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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BackgroundA prenatal skin atlas reveals immune regulation of human skin morphogenesis
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MethodBiofabrication of human skin with its appendages
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“Future studies may explore the integration of ourmodels into systems that recapitulate human tissue interactions, such as 3D skin (78) or skin organoids (79), the implantation of our cells into mice of different ages, or the cells’ exposure to ultraviolet radiation.”
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Membranous Extracellular Matrix-Based Scaffolds for Skin Wound Healing
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Developing nociceptor-selective treatments for acute and chronic pain
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BackgroundEngineering multiscale structural orders for high-fidelity embryoids and organoids
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Du, X., Chen, Z., Li, Q., Yang, S., Jiang, L., Yang, Y., Li, Y., & Gu, Z. (2023) · Bio-Design and Manufacturing · doi:10.1007/s42242-022-00226-y · Cited by 57
“…cells and induced pluripotent stem cells by cultivating them to differentiate and self-assemble into various 3D structures similar to human tissues, creating most types of non-tumor-derived organoids, such as skin [5], brain [6], liver [7], intestine [8], prostate [9], lung [10], and pancreas [11].”
BackgroundDevelopment of physiologically relevant skin organoids from human induced pluripotent stem cells
Shafiee, A., Sun, J., Ahmed, I. A., Phua, F., Rossi, G. R., Lin, C., Souza‐Fonseca‐Guimaraes, F., Wolvetang, E. J., Brown, J., & Khosrotehrani, K. (2024) · Small · doi:10.1002/smll.202304879 · Cited by 54
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Patient-derived tumor organoids: A preclinical platform for personalized cancer therapy
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Generation of Skin Organoids: Potential Opportunities and Challenges
Sun, H., Zhang, Y., & Li, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.709824 · Cited by 55
Wang, M., Zhou, X., Zhou, S., Wang, M., Jiang, J., Wu, W., Liu, T., Xu, W., Zhang, J., Liu, D., et al. (2023) · Theranostics · doi:10.7150/thno.83217 · Cited by 55
“To explore the mechanisms by which the dermal cells attach to the epidermal cyst, we analyzed the single-cell RNA sequencing (scRNA-seq) data performed for the D48 human skin organoid with a skin cyst that has the epithelial and mesenchymal components [3] (Figure 2A).”
BackgroundMethodInfluentialKwak, S., Song, C. L., Lee, J., Kim, S., Nam, S., Park, Y.-J., & Lee, J. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122522 · Cited by 58
Self-citationAdvancing Organoid Engineering for Tissue Regeneration and Biofunctional Reconstruction
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“Lee et al. [184] successfully cultured skin organoids with intact neural circuits and skin appendages using hPSCs over 140 days.”
MethodRothbauer, M., Bachmann, B., Eilenberger, C., Kratz, S. R. A., Spitz, S., Höll, G., & Ertl, P. (2021) · Micromachines · doi:10.3390/mi12050470 · Cited by 53
“, follicles and glands, which can be grown with organoid technology [80], as demonstrated by Lee et al.”
MethodRecreation of a hair follicle regenerative microenvironment: Successes and pitfalls
Abreu, C. M., & Marques, A. P. (2021) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10235 · Cited by 50
“The formation of a cyst-like skin organoid was attained from aggregates of pluripotent stem cells and using a step-by-step modulation of the TGF-β, BMP, and FGF signaling pathways, to promote ectoderm and cranial-neural crest induction.(162) The formation of pigmented HFs within the skin organoids was observed after a…”
BackgroundInfluentialDesign of an Integrated Microvascularized Human Skin-on-a-Chip Tissue Equivalent Model
Jones, C. F. E., Ciò, S. D., Connelly, J. T., & Gautrot, J. E. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.915702 · Cited by 53
Uniaxial and Coaxial Vertical Embedded Extrusion Bioprinting
Lian, L., Zhou, C., Tang, G., Xie, M., Wang, Z., Luo, Z., Japo, J. O., Wang, D., Zhou, J., Wang, M., et al. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202102411 · Cited by 50
Translating Embryogenesis to Generate Organoids: Novel Approaches to Personalized Medicine
Sahu, S., & Sharan, S. K. (2020) · iScience · doi:10.1016/j.isci.2020.101485 · Cited by 52
Microenvironmental reprogramming of human dermal papilla cells for hair follicle tissue engineering
Liu, Z., Huang, J., Kang, D., Zhou, Y., Du, L., Qu, Q., Wang, J., Wen, L., Fu, D., Hu, Z., et al. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.11.004 · Cited by 50
Engineering Photoresponsive Ligand Tethers for Mechanical Regulation of Stem Cells
Zhang, J., Wong, S. H. D., Wu, X., Lei, H., Qin, M., Shi, P., Wang, W., Bian, L., & Cao, Y. (2021) · Advanced Materials · doi:10.1002/adma.202105765 · Cited by 48
In vitro strategies for mimicking dynamic cell–ECM reciprocity in 3D culture models
Urciuolo, F., Imparato, G., & Netti, P. A. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1197075 · Cited by 51
Hu, X., Zheng, S., Zhāng, Q., Wan, X.-X., Li, J., Mao, R., Yang, R., & Xiong, K. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.11.049 · Cited by 46
Vascularized 3D Human Skin Models in the Forefront of Dermatological Research
Rimal, R., Muduli, S., Desai, P., Marquez, A. B., Möller, M., Platzman, I., Spatz, J., & Singh, S. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202303351 · Cited by 46
Stem and progenitor cells in sebaceous gland development, homeostasis and pathologies
Geueke, A., & Niemann, C. (2021) · Experimental Dermatology · doi:10.1111/exd.14303 · Cited by 46
“A major step forwards the generation of complete skin organoids comprised of functional HF and SG structures from human pluripotent stem cells (hiPSCs) was reported by Lee et al 2020.”
BackgroundModeling an Optimal 3D Skin-on-Chip within Microfluidic Devices for Pharmacological Studies
Fernández-Carro, E., Angenent, M. L., Gracia‐Cazaña, T., Gilaberte, Y., Alcaine, C., & Ciriza, J. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14071417 · Cited by 47
“In addition, organoids show pigmentation, hyaline cartilage, a layer of lipid-rich adipocytes surrounding the culture, and a basic nervous system like that of an 18-week human fetus [69].”
BackgroundJiang, J., Shao, X., Liu, W., Wang, M., Li, Q., Wang, M., Xiao, Y., Li, K., Liang, H., Wang, N., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114513 · Cited by 45
Evolution of organoid technology: Lessons learnt in Co-Culture systems from developmental biology
Zahmatkesh, E., Rad, N. K., Mirzaei, H., Shpichka, A. I., Timashev, P. S., Mahmoudi, T., & Vosough, M. (2021) · Developmental Biology · doi:10.1016/j.ydbio.2021.03.001 · Cited by 46
Characterization of the epidermal-dermal junction in hiPSC-derived skin organoids
Ramovs, V., Janssen, H., Fuentes, I., Pitaval, A., Rachidi, W., Chuva de Sousa Lopes, S. M., Freund, C., Gidrol, X., Mummery, C. L., & Raymond, K. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.04.008 · Cited by 44
“HFs showed similar organization to that previously reported in organoid-derived HFs, occasionally containing sebumproducing sebaceous glands (Figures 1C, S1A, and S1B) and innervation as illustrated by TUJ1 neuronal processes and TUJ1 Merkel-like cells (Figure S1C) (Lee et al., 2020).”
BackgroundResultInfluentialMicrofluidic 3D printing polyhydroxyalkanoates-based bionic skin for wound healing
Guo, W., Wang, X., Yang, C., Huang, R., Wang, H., & Zhao, Y. (2021) · Materials Futures · doi:10.1088/2752-5724/ac446b · Cited by 43
“The healing of skin wound is a common and challenging clinical problem with a huge financial burden to healthcare systems worldwide [1, 2].”
BackgroundHarnessing the power of artificial intelligence for human living organoid research
Wang, H., Li, X., You, X., & Zhao, G. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.08.027 · Cited by 43
Zhuang, P., Yao, Y., Su, X., Zhao, Y., Liu, K., Wu, X., & Dai, H. (2022) · Composites Part B Engineering · doi:10.1016/j.compositesb.2022.110030 · Cited by 43
Llamas‐Molina, J. M., Carrero-Castaño, A., Ruíz‐Villaverde, R., & Campos, A. (2022) · Life · doi:10.3390/life12010117 · Cited by 43
“[65] recently succeeded in generating full-form hairy skins derived from iPSCs based on an organoid culture system.”
Background3-D bioprinted human-derived skin organoids accelerate full-thickness skin defects repair
Zhang, T., Sheng, S., Cai, W., Yang, H., Li, J., Niu, L., Chen, W., Zhang, X., Zhou, Q., Gao, C., et al. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.08.036 · Cited by 42
“In 2020, Jiyoon et al. [10] engineered an organoid culture system capable of generating intricate skin constructs from human pluripotent stem cells in vitro.”
BackgroundSelf-citation3D skin models in domestic animals
Souci, L., & Denesvre, C. (2021) · Veterinary Research · doi:10.1186/s13567-020-00888-5 · Cited by 52
“Recently, hair-bearing human skin was reconstructed by using human pluripotent stem cells only, thanks to an organoid system [117].”
BackgroundSutterby, E., Thurgood, P., Baratchi, S., Khoshmanesh, K., & Pirogova, E. (2021) · Open Research (University of Surrey) · doi:10.1002/viw.20210012 · Cited by 44
Usmani, S. M., Bremer‐Hoffmann, S., Cheyns, K., Cubadda, F., Dumit, V. I., Escher, S. E., Fessard, V., Gutleb, A. C., Léger, T., Liu, Y., et al. (2024) · EFSA Supporting Publications · doi:10.2903/sp.efsa.2024.en-8826 · Cited by 47
Self-citationKawai, M., Nie, M., Oda, H., Morimoto, Y., & Takeuchi, S. (2022) · Matter · doi:10.1016/j.matt.2022.05.019 · Cited by 41
Liu, Y., Tosti, A., Wang, E. C. E., Heilmann‐Heimbach, S., Aguh, C., Jiménez, F., Lin, S., Kwon, O., & Plikus, M. V. (2025) · Nature Reviews Disease Primers · doi:10.1038/s41572-025-00656-9 · Cited by 56
“Although new human hair follicles can be produced in embryonic stem cell-derived organoids 247 or via cell seeding into micropatterned extracellular matrix constructs 248–251 , considerable future progress is necessary to assure that bioengineered hair follicles competently grow cyclically and…”
Self-citationSun, L., Wang, Y., Fan, L., & Zhao, Y. (2022) · Chemical Engineering Journal · doi:10.1016/j.cej.2022.141206 · Cited by 40
Sun, J., Liu, X., Shen, C., Zhang, W., & Niu, Y. (2021) · Cell Proliferation · doi:10.1111/cpr.13155 · Cited by 38
In vitro hair follicle growth model for drug testing
Kageyama, T., Miyata, H., Seo, J., Nanmo, A., & Fukuda, J. (2023) · Scientific Reports · doi:10.1038/s41598-023-31842-y · Cited by 43
The mechano-chemical circuit drives skin organoid self-organization
Lei, M., Harn, H. I., Li, Q., Jiang, J., Wu, W., Zhou, W., Jiang, T., Wang, M., Zhang, J., Lai, Y., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2221982120 · Cited by 42
“Another major advance is the use of human pluripotent stem cells to generate skin organoids which form hairs upon transplantation to the back of nude mice (11).”
Application of an iPSC‐Derived Organoid Model for Localized Scleroderma Therapy
Ma, J., Li, W., Cao, R., Gao, D., Zhang, Q., Li, X., Li, B., Lv, L., Li, M., Jiang, J., et al. (2022) · Advanced Science · doi:10.1002/advs.202106075 · Cited by 38
Hair Follicle Morphogenesis During Embryogenesis, Neogenesis, and Organogenesis
Park, S. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.933370 · Cited by 40
Biomaterial-assisted organoid technology for disease modeling and drug screening
Shao, Y., Wang, J., Jin, A., Jiang, S., Lei, L., & Liu, L. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.101438 · Cited by 45
Zhang, Y., Fu, Y., Sun, T., Li, W., Yu, L., & Ding, J. (2025) · Advanced Materials · doi:10.1002/adma.202512919 · Cited by 42
Clinical, mechanistic, and therapeutic landscape of cutaneous fibrosis
Li, D. J., Berry, C. E., Wan, D. C., & Longaker, M. T. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adn7871 · Cited by 40
Immune and Non-immune Interactions in the Pathogenesis of Androgenetic Alopecia
Xiao, Y., Zhang, Y., Deng, S., Yang, X., & Yao, X. (2025) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-025-09034-5 · Cited by 44
“However, a detailed examination showed a lack of medulla layer in the HF, a characteristic of adult terminal hair, which requires further improvement in the future [226].”
Organoid‐Guided Precision Medicine: From Bench to Bedside
Tao, B., Li, X., Hao, M., Tian, T., Li, Y., Li, X., Yang, C., Li, Q., Feng, Q., Zhou, H., et al. (2025) · MedComm · doi:10.1002/mco2.70195 · Cited by 38
“Subsequently, hair plate-like structures are induced within the dermis [19, 148].”
InfluentialBack to the Future: From Appendage Development Toward Future Human Hair Follicle Neogenesis
de Groot, S. C., Ulrich, M. M. W., Gho, C. G., & Huisman, M. A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.661787 · Cited by 33
“…of fibroblast and keratinocytes from the skin of newborn mice mixed in a collagen I gel, showed morphological transition of the cells into six different phases: dissociated cells, cell aggregates, polarized cysts, cyst coalescence, planar skin, and hair-bearing skin (Figure 8; Lei et al., 2017).”
BackgroundTissue Engineering-Based Strategies for Diabetic Foot Ulcer Management
Chiu, A., Sharma, D., & Zhao, F. (2021) · Advances in Wound Care · doi:10.1089/wound.2021.0081 · Cited by 34
“155 Lee et al. 155 recently reported hair generation from a successful organoid culture system for iPSCs.”
Regenerative Medicine Clinical Readiness
Yamada, S., Behfar, A., & Terzic, A. (2021) · Regenerative Medicine · doi:10.2217/rme-2020-0178 · Cited by 37
Shim, J., Park, J., Abudureyimu, G., Kim, M.-H., Shim, J. S., Jang, K., Kwon, E. J., Jang, H., Yeo, E., Lee, J. H., et al. (2022) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2022.06.022 · Cited by 35
Self-citationGene expression in organoids: an expanding horizon
Smirnov, A., Melino, G., & Candi, E. (2023) · Biology Direct · doi:10.1186/s13062-023-00360-2 · Cited by 33
“These achievements enable modelling of human organ development in a Petri dish including lung [11], skeletal muscle [12], bile duct [13], heart [14], neurone system [15] and hair-bearing skin [16].”
BackgroundSkin-on-a-chip technologies towards clinical translation and commercialization
Ismayilzada, N., Tarar, C., Dabbagh, S. R., Tokyay, B. K., Dilmani, S. A., Sokullu, E., Abaci, H. E., & Taşoğlu, S. (2024) · Biofabrication · doi:10.1088/1758-5090/ad5f55 · Cited by 38
“…offers packages specified for certain applications, including the OoC package containing flow rate sensors, reservoirs and channels with the optional microfluidic distribution valve, bubble trap, pressure sensors, recirculation valve, and additional pumping channels and flow rate sensors [226].”
Epidermal stem cells: skin surveillance and clinical perspective
Tang, X., Wang, J., Chen, J., Liu, W., Qiao, P., Quan, H., Li, Z., Dang, E., Wang, G., & Shao, S. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05600-1 · Cited by 41
“Skin regeneration assays test EpSC regenerative abilities and are complemented by transplanting cultured EpSCs or organoids onto mice for more comprehensive functional assessment [58, 159].”
BackgroundHuman primary epidermal organoids enable modeling of dermatophyte infections
Wang, X., Wang, S., Guo, B., Su, Y., Tan, Z., Chang, M., Diao, J., Zhao, Y., & Wang, Y. (2021) · Cell Death and Disease · doi:10.1038/s41419-020-03330-y · Cited by 41
Innovative Approaches and Advances for Hair Follicle Regeneration
Zheng, W., & Xu, C.-H. (2023) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.3c00028 · Cited by 32
Lombardi, F., Augello, F. R., Ciafarone, A., Ciummo, V., Altamura, S., Cinque, B., & Palumbo, P. (2024) · Biomolecules · doi:10.3390/biom14091066 · Cited by 33
“The development of these sophisticated models allows for studying skin aging processes, thus providing a precious tool for understanding skin physiology and pathology and testing pharmacological and cosmetic treatments.”
BackgroundJawbone-like organoids generated from human pluripotent stem cells
Motoike, S., Inada, Y., Toguchida, J., Kajiya, M., & Ikeya, M. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01419-3 · Cited by 39
“Previous ectodermal organoids such as inner ear 22 and skin organoids 52,53 require the optimization of BMP4 concentration potentially owing to different endogenous BMP4 expression levels.”
Skin microbiota analysis in human 3D skin models—“Free your mice”
Emmert, H., Rademacher, F., Gläser, R., & Harder, J. (2020) · Experimental Dermatology · doi:10.1111/exd.14164 · Cited by 32
The Emergent Power of Human Cellular vs Mouse Models in Translational Hair Research
Castro, A. R., Portinha, C., & Logarinho, E. (2022) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szac059 · Cited by 33
O’Sullivan, J. D. B., Peters, E. M. J., Amer, Y., Atuluru, P., Chéret, J., Rosenberg, A. M., Picard, M. A., & Paus, R. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.101008 · Cited by 32
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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