 35, 583–589 (2017). sourceExperimental — accuracy not yet measured
The paper reports FGF-2/LDN co-treatment and, later, cranial neural crest–like cells forming mesenchyme around otic pits (main text, page unavailable). But those cells were observed after an additional CHIR99021 treatment; the cited passages do not establish that FGF-2/LDN co-treatment itself promotes their induction. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Genes encoding WNT signalling pathway modulators were differentially expressed between epidermal (WNT6, LEF1) and dermal (SFRP2, TCF4, WIF1, APCDD1) cell populations (Extended Data Fig. 6d, e)27.”
What the sources say
- Partly supportedcites [27] Lim, X. & Nusse, R. Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb. Perspect. Biol. 5, a008029 (2013). sourceExperimental — accuracy not yet measured
The section “WNT IN THE DEVELOPMENT OF SKIN AND ITS APPENDAGES” (page unavailable) identifies Wnt6 among ligands expressed in mouse epidermis, and “Wnt Signaling in Skin Development” (page unavailable) reports LEF1 expression in hair-follicle matrix cells. Our copy does not report the claimed differential-expression comparison between epidermal and dermal cell populations or establish the specified dermal gene list. (LLM, conf=0.83)
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“From this study, we recognised that a 3D cyst composed of surface ectoderm (i.e. epidermal precursors) enveloped by mesenchymal cells (i.e. dermal precursors) can self-organize and mimic cell-to-cell signalling mechanisms critical for hair follicle (HF) development.”
What the sources say
- Partly supportedcites [3] Yang, R. et al. Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells. Nat. Commun. 5, 3071 (2014). sourceExperimental — accuracy not yet measured
The Results (page unavailable) report that injected epithelial cells formed cystic spheres, hair follicles grew from them, and surrounding mesenchymal components were mouse-derived. The paper also says the epithelial cells responded to inductive dermal signals. It does not establish that the cysts were enveloped by mesenchymal cells or demonstrate that they mimicked the cell-to-cell signalling mechanisms critical for hair follicle development. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
- Probably not a substantial claim. 15
- It may state two separate claims as one. 26
- The quote only partly states this claim. 2
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Culture systems containing epidermal and dermal cells have been used to model human skin outside of the body for research or clinical uses for over 40 years7,8,10; however, growing functional skin appendages in these systems has been persistently difficult.”
What the sources say
- Could not verifycites [7] Lei, M. et al. Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells. Proc. Natl Acad. Sci. USA 114, E7101–E7110 (2017). sourceExperimental — accuracy not yet measured
The Discussion addresses pertussis vaccination and community immunity, not skin culture systems. Searches for epidermal and dermal cell cultures, skin models, and the claimed 40-year history found no relevant passage in our copy. (LLM, conf=0.78)
- Partly supportedcites [8] Heitman, N., Saxena, N. & Rendl, M. Advancing insights into stem cell niche complexities with next-generation technologies. Curr. Opin. Cell Biol. 55, 87–95 (2018). sourceExperimental — accuracy not yet measured
The “Modeling complexity” section (page unavailable) describes cultured epidermal and dermal clusters as a skin model, supporting the general point that these cells have been used in culture. Its example uses mouse cells, however, and our copy does not establish use to model human skin for over 40 years or for clinical purposes. (LLM, conf=0.83)
- Could not verifycites [10] Koehler, K. R., Mikosz, A. M., Molosh, A. I., Patel, D. & Hashino, E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500, 217–221 (2013). sourceExperimental — accuracy not yet measured
The paper’s Abstract describes a 3D culture model of inner-ear development and notes an epithelium that mimics embryonic epidermis. Our copy does not address culture systems combining epidermal and dermal cells to model human skin, their research or clinical uses, or a 40-year history (searched for skin culture and its history). (LLM, conf=0.77)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Moreover, organoid HFs are periodically spaced throughout the epidermis suggesting that appendage patterning mechanisms are preserved in organoids18.”
What the sources say
- Partly supportedcites [18] Chuong, C.-M., Yeh, C.-Y., Jiang, T. X. & Widelitz, R. Module-based complexity formation: periodic patterning in feathers and hairs. Wiley Interdiscip. Rev. Dev. Biol. 2, 97–112 (2013). sourceExperimental — accuracy not yet measured
Section 4, “Engineering of the Periodic Patterning Process” (page unavailable), reports evenly spaced hairs in reconstituted skin grown on a matrix on a mouse. This supports periodic spacing as a feature of hair formation, but the paper does not report hair follicles in organoids or establish that appendage-patterning mechanisms are preserved in organoids. (LLM, conf=0.87)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“TGFβ inhibition promotes ectoderm induction from pluripotent stem cells, whereas BMP activation promotes surface ectoderm (alternatively, non-neural ectoderm) induction and suppresses neuroectoderm induction9–12.”
What the sources say
- Supportedcites [9] Koehler, K. R. et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat. Biotechnol. 35, 583–589 (2017). source
The differentiation results (passages 1–2; page not provided) show that BMP4 treatment promoted non-neural, surface ectoderm–like epithelium in human pluripotent stem-cell cultures. Passage 1 also reports that BMP inhibition increased neuroectoderm markers and abolished non-neural markers, supporting the stated contrast between the two fates. (LLM, conf=0.90)
- Supportedcites [10] Koehler, K. R., Mikosz, A. M., Molosh, A. I., Patel, D. & Hashino, E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500, 217–221 (2013). source
The paper states that BMP signaling is critical for inducing non-neural ectoderm. In the provided passage labeled Abstract (page not supplied), BMP4 treatment increased the non-neural ectoderm marker Dlx3 and decreased the neuroectoderm marker Sox1, supporting both parts of the attributed claim. (LLM, conf=0.93)
- Supportedcites [11] Tchieu, J. et al. A modular platform for differentiation of human PSCs into all major ectodermal lineages. Cell Stem Cell 21, 399–410 (2017). source
In the Results section (“BMP signaling through TFAP2A is necessary to generate non-CNS fates”; page not supplied), the authors report that strong BMP4 signaling triggers non-neural ectoderm and describe using BMP stimulation to suppress CNS differentiation. This supports both parts of the attributed claim. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [12] Wilson, P. A. & Hemmati-Brivanlou, A. Induction of epidermis and inhibition of neural fate by Bmp-4. Nature 376, 331–333 (1995). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Dermal fibroblasts have two embryonic origins: mesoderm cells (body and scalp skin) and cranial neural crest cells (CNCC; facial skin)13,14.”
What the sources say
- Not checked — no full text of the sourcecites [13] Minoux, M. & Rijli, F. M. Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development 137, 2605–2621 (2010). source
- Could not verifycites [14] Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013). sourceExperimental — accuracy not yet measured
The paper’s Abstract describes two dermal fibroblast lineages that form the upper and lower dermis, not two embryonic origins. Searches for mesoderm, cranial neural crest, and the claimed body/scalp versus facial-skin distinction found no passage addressing those origins. (LLM, conf=0.75)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“All cell sub-types were present in WA25 and DSP-GFP organoids, but in different proportions (Fig. 2b, c), suggesting further protocol optimization may be needed to reduce variability19.”
What the sources say
- Could not verifycites [19] Velasco, S. et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature 570, 523–527 (2019). sourceExperimental — accuracy not yet measured
The paper’s Methods (Statistics and Reproducibility) lists the stem cell lines studied, but not WA25 or DSP-GFP. The paper reports consistent overall cell-type proportions across its own lines, so its findings cannot verify which subtypes were present in WA25 and DSP-GFP organoids or whether their proportions differed (searched: WA25, DSP-GFP, cell-type proportions). (LLM, conf=0.76)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Presumptive dermal cells expressed FGF7 (Keratinocyte Growth Factor), which may be a key driver of epidermal stratification in this system (Extended Data Fig. 6f)28,29.”
What the sources say
- Supportedcites [28] Zhu, X.-J. et al. BMP-FGF signaling axis mediates Wnt-induced epidermal stratification in developing mammalian skin. PLoS Genet. 10, e1004687 (2014). source
The Discussion (page not provided) identifies FGF7 expression in the dermis and proposes that dermis-secreted FGF7 and FGF10 help regulate embryonic epidermal stratification. The Results section reports that supplying both factors improved stratification in mutant mouse skin explants, supporting the hedged suggestion that FGF7 may be a driver. The paper does not test FGF7 alone or the citing authors’ particular system. (LLM, conf=0.88)
- Supportedcites [29] Richardson, G. D. et al. KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin. Development 136, 2153–2164 (2009). source
The localisation section reports that KGF (FGF7) transcripts were detected only in the dermis of developing mouse skin. The epidermal-fate section reports that KGF treatment prematurely induced filaggrin, a stratification marker, and promoted epidermal differentiation. These findings support the proposed role of dermal FGF7; the citing paper’s observation in its own system is shown separately in its Extended Data Fig. 6f. (LLM, conf=0.88)
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We recently reported that appendage-bearing skin organoids can be generated via directed differentiation of epidermal and dermal cells from mouse pluripotent stem cells (PSCs)3.”
What the sources say
- Partly supportedcites [3] Yang, R. et al. Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells. Nat. Commun. 5, 3071 (2014). sourceExperimental — accuracy not yet measured
The Results (Characterization of iPSCs-derived EpSCs in vivo) report hair-follicle formation after combining pluripotent-stem-cell-derived epithelial cells with dermal cells. But the epithelial cells came from human iPSCs, while the dermal cells were freshly isolated from neonatal mice—not differentiated from mouse PSCs. The cited study therefore does not support the claim that both cell types were directed-differentiated from mouse PSCs. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Neural clusters contained cells expressing SOX2 (neural progenitors), DCX (CNS neurons) or PRPH (PNS neurons) (Extended Data Fig. 5)23.”
What the sources say
- Could not verifycites [23] Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014 (2018). sourceExperimental — accuracy not yet measured
The Results sections on postnatal neurogenesis and the peripheral nervous system describe progenitor and neuronal clusters, but the passages retrieved do not identify them by SOX2, DCX, or PRPH expression. Searches for all three gene names, individually and together, found no passage in our copy establishing the claimed marker assignments; no page numbers were available. (LLM, conf=0.74)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The expression pattern of NFATC1 was predominantly cytoplasmic, which was consistent with follicular bulges in foetal skin; by contrast, adult bulge cells displayed nuclear NFATC1 expression, a sign of maturity (Extended Data Fig. 10)2,36.”
What the sources say
- Partly supportedcites [2] Lee, J. et al. Hair follicle development in mouse pluripotent stem cell-derived skin organoids. Cell Rep. 22, 242–254 (2018). sourceExperimental — accuracy not yet measured
The Results section, “Skin organoid-derived HFs contain bulge-like regions” (page not available), reports predominantly cytosolic NFATc1 in organoid bulge cells and likens those cells to late-embryonic stem cells. It also identifies nuclear NFATc1 as a marker of both nascent and adult hair-follicle stem cells and suggests that its rarity may indicate limited maturation. It does not directly show the stated fetal-versus-adult expression contrast or establish nuclear localization as specific to adult maturity. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [36] Horsley, V., Aliprantis, A. O., Polak, L., Glimcher, L. H. & Fuchs, E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132, 299–310 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The organoid neurons were reminiscent of NC-derived neurons found in cranial or dorsal root ganglia, with medium-large soma Neurofilament-Heavy Chain (NEFH)+ Peripherin (PRPH)+ neurons and smaller soma NEFH−PRPH+ neurons (Fig. 3o, Supplementary Video 7)23,31.”
What the sources say
- Partly supportedcites [23] Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014 (2018). sourceExperimental — accuracy not yet measured
The Results section, “Peripheral Nervous System” (page unavailable), identifies dorsal-root-ganglion sensory neurons and a neurofilament branch, supporting part of the comparison. It does not describe the claimed NEFH/PRPH combinations or their association with medium-large versus smaller somata, nor does it establish the comparison with cranial ganglion neurons. The organoid observations are presented as the citing authors’ own results, not as findings of this source. (LLM, conf=0.83)
- Partly supportedcites [31] Gatto, G., Smith, K. M., Ross, S. E. & Goulding, M. Neuronal diversity in the somatosensory system: bridging the gap between cell type and function. Curr. Opin. Neurobiol. 56, 167–174 (2019). sourceExperimental — accuracy not yet measured
The “Sensory afferent heterogeneity” section describes neural-crest-derived trigeminal and dorsal root ganglion sensory neurons as having similar molecularly defined types. It mentions neurofilament as a historical sensory-afferent marker, but does not describe the claimed NEFH/PRPH combinations or their association with soma size. The organoid observations are the citing authors’ own results, not findings reported by this source. (LLM, conf=0.86)
plaincorrelationaln = 30- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
In the paper
“Furthermore, we noted a lack of HOX gene expression, which would indicate more caudal PAs (Extended Data Fig. 5)26.”
What the sources say
- Not checked — no full text of the sourcecites [26] Minoux, M. et al. Mouse Hoxa2 mutations provide a model for microtia and auricle duplication. Development 140, 4386–4397 (2013). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As in nascent mouse HFs, immunostaining revealed that epidermal germ cells were LHX2+PCAD+EDAR+, and dermal condensates were SOX2+PDGFRα+P75+ (Fig. 1i–l, Extended Data Fig. 4).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hair-bearing skin organoid generation was not restricted to these cell lines or the Koehler laboratory.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The neuro-glial group contained clusters of Schwann cell precursor cell (SCP)-like cells (PLP1+MPZ+), as well as melanocytes (PMEL+MITF+) (Fig. 2h, Extended Data Fig. 5).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On average, hair germs appeared at 70 ± 5 days for WA25 and 72 ± 4 days for DSP-GFP organoids.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“WA25: average 48 hair follicles per organoid, min=9, max=285”
plainn = 80- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The other grafts had in-grown hairs (22%) or failed (22%) due to technical issues (Fig. 4c).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In pigmented skin organoids, we found premelanosome protein (PMEL)+ melanocytes evenly distributed throughout the epithelium and concentrated in the matrix region of HFs (Fig. 3d, e, Supplementary Video 3).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Another interesting feature of late-stage organoids was hyaline cartilage, which developed in the tail region (Fig. 3a, b, Extended Data Fig. 8).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For out-grown xenografts, histology confirmed that the organoid epidermis had integrated with the host epidermis, and the hair shafts were oriented perpendicular to the skin surface, reminiscent of bona-fide human skin tissue (Fig. 4f, g).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Morphologically, xenograft sebaceous glands had multiple lobes similar to adult sebaceous glands and were located superficial to the HF bulge region (Fig. 4i, Extended Data Fig. 9).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Statistical significance was determined in Figure 3g using an unpaired Student’s t-test with Welch’s correction to account for unequal standard deviations and sample sizes, p=0.077.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DSP-GFP: average 48 hair follicles per organoid, min=7, max=128”
plainn = 80- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, our results demonstrate that nearly complete skin can self-assemble in vitro and be used to reconstitute skin in vivo.”
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In general, experiments were not randomized; however, organoid specimens used for histology and single-cell RNA-sequencing analysis were selected at random and not screened for quality or specific morphological characteristics.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The culture method was optimized and replicated by three investigators (K.R.K., J.L., and M.S.) using the WA25 and DSP-GFP cell lines.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data reinforce a tissue architecture model whereby skin organoids represent craniofacial skin (superficial tissue) and cartilage (deep tissue) developing inside-out.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“S.H. and B.M.W. were blinded to the data already generated for this study with WA25 and DSP-GFP PSCs; thus, they were unfamiliar with the expected morphological changes during skin organogenesis.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical test was used to predetermine sample size, the investigators were not blinded to the treatment groups.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In vivo experiments were performed after an approval from the Indiana University Animal Care and Use Committee (IACUC) and complied with federal regulations.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In general, experiments were not randomized; however, organoid specimens used for histology and single-cell RNA-sequencing analysis were selected at random and not screened for quality or specific morphological characteristics.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Final cell concentration was ~1,000 cells/μl and >90% viability.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After ~150 days in culture, we observed a build-up of squamous cells in the core of skin organoids (Extended Data Fig. 9b) and abnormal HF morphologies, suggesting that this timepoint may be the upper limit for skin organoid culture.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical test was used to predetermine sample size, the investigators were not blinded to the treatment groups.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All representative skin organoid images shown in this manuscript represent results from nine independent experiments of WA25 and DSP-GFP cultures and one WA01 culture (Figure 1c–f, i–l and Figure 3b, d–f”, h, i, k–m, o–r).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Unless stated otherwise, images are representative of specimens obtained from at least 3 separate experiments.”
- Also stated in: § METHODS · plain
“All immunostaining images shown in this manuscript are representative of minimum 3 times of the same staining.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Also stated in: § METHODS · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these findings suggest that skin organoid HFs reach a level of maturity roughly equivalent to second trimester foetal hair and have the cellular components for further maturation.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our study establishes a novel model to investigate the cellular dynamics of developing human skin and its appendages—including sweat glands, which were absent from the skin organoids reported here.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The authors state this as an assumption.
The site of axon targeting in organoid HFs is the bulge region.
“which we presume to be the bulge region of the HFs”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“They often display inverted polarity, in which the epidermis is positioned internally and the dermis externally, and frequently undergo ectopic cartilage differentiation 14,15 .”
From Vascularized human skin assembloids model compartmental skin organization and immune responsiveness in vitro (2026) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The skin organoids were shown to be equivalent to the embryonic skin in development and mimicked normal hair folliculogenesis.”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“While many attempts to generate complex 3D skin equivalents have achieved vascularization, hair follicle generation, and immune cell co‐cultures, there has been a complete absence of endogenously differentiating a vascularized, hair‐bearing human skin equivalent that contains immune cell populations.[ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]”
From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent advances in human induced pluripotent stem cell (hiPSC) technology have enabled the generation of skin organoids (SKO) with hair follicles, pigmentation, dermal stratification, appendage patterning, and innervation.[ 25 , 26 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]”
From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Figure 7c also shows that the hair follicles in VSKOs are SRY‐box transcription factor 2 (SOX2)+, K14+, cytokeratin 15 (K15)+, and K17+, as seen in the current SKO model.[ 25 , 26 ]”
From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [26]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous reports described the absence of immune and vascular components during hiPSC‐derived SKO differentiation.[ 25 , 26 , 33 ]”
From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous human SKO models were devoid of vascularization and immune cells.[ 25 , 26 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 59 ]”
From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“By days 110–130, the hair pegs formed more elaborate hair follicles containing sebaceous glands (sebum-producing glands) and a bulge region with Merkel cells (touch-sensing cells) and nuclear factor of activated T cells 1 (NFATC1)+ hair follicle stem cell-like cells”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As previously shown25, we anticipate that at least an average of 87% of skin organoids will generate hair follicles when incubated with 2.5 ng/mL BMP4 on day 0 of differentiation.”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“After 1 month of transplantation, we found that the skin organoid cysts had unfurled and integrated into the host skin, forming about 1–2 mm sized planar skin with outward-growing hairs.”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Skin organoids form a sphere-like cyst where hair shafts sprout inward toward the fluid-filled core, with hair bulbs protruding outward from the surface of the cysts”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Our comparative analysis with fetal hair suggests that the skin organoids in vitro are reminiscent of lanugo hair, which sheds just before or after birth”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although these skin spheroids resemble fetal facial skin, their long incubation period and small size are not ideal for genetic manipulation of individual cell types or for grafting in the clinic.”
From Single-cell transcriptomics of human-skin-equivalent organoids (2023) · cites this paper as [10]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“hPSC-derived skin organoids, with their enhanced complexity, resemble a more fetal developmental stage [19]”
From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [19]
The cited source says what the claim attributes to it.
In the citing paper
“The pioneering protocol for human skin organoid generation, by Lee et al., involves forming hiPSC aggregates, maintaining these for 2 days in maintenance media, and then performing stepwise modulation of the TGFβ/FGF pathways to drive skin development [8].”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“Therefore, the development of the human skin organoid (SKO) by Lee et al. in 2020 was a significant breakthrough in the field, as this skin model has far greater complexity and physiological accuracy than its predecessors [8].”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“In SKO differentiation, for example, the modulation of the transforming growth factor beta (TGFβ) and fibroblast growth factor (FGF) signaling pathways co-induces the differentiation of epithelial and mesenchymal lineages, mimicking human fetal skin development [8, 9].”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“Skin organoids (SkOs) derived from hiPSCs recapitulate epidermal and dermal differentiation and generate appendages such as hair follicles, melanocytes and neurons 13,14 .”
From Vascularized human skin assembloids model compartmental skin organization and immune responsiveness in vitro (2026) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“In addition to the dermal and epidermal compartments, they harbor anatomically complex structures, such as hair follicles and sebaceous glands [3,4].”
The cited source says what the claim attributes to it.
In the citing paper
“More recently, human induced pluripotent stem cells were used to generate skin organoids with appendages including hair follicles in 4 to 5 months of culture (13).”
From Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction (2022) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Notably, this observation aligns with previous studies that mature human SKOs resemble human fetal craniofacial skin at 18‐week of gestation.[ 26 , 78 ]”
From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“This protocol provides step-by-step guidance to form human pluripotent stem cell (hPSC)-derived skin organoids, which we have previously shown can recapitulate many features of full-thickness human fetal skin and be xenografted on nude mice”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
The cited source says what the claim attributes to it.
In the citing paper
“Based on our scRNA-seq and immunostaining data, the end-stage skin organoids (~150 days of culture) represent the human skin tissues at the second-trimester stage of the developing fetus”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
The cited source says what the claim attributes to it.
In the citing paper
“Before day 150, skin organoids can be extracted from culture and used for downstream assays (e.g., single-cell sequencing) or xenografting experiments (as demonstrated in ref. 25).”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [25]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“their composition and culture conditions vary greatly from lab to lab, which can affect interpretation of similar experiments.”
From Single-cell transcriptomics of human-skin-equivalent organoids (2023) · cites this paper as [10]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Abstract
“By manual counting, we estimated an average of 64 HFs per WA25 and 48 HFs per DSP-GFP organoid (Fig. 1h).”
§ METHODS
“WA25: average 48 hair follicles per organoid, min=9, max=285; DSP-GFP: average 48 hair follicles per organoid, min=7, max=128.”
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Sorted by citations
Items 201–300 of 487
Emergence and properties of adult mammalian epidermal stem cells
Gadre, P., Markova, P., Ebrahimkutty, M. P., Jiang, Y., Bouzada, F. M., & Watt, F. M. (2024) · Developmental Biology · doi:10.1016/j.ydbio.2024.07.014 · Cited by 14
The mechanical forces that shape our senses
Le, A. P., Kim, J., & Koehler, K. R. (2022) · Development · doi:10.1242/dev.197947 · Cited by 11
Self-citationDiversity of human skin three-dimensional organotypic cultures
Jia, Y. Y., & Atwood, S. X. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102275 · Cited by 12
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Self-citationWang, Y., Ouyang, Q., Zhao, S., Zhang, Y., Tian, R.-Z., Guo, Y.-P., Zheng, R., Nasser, M. I., Li, G., & Zhu, P. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2809221 · Cited by 11
“At present, organoids are expected to be applied to many research fields, such as establishing disease models, studying the molecular mechanism of disease, drug research and regenerative medicine [34–36].”
BackgroundMazio, C., Mavaro, I., Palladino, A., Casale, C., Urciuolo, F., Banfi, A., D’Angelo, L., Netti, P. A., de Girolamo, P., Imparato, G., et al. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.100949 · Cited by 12
“In this regard, the transplantation of skin organoids derived from human pluripotent stem cells has proven successful in generating hairy-skin after grafting onto nude mice) [44].”
BackgroundGenetic Tools for Cell Lineage Tracing and Profiling Developmental Trajectories in the Skin
Nathans, J. F., Ayers, J., Shendure, J., & Simpson, C. L. (2024) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2024.02.006 · Cited by 12
Sebaceous gland organoid engineering
Liu, Y., Gao, H., Chen, H., Ji, S., Wu, L., Zhang, H., Wang, Y., Fu, X., & Sun, X. (2024) · Burns & Trauma · doi:10.1093/burnst/tkae003 · Cited by 14
“Human skin organoids bearing SGs and HFs were derived from the WA25 human embryonic stem cell line [61,62].”
Self-citationTHSD4 promotes hair growth by facilitating dermal papilla and hair matrix interactions
Wang, M., Wang, M., Jiang, J., Li, K., Liang, H., Wang, N., Zou, Y., Wang, D., Zhou, S., Tang, Y., et al. (2025) · Theranostics · doi:10.7150/thno.103221 · Cited by 14
“We then transferred the aggregates to new plates containing differentiation medium to promote epidermal differentiation as previously described [67, 68].”
Prenatal Development and Function of Human Mononuclear Phagocytes
Miah, M., Goh, I., & Haniffa, M. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.649937 · Cited by 13
Disease Modeling with Kidney Organoids
Karp, S., Pollak, M. R., & Subramanian, B. (2022) · Micromachines · doi:10.3390/mi13091384 · Cited by 13
“, tear production in lacteal organoids and hair growth in skin organoids) [1,2].”
BackgroundConnolly, K., & Gonzalez-Cordero, A. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.049593 · Cited by 14
Mori, A., Murata, S., Tashiro, N., Tadokoro, T., Okamoto, S., Otsuka, R., Wada, H., Murata, T., Takahashi, T., Seino, K., et al. (2021) · Cells · doi:10.3390/cells10020476 · Cited by 12
Marx, U., Accastelli, E., David, R. M., Erfurth, H., Koenig, L., Lauster, R., Ramme, A. P., Reinke, P., Volk, H., Winter, A., et al. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.728866 · Cited by 15
“The period of generating PSC-derived organoids varies depending on the tissue type and usually requires between 2 weeks and 3 months (17) but can continue for half a year or longer, as seen in skin (18) or brain organoids (19).”
BackgroundCurrent controversies in trichology: a European expert consensus statement
Meyer-González, T., Bacqueville, D., Grimalt, R., Mengeaud, V., Piraccini, B. M., Rudnicka, L., Saceda‐Corralo, D., Vogt, A., Trichology Experts Network Group, & Vano‐Galvan, S. (2021) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.17601 · Cited by 12
3D sheep rumen epithelial structures driven from single cells in vitro
Xu, Z., Xu, X., Yang, B., Mi, Y., & Wang, J. (2023) · Veterinary Research · doi:10.1186/s13567-023-01234-1 · Cited by 11
“Fibroblast growth factors (FGF7 and FGF10) stimulate the division of skin keratinocytes and intestinal epithelial cells and are essential for the expansion of human skin organoids and mouse gastric organoids [5, 32, 33].”
BackgroundGuidelines for Manufacturing and Application of Organoids: Skin
Lee, S., Rim, Y. A., Kim, J., Lee, S. H., Park, H. J., Kim, H., Ahn, S.-J., & Ju, J. H. (2024) · International Journal of Stem Cells · doi:10.15283/ijsc24045 · Cited by 14
“…the limitations of existing established technologies or to establish alternative animal testing methods for undeveloped areas, it is necessary to continue developing testing methods using the latest skin or-ganoid technology (11, 12), which is gradually increasing in similarity to human skin.”
BackgroundPluripotent stem cell‐derived organoids: A brief history of curiosity‐led discoveries
Lancaster, M. A. (2024) · BioEssays · doi:10.1002/bies.202400105 · Cited by 11
Riabinin, A. A., Pankratova, M., Rogovaya, O. S., Vorotelyak, E. A., Terskikh, V. V., & Vasiliev, A. V. (2024) · BioMed Research International · doi:10.1155/2024/9947692 · Cited by 13
“A Matrigel®-based culture system has been successfully used to generate dermal papilla spheroids and skin organoids with HFs from iPSCs [34, 35, 106, 107].”
BackgroundMethodMaterials-based hair follicle engineering: Basic components and recent advances
Lv, Y., Yang, W., Kannan, P. R., Zhang, H., Zhang, R., Zhao, R., & Kong, X. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.101303 · Cited by 12
Evolution of long scalp hair in humans
Chang, L., Plikus, M. V., Jablonski, N. G., & Lin, S. (2025) · British Journal of Dermatology · doi:10.1093/bjd/ljae456 · Cited by 15
“Moreover, advances in organotypic human HF culture, 91 skin organoid culture 92 and human-on-mouse HF xenograft models 40,42,86 are currently enabling validation of candidate regulators of long-lasting anagen in addition to preclinical testing of hair growth-enhancing drug candidates.”
The Bioengineering of Microspheric Skin Organoids and Their Application in Drug Screening
Xie, J., Yang, Q., Zhang, Y., Zheng, K., Geng, H., & Wu, Y. (2025) · Advanced Science · doi:10.1002/advs.202416863 · Cited by 14
Saeki, T., Yoshimatsu, S., Ishikawa, M., Hon, C.-C., Koya, I., Shibata, S., Hosoya, M., Saegusa, C., Ogawa, K., Shin, J. W., et al. (2022) · Regenerative Therapy · doi:10.1016/j.reth.2022.04.008 · Cited by 13
Xie, S., Chen, L., Zhang, M., Zhang, C., & Li, H. (2022) · Annals of Translational Medicine · doi:10.21037/atm-22-3252 · Cited by 11
“To judge whether the structure and function of organoids are consistent with those of native tissue, current research has compared the results of HE and the immunohistochemical expression of marker proteins in specific sites within HF organoids with those of native HF (8,9,12,14).”
BackgroundResultThe ROC skin model: A robust skin equivalent for permeation and live cell imaging studies
Jakobsen, N. D., Kaiser, K., Ebbesen, M. F., Lauritsen, L., Gjerstorff, M. F., Kuntsche, J., & Brewer, J. R. (2022) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2022.106282 · Cited by 11
Lemaı̂tre, J.-M. (2024) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.19820 · Cited by 13
“A striking example has been provided recently by the generation of hair-bearing human skin entirely from PSCs. 68 Lee et al. 68 developed a skin organoid culture system in which human ESCs were pre-aggregated in uniform aggregates and then transferred to a differentiation medium containing a TGFß…”
BackgroundInfluentialA scalable, GMP-compatible, autologous organotypic cell therapy for Dystrophic Epidermolysis BullosaPreprint
Neumayer, G., Torkelson, J. L., Li, S., McCarthy, K., Zhen, H. H., Vangipuram, M., Jackow, J., Rami, A., Hansen, C. S., Guo, Z., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.28.529447 · Cited by 11
Engineering Biomimetic Microenvironment for Organoid
Chen, S., Wang, L., Yang, L., Rana, A. S., & He, C. (2023) · Macromolecular Bioscience · doi:10.1002/mabi.202300223 · Cited by 10
Microfluidic Electrospray of Multifunctional Discal Microparticles for Wound Healing
Luo, Z., Cai, L., Bian, F., & Zhao, Y. (2023) · ACS Materials Letters · doi:10.1021/acsmaterialslett.3c01182 · Cited by 10
A Chemically Defined Culture for Tooth Reconstitution
Zhang, Z., Hu, H., Xu, Z., Shan, C., Chen, H., Xie, K., Wang, K., Wang, Y., Zhu, Q., Yin, Y., et al. (2024) · Advanced Science · doi:10.1002/advs.202404345 · Cited by 11
Development of in vitro hair pigmentation model using hair follicle organoids
Tu, S., Kageyama, T., Seo, J., Zhou, Y., & Fukuda, J. (2024) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2024.11.003 · Cited by 11
Advances in lacrimal gland organoid development: Techniques and therapeutic applications
Dayem, A. A., Jang, S. B., Lim, N., Yeo, H. C., Kwak, Y., Lee, S., Shin, H. J., & Cho, S. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117870 · Cited by 12
Biomimetic Structure and Phase Change Materials for Multifunctional Personal Thermal Management
Su, Q., Sheng, G., Li, Y., Lü, X., Wang, C., Xin, C., Wang, H. S., & Jiang, H. (2025) · Journal of Bionic Engineering · doi:10.1007/s42235-025-00647-2 · Cited by 11
“Human body dissipates heat through various mechanisms to maintain thermal comfort, with the skin serving as the larg - est organ [67] responsible for heat dissipation [68].”
Li, T., Li, X., Xiao, X., Huang, J., Shen, X., Wang, M., Jiang, J., Shao, S., Li, Z., Xie, T., et al. (2025) · Advanced Science · doi:10.1002/advs.202502436 · Cited by 10
Louis, B., Tewary, M., Bremer, A. W., Philippeos, C., Negri, V. A., Zijl, S., Gartner, Z. J., Schaffer, D. V., & Watt, F. M. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.07.054 · Cited by 10
Circular RNA Involvement in Aging and Longevity
Liu, J., & Niu, R. (2022) · Current Genomics · doi:10.2174/1389202923666220927110258 · Cited by 10
“Fortunately, multiple system-related organoids have been developed to capture the phenotypic and molecular heterogeneity of different organs for developmental, aging and drug studies, including skin, hepatocytes, mini-intestines, retina, brain, heart and multiple cancers [40-49].”
BackgroundUse of mouse primary epidermal organoids for USA300 infection modeling and drug screening
Xie, X., Tong, X., Li, Z., Cheng, Q., Wang, X., Yin, L. W., Liu, F., Wang, Y., Wang, J., & Liu, L. (2023) · Cell Death and Disease · doi:10.1038/s41419-022-05525-x · Cited by 13
Carpena, N. T., Chang, S., Choi, J. E., Jung, J. Y., & Lee, M. Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910306 · Cited by 10
Diverse cellular players orchestrate regeneration after wounding
Williams, K. L., & Garza, L. A. (2020) · Experimental Dermatology · doi:10.1111/exd.14248 · Cited by 10
Human epidermis organotypic cultures, a reproducible system recapitulating the epidermis in vitro
Agarwal, R., Dittmar, T., Beer, H., Kunz, M., Müller, S., Kappos, E. A., Contassot, E., & Navarini, A. A. (2023) · Experimental Dermatology · doi:10.1111/exd.14823 · Cited by 7
Zheng, C., Sui, B., & Jin, Y. J. (2023) · Aggregate · doi:10.1002/agt2.497 · Cited by 10
Periodic pattern formation during embryonic development
Sudderick, Z. R., & Glover, J. D. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230197 · Cited by 12
Towards the development of sensation-enabled skin substitutes
Moradikhah, F., Farahani, M., & Shafiee, A. (2024) · Biomaterials Science · doi:10.1039/d4bm00576g · Cited by 9
Liu, J., Xu, D., Yan, J., Wang, B., Zhang, L., Liu, X., Zhang, H., Yan, G., Yang, J., Zeng, Q., et al. (2024) · Photodiagnosis and Photodynamic Therapy · doi:10.1016/j.pdpdt.2024.104238 · Cited by 9
Bravo, I. G., Belkhir, S., & Paget‐Bailly, P. (2024) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuae029 · Cited by 8
“The skin is indeed a highl y heter ogeneous , complex cellular en vironment that we start only to be able to engineer and reproduce (Lee et al. 2020 ).”
Innovative strategies for the discovery of new drugs against androgenetic alopecia
McElwee, K. J., & Sundberg, J. P. (2025) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2025.2473905 · Cited by 9
“Transplantation to immunodeficient mice enables the formation of stratified skin with emergent hair [223,224].”
Emerging biomedical engineering strategies for hair follicle regeneration
Cao, X., Lu, M., Li, N., Cai, L., Wang, Y., & Zhao, Y. (2025) · Bioactive Materials · doi:10.1016/j.bioactmat.2025.06.051 · Cited by 13
Innovations in skin microphysiological systems for nonclinical testing and FDA modernization
Lee, T., Kyung, S. Y., Kwon, M., Park, B., & Ko, J. (2026) · Microsystems & Nanoengineering · doi:10.1038/s41378-025-01149-1 · Cited by 16
“The maturation of these appendages typically requires prolonged culture and staged media formulations, with early induction phase followed by maintenance in calcium-and lipid-rich environments 98 .”
Fan, L., Kishore, A., Jansen‐Olliges, L., Wang, D., Stahl, F., Psathaki, O. E., Harre, J., Warnecke, A., Weder, J., Preller, M., et al. (2022) · ACS Omega · doi:10.1021/acsomega.2c02331 · Cited by 9
Zhang, S., Sui, Y., Zhang, Y., et al. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10431-y · Cited by 9
Jiao, Y., Niu, Y., Chen, X., et al. (2022) · Advances in Wound Care · doi:10.1089/wound.2022.0034 · Cited by 9
“32 The immunofluorescence results showed that there were more LipidTOX + sebaceous glands in WJMSCs + GM + PF-127 + SAP group than other control groups (Supplementary Fig.”
Exceed the Traditional Dead Leather to Intelligent E‐Skin
Yao, Y., Fan, Z., Gong, X., Li, D., Yang, W., Leung, K. C., Wang, X., Liu, S., Yang, J., & Xuan, S. (2025) · Advanced Functional Materials · doi:10.1002/adfm.202500572 · Cited by 9
Inhibition of class I HDACs preserves hair follicle inductivity in postnatal dermal cells
Park, M., Jang, S., Chung, J. H., Kwon, O., & Jo, S. J. (2021) · Scientific Reports · doi:10.1038/s41598-021-03508-0 · Cited by 10
Shin, G. J.-E., Abaci, H. E., & Smith, M. C. (2022) · Frontiers in Pain Research · doi:10.3389/fpain.2022.912977 · Cited by 9
Jiao, Y., Chen, X., Nong, B., Luo, M., Niu, Y., Huang, S., Zhang, J., Wei, A., & Huang, J. (2022) · Journal of Materials Chemistry B · doi:10.1039/d2tb01649d · Cited by 9
Wang, M., Lai, Z., Zhang, H., Yang, W., Zheng, F., He, D., Liu, X., Zhong, R., Qahar, M., & Yang, G. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s469239 · Cited by 9
Generation and characterization of vestibular inner ear organoids from human pluripotent stem cells
van der Valk, W. H., Nist-Lund, C. A., Zhang, J., Perea, C., Jin, J., Gim, K. Y., Steinhart, M. R., Lee, J., & Koehler, K. R. (2025) · Nature Protocols · doi:10.1038/s41596-025-01191-3 · Cited by 12
Self-citationZhou, H., Zhang, Y.-X., Lei, Q.-K., Li, Y., & Zheng, Y. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04447-7 · Cited by 9
“Lee et al. [16] constructed a human cyst-like skin organoid consisting of a stratified epidermis, a fat-rich dermis, and pigmented hair follicles equipped with sebaceous glands.”
Jiang, Y., Liu, H., Zou, Q., Li, S., & Ding, X. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.902026 · Cited by 8
Generation and integration of hair follicle-primed spheroids in bioengineered skin constructs
Tan, C. T., Leo, Z. Y., & Lim, C. Y. (2022) · Biomedical Materials · doi:10.1088/1748-605x/ac99c6 · Cited by 9
“To achieve further differentiation into mature hair follicles, the KCDP spheroids or skin organoids are often grafted onto animal skin [11, 14, 18].”
BackgroundBiomimetic Gland Models with Engineered Stratagems
Lin, X., Sun, L., Lu, M., & Zhao, Y. (2023) · Research · doi:10.34133/research.0232 · Cited by 8
“(A) Schematic diagram of (i) skin organoid construction and (ii) skin organ sample on day 85 [170], Copyright 2020, Springer Nature.”
MethodCorneal epithelium models for safety assessment in drug development: Present and future directions
Abdalkader, R., & Fujita, T. (2023) · Experimental Eye Research · doi:10.1016/j.exer.2023.109697 · Cited by 9
Modelling Human Hair Follicles—Lessons from Animal Models and Beyond
Tan, C. T., Lim, C. Y., & Lay, K. (2024) · Biology · doi:10.3390/biology13050312 · Cited by 8
Late stage melanoma is hallmarked by low NLGN4X expression leading to HIF1A accumulation
Schörghofer, D., Vock, L., Mirea, M. A., Eckel, O., Gschwendtner, A., Neesen, J., Richtig, E., Hengstschläger, M., & Mikula, M. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02758-9 · Cited by 8
“Skin organoids were generated using human embryonic stem cells WA19 (WiCell CVCL_9780) of early passages (p16 – 19) after the protocol of Lee et al. [19].”
Skin Cyst: A Pathological Dead-End With a New Twist of Morphogenetic Potentials in Organoid Cultures
Qiu, W., Gu, P.-R., Chuong, C., & Lei, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.628114 · Cited by 9
“Skin is constantly subjected to insults such as UV radiation, toxin, invasive pathogens, etc (Lei and Chuong, 2018).”
BackgroundBuilding bridges between fields: bringing together development and homeostasis
Weterings, S. D. C., van Oostrom, M. J., & Sonnen, K. F. (2021) · Development · doi:10.1242/dev.193268 · Cited by 10
Vermeer, M. C. S. C., Andrei, D., Kramer, D., et al. (2022) · Experimental Dermatology · doi:10.1111/exd.14571 · Cited by 8
Vermeer, M. C. S. C., Andrei, D., Marsili, L., van Tintelen, J. P., Silljé, H. H. W., van den Berg, M. P., van der Meer, P., & Bolling, M. C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810765 · Cited by 8
Translational Utility of Organoid Models for Biomedical Research on Gastrointestinal Diseases
Banerjee, P., & Senapati, S. (2024) · Stem Cell Reviews and Reports · doi:10.1007/s12015-024-10733-3 · Cited by 7
“These tissues include the pancreas [16], breast [17], airway and lung [18, 19], stomach [20], small intestine [21], prostate [22], kidney [23], liver [24], brain and neural tissue [25], and skin [26] (Table 1 ) .”
Ahmed, I. A., Sun, J., Kong, M. J., Khosrotehrani, K., & Shafiee, A. (2024) · Experimental Dermatology · doi:10.1111/exd.70017 · Cited by 7
“The SKOs recapitulate early skin development and have a structural resemblance to the human foetal organ [21].”
Fu, H., Zhao, W., Jiang, L., & Shan, S. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s522458 · Cited by 7
Zhang, H., Su, L., Qiang, Y., Chen, J., Hang, S., Liu, M., Ding, H., Ouyang, Q., Zhu, Y., Wang, X., et al. (2025) · Phytomedicine · doi:10.1016/j.phymed.2025.156963 · Cited by 8
Centimeter‐Scale Self‐Assembling Tendon Organoids Drive Tissue Regeneration
Fang, T., Zhang, H., Xie, Y., Li, X., Liu, X., Wang, Z., Xue, Y., Xia, X., Wang, Z., Lei, T., et al. (2025) · Advanced Science · doi:10.1002/advs.202509453 · Cited by 7
Human skin organoids are valid models of mpox virus infection
(2023) · Nature Microbiology · doi:10.1038/s41564-023-01490-z · Cited by 7
Beyond skin deep: Revealing the essence of iPS cell-generated skin organoids in regeneration
Zhang, Y.-X., Zhou, Y., Xiong, Y., & Li, Y. (2024) · Burns · doi:10.1016/j.burns.2024.06.011 · Cited by 8
Wiring the senses: Factors that regulate peripheral axon pathfinding in sensory systems
Nomdedeu‐Sancho, G., & Alsina, B. (2022) · Developmental Dynamics · doi:10.1002/dvdy.523 · Cited by 7
“So far, human pluripotent stem cellderived organoids have been described for some sensory systems, including the inner ear,(155) and the skin.(156) In addition, lingual organoids have been produced using rat stem cells,(157) and the translation of this protocol to human stem cells could be assessed in the future.”
BackgroundHolistic health record for Hidradenitis suppurativa patients
Tricarico, P. M., Moltrasio, C., Gradišek, A., Marzano, A. V., Flacher, V., Boufenghour, W., von Stebut, E., Schmuth, M., Jaschke, W., Gams, M., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-11910-5 · Cited by 7
Steinhart, M. R., Serdy, S. A., van der Valk, W. H., Zhang, J., Kim, J., Lee, J., & Koehler, K. R. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3974124 · Cited by 7
Self-citationKageyama, T., Anakama, R., Hamano, S., Tu, S., Migita, Y., Asaba, T., Nanmo, A., Ishikawa, K., Yan, L., Seo, J., et al. (2026) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c01780 · Cited by 6
“12,13 14 − 18 However, their induction involves multiple differentiation steps starting with ectoderm induction, which requires a long culture period (4 − 5 months), and undifferentiated and unknown cells may ultimately be induced.”
Marinho, P. A., Jeong, G., Shin, S. H., Kim, S. N., Choi, H., Lee, S. H., Park, B. C., Hong, Y. D., Kim, H.-J., & Park, W.-S. (2024) · Biomedical Materials · doi:10.1088/1748-605x/ad2707 · Cited by 7
Yang, J., Wang, Z., Zhou, H., Xiong, Y., Li, Y., Zheng, Y., & Liu, L. (2025) · iScience · doi:10.1016/j.isci.2025.112373 · Cited by 6
3D bioprinting of in vitro vascularized skin models and in vivo skin grafts
Zhang, S., Wan, Y., Niu, S., Zhou, H., Yang, H., Yin, J., Wu, Q., & Xu, H. (2026) · International Journal of Extreme Manufacturing · doi:10.1088/2631-7990/ae39b6 · Cited by 7
“In one representative work published in Nature, skin organoids were found to be capable of forming skin appendages including hair follicles, to recapitulate native skin [286] .”
Organoids as platforms for infectious disease research
Liu, K., Zhao, Y., Joloya, E. M., Artegiani, B., Bartfeld, S., Choi, Y. K., Han, Y., Hendriks, D. F. G., Hoogduijn, M. J., Hudson, J. E., et al. (2026) · Nature Reviews Bioengineering · doi:10.1038/s44222-026-00445-3 · Cited by 7
“These units are skin appendages that co-develop and self-assemble within the organoids 116,117 .”
A 4D road map for the formation of hair follicles
Saxena, N., & Rendl, M. (2021) · Nature · doi:10.1038/d41586-021-01482-1 · Cited by 6
Innovative approaches in skin therapy: The rise of organoid cultivation
Zhou, R., Luo, X., Chen, S., Jia, K., Yu, H., Huang, Z., Tan, Y., Ma, M., Zhao, J., Xing, J., et al. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.162248 · Cited by 6
Xu, H., Kang, J., Gao, X., Lan, Y., & Li, M. (2025) · Bioengineering · doi:10.3390/bioengineering12040393 · Cited by 6
“A cyst-like skin organoid comprising stratified epidermis, fat-rich dermis, pigmented hair follicles, and sebaceous glands has been generated, equivalent to human fetuses’ facial skin [51].”
Injectable hydrogel based on the furoic acid-modified chitosan for accelerating wound healing
Su, Y., Li, C., Hou, Y., Zhao, J., Zhao, B., Lu, Y., Wang, Y., Lv, C., Ren, T., Lv, S., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.146280 · Cited by 6
Bioengineering of Hair Follicle-like Structure for Validation of Hair Growth Promoting Compounds
Joo, H. W., Kim, M. K., Bak, S., & Sung, Y. K. (2022) · Bioengineering · doi:10.3390/bioengineering9110645 · Cited by 6
“Various methods of using hair follicle tissues and hair follicle cells have previously been reported to screen treatment candidates for hair follicular growth [13,15].”
Pan, X., Ma, Z., Sun, X., Li, H., Zhang, T., Zhao, C., Wang, N., Heller, R., Wong, W. H., Wang, W., et al. (2022) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2022.11.007 · Cited by 6
“We further associated those TTFs with 6 cell types by scRNA-seq data in the skin organoid culture system [29], and they showed specific expression levels at single-cell resolution in a complex skin organ model by reprogramming pluripotent stem cells.”
MethodWang, S., Hu, T., He, M., Gu, Y., Cao, X., Yuan, Z., Lv, X., Getachew, T., Quan, K., & Sun, W. (2023) · Frontiers in Veterinary Science · doi:10.3389/fvets.2023.1127501 · Cited by 6
Gao, H., Liu, Y., Shi, Z., Zhang, H., Wang, M., Chen, H., Li, Y., Ji, S., Xiang, J., Pi, W., et al. (2023) · Burns & Trauma · doi:10.1093/burnst/tkad027 · Cited by 6
Self-citationDirected differentiation of human pluripotent stem cells into epidermal stem and progenitor cells
Ruiz-Torres, S., Lambert, P. F., Wikenheiser‐Brokamp, K. A., & Wells, S. I. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06588-3 · Cited by 6
Cancer Risk and Mutational Patterns Following Organ Transplantation
Shen, Y., Lian, D., Shi, K., Gao, Y., Hu, X., Yu, K., Zhao, Q., & Feng, C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.956334 · Cited by 6
“Due to its unique proliferative ability and tissue specificity, organoid transplantation restored and repaired the structure of the body well without malformation or tumors (Lee et al., 2020).”
BackgroundAn integrated single cell and spatial omics atlas of human prenatal developmentPreprint
Webb, S., Rose, A., Xu, C., Steele, L., Kuri, M. A., Stephenson, E., İnecik, K., Jafree, D. J., Foster, A. R., Basurto-Lozada, D., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.30.714220 · Cited by 7
Self-citationWu, L., Lin, W., Liu, J.-J., Chen, W., He, W., Shi, Y., Liu, X., & Li, K. (2023) · World Journal of Stem Cells · doi:10.4252/wjsc.v15.i7.713 · Cited by 5
Eckel, O., Mirea, M. A., Gschwendtner, A., et al. (2025) · Neoplasia · doi:10.1016/j.neo.2025.101154 · Cited by 5
“Skin organoids were generated using human embryonic stem cells WA19 (WiCell CVCL_9780) of early passages (p16-19) according to the protocol of Lee et al. [38].”
Advancing dermatology with skin equivalents and organoids in pathophysiology and drug testing
Lakeh, B., & Shafiee, A. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.10.008 · Cited by 8
Immune and Immune‐Integrated Organoids as NextGeneration Platforms for Disease Modeling
Rashidan, K., Ayadilord, M., Hazrati, A., Nazerian, A., Shafiee, A., & Hashemi, S. M. (2025) · MedComm · doi:10.1002/mco2.70531 · Cited by 6
“Consequently, semicomplete skin organoids with hair follicles were introduced by Lee et al. in 2020 [13], offering potential for studying skin development and serving as a strong platform for dermatology research, or skin graft applications.”
Du, L., Huang, Y., & Liu, F. (2026) · Stem Cell Reports · doi:10.1016/j.stemcr.2025.102755 · Cited by 5
Laboratory Management of Mammalian Hosts for Ixodes scapularis-Host-Pathogen Interaction Studies
Narasimhan, S., Cibichakravarthy, B., Wu, M.-J., et al. (2024) · Comparative Medicine · doi:10.30802/aalas-cm-24-036 · Cited by 5
Metadata
- Authors
- Lee, J., Rabbani, C. C., Gao, H., Steinhart, M. R., Woodruff, B. M., Pflum, Z. E., Kim, A., Heller, S., Liu, Y., Shipchandler, T. Z., & Koehler, K. R.
- Affiliations
- Boston Children's Hospital (US)
- Johns Hopkins University (US)
- Indiana University School of Medicine
- Stanford Medicine (US)
- Corresponding author
- Koehler, Karl R.
- ORCID
- Venue
- Nature
- Published
- 2020-06-03
- Volume
- 582
- Issue
- 7812
- Pages
- 399-404
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7593871
- OpenAlex
- W3032142305
- Semantic Scholar
- ca18b7b0af03573e144b07317b08925d4f05acf8
- Cited by
- 487
- References
- 44
- Citations by year
- 2026: 82 · 2025: 85 · 2024: 85 · 2023: 75 · 2022: 80 · 2021: 68 · 2020: 12
- FWCI
- 58.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- Indiana Clinical and Translational Sciences Institute (UL1TR001108, RR020128, TR001108)
- University of Washington (5R24HD000836)
- National Institutes of Health (1c06rr020128-01, 5R24 HD000836, UL-1-TR001108, TR001108, R01DC017461, R03DC015624, R01AR075018)
- National Institute on Deafness and Other Communication Disorders (R01 DC017461, R03DC015624)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR075018)
- National Institute of Child Health and Human Development
- National Center for Research Resources (C06-RR020128)
- National Center for Advancing Translational Sciences (UL1TR-001108)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24 HD000836, 5R24HD000836)
- Topics
- Health Sciences › Medicine › Dermatology › Hair Growth and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- skin organoids, pluripotent stem cells, hair follicle, sebaceous glands, TGF-beta signaling, FGF signaling, neural crest cells, Merkel cells, sensory neurons, Schwann cells, epidermis, dermis, skin grafting, skin development, disease modeling, reconstructive surgery
- MeSH terms
- RNA-Seq, Animals, Ectoderm, Female, Hair, Hair Color, Head, Humans, Mice, Nude, Organoids, Skin, Skin Transplantation, Hair Follicle, Pluripotent Stem Cells, Mice, Single-Cell Analysis, Heterografts
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