CoChat
Sign Up
Cited by 125Hair Growth and DisordersPluripotent Stem Cells ResearchSkin and Cellular Biology Research

Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells

Open access
Yang, Ruifeng, Zheng, Ying, Burrows, Michelle, Liu, Shujing, Wei, Zhi, Nace, Arben, Guo, Wei, Kumar, Suresh +2 more·2014·Nature Communications
DOI 10.1038/ncomms4071PMC PMC4049184
Open this paper in CoChat — free accountOpen PDF

Abstract

Epithelial stem cells (EpSCs) in the hair follicle bulge are required for hair follicle growth and cycling. The isolation and propagation of human EpSCs for tissue engineering purposes remains a challenge. Here we develop a strategy to differentiate human iPSCs (hiPSCs) into CD200(+)/ITGA6(+) EpSCs that can reconstitute the epithelial components of the hair follicle and interfollicular epidermis. The hiPSC-derived CD200(+)/ITGA6(+) cells show a similar gene expression signature as EpSCs directly isolated from human hair follicles. Human iPSC-derived CD200(+)/ITGA6(+) cells are capable of generating all hair follicle lineages including the hair shaft, and the inner and outer root sheaths in skin reconstitution assays. The regenerated hair follicles possess a KRT15(+) stem cell population and produce hair shafts expressing hair-specific keratins. These results suggest an approach for generating large numbers of human EpSCs for tissue engineering and new treatments for hair loss, wound healing and other degenerative skin disorders.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ncomms4071

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Reconstruction of appendage-bearing skin in cultures and in bioengineered grafts remains an unmet biomedical challenge.

    “Reconstruction of appendage-bearing skin in cultures and in bioengineered grafts remains an unmet biomedical challenge3–9.”

    From Hair-bearing human skin generated entirely from pluripotent stem cells (2020) · cites this paper as [3]

    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)

    Experimental — accuracy not yet measured

  • Appendage-bearing skin organoids can be generated via directed differentiation of epidermal and dermal cells from mouse pluripotent stem cells.

    “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.”

    From Hair-bearing human skin generated entirely from pluripotent stem cells (2020) · cites this paper as [3]

    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)

    Experimental — accuracy not yet measured

  • A 3D cyst composed of surface ectoderm enveloped by mesenchymal cells can self-organize and mimic cell-to-cell signalling mechanisms critical for hair follicle development.

    “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.”

    From Hair-bearing human skin generated entirely from pluripotent stem cells (2020) · cites this paper as [3]

    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)

    Experimental — accuracy not yet measured

  • Human skin equivalents have notable drawbacks, such as a lack of crucial skin tissue structures (e.g., hair follicles and sebaceous glands) and limited culture durations (e.g., 2-3 weeks).

    “However, human skin equivalents have notable drawbacks, such as a lack of crucial skin tissue structures (e.g., hair follicles and sebaceous glands) and limited culture durations (e.g., 2–3 weeks)”

    From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [20]

    The Results section (page unavailable) reports that the authors’ 3D skin equivalents formed a multilayered epidermis and that they could not identify human sebaceous glands in their skin reconstitution assays. It does not establish a general absence of hair follicles in human skin equivalents or a 2–3-week culture-duration limit; the reported two-and-a-half-week interval concerns an in vivo assay, not culture duration. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • To successfully generate skin, co-development of epidermis and dermis is required, and precise alterations of major signaling pathways (TGF-β, BMP4, and bFGF) are critical.

    “To successfully generate skin, co-development of epidermis and dermis is required, and precise alterations of major signaling pathways (TGF-β, BMP4, and bFGF) are critical”

    From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [20]

    The Methods (Patch assay for skin reconstitution; page unavailable) combine epithelial cells with neonatal mouse dermal cells, and the Results (Generation of iPSCs-derived EpSCs; page unavailable) say that the timing of EGF was critical in a protocol using BMP4. The paper does not establish that epidermis and dermis must co-develop to generate skin generally, or identify precise alterations of TGF-β and bFGF as critical; its differentiation protocol emphasizes EGF, retinoic acid, and BMP signaling. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 40 · Cited by 125

Research works printed but not linked: 36

  1. [1]Cherry AB Daley GQ Reprogrammed cells for disease modeling and regenerative medicine Annu Rev Med 2013 64 277 290 23327523 PMC3629705
  2. [2]Cherry AB Daley GQ Reprogramming cellular identity for regenerative medicine Cell 2012 148 1110 1122 22424223 PMC3354575
  3. [3]Morris RJ Capturing and profiling adult hair follicle stem cells Nat Biotechnol 2004 22 411 417 15024388
  4. [4]Ito M Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding Nature 2007 447 316 320 17507982
  5. [6]Lyle S Christofidou-Solomidou M Liu Y Elder DE Albelda S Cotsarelis G Human hair follicle bulge cells are biochemically distinct and possess an epithelial stem cell phenotype J Investig Dermatol Symp Proc 1999 4 296 301 10674385
  6. [7]Lyle S Christofidou-Solomidou M Liu Y Elder DE Albelda S Cotsarelis G The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells J Cell Sci 1998 111 Pt 21 3179 3188 9763512
  7. [8]Ohyama M Characterization and isolation of stem cell-enriched human hair follicle bulge cells J Clin Invest 2006 116 249 260 16395407 PMC1323261
  8. [9]Metallo CM Ji L de Pablo JJ Palecek SP Retinoic acid and bone morphogenetic protein signaling synergize to efficiently direct epithelial differentiation of human embryonic stem cells Stem Cells 2008 26 372 380 17962700
  9. [10]Guenou H Human embryonic stem-cell derivatives for full reconstruction of the pluristratified epidermis: a preclinical study Lancet 2009 374 1745 1753 19932355
  10. [11]Itoh M Kiuru M Cairo MS Christiano AM Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells Proc Natl Acad Sci U S A 2011 108 8797 8802 21555586 PMC3102348
  11. [12]Draheim KM Lyle S Epithelial stem cells Methods Mol Biol 2011 750 261 274 21618097
  12. [13]Takahashi K Yamanaka S Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors Cell 2006 126 663 676 16904174
  13. [14]Takahashi K Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 2007 131 861 872 18035408
  14. [15]Nakagawa M Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts Nat Biotechnol 2008 26 101 106 18059259
  15. [16]Park IH Reprogramming of human somatic cells to pluripotency with defined factors Nature 2008 451 141 146 18157115
  16. [17]Nissan X Functional melanocytes derived from human pluripotent stem cells engraft into pluristratified epidermis Proc Natl Acad Sci U S A 2011 108 14861 14866 21856949 PMC3169131
  17. [18]Garza LA Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells J Clin Invest 2011 121 613 622 21206086 PMC3026732
  18. [19]Tang C An antibody against SSEA-5 glycan on human pluripotent stem cells enables removal of teratoma-forming cells Nat Biotechnol 2011 29 829 834 21841799 PMC3537836
  19. [20]Jaks V Lgr5 marks cycling, yet long-lived, hair follicle stem cells Nat Genet 2008 40 1291 1299 18849992
  20. [21]Snippert HJ Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin Science 2010 327 1385 1389 20223988
  21. [23]Zheng Y Du X Wang W Boucher M Parimoo S Stenn K Organogenesis from dissociated cells: generation of mature cycling hair follicles from skin-derived cells J Invest Dermatol 2005 124 867 876 15854024
  22. [24]Zheng Y Mature hair follicles generated from dissociated cells: a universal mechanism of folliculoneogenesis Dev Dyn 2010 239 2619 2626 21038446
  23. [25]Dubois NC SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells Nat Biotechnol 2011 29 1011 1018 22020386 PMC4949030
  24. [26]Ghosh Z Huang M Hu S Wilson KD Dey D Wu JC Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells Cancer Res 2011 71 5030 5039 21646469 PMC3138859
  25. [27]Tong M Mice generated from tetraploid complementation competent iPS cells show similar developmental features as those from ES cells but are prone to tumorigenesis Cell Res 2011 21 1634 1637 21876560 PMC3364724
  26. [28]Ehama R Hair follicle regeneration using grafted rodent and human cells J Invest Dermatol 2007 127 2106 2115 17429436
  27. [29]Lichti U Anders J Yuspa SH Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice Nat Protoc 2008 3 799 810 18451788 PMC6299324
  28. [30]Roh C Roche M Guo Z Photopoulos C Tao Q Lyle S Multi-potentiality of a new immortalized epithelial stem cell line derived from human hair follicles In Vitro Cell Dev Biol Anim 2008 44 236 244 18568376 PMC2703193
  29. [31]Trempus CS Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34 J Invest Dermatol 2003 120 501 511 12648211
  30. [32]Bilousova G Chen J Roop DR Differentiation of mouse induced pluripotent stem cells into a multipotent keratinocyte lineage J Invest Dermatol 2011 131 857 864 21150926
  31. [33]Veraitch O Human Induced Pluripotent Stem Cell-Derived Ectodermal Precursor Cells Contribute to Hair Follicle Morphogenesis In Vivo J Invest Dermatol 2013 23321923
  32. [34]Yang R Generation of melanocytes from induced pluripotent stem cells J Invest Dermatol 2011 131 2458 2466 21833016 PMC3213325
  33. [35]Kishimoto J Ehama R Wu L Jiang S Jiang N Burgeson RE Selective activation of the versican promoter by epithelial- mesenchymal interactions during hair follicle development Proc Natl Acad Sci U S A 1999 96 7336 7341 10377415 PMC22086
  34. [36]Du P Kibbe WA Lin SM lumi: a pipeline for processing Illumina microarray Bioinformatics 2008 24 1547 1548 18467348
  35. [37]Smyth GK Linear models and empirical bayes methods for assessing differential expression in microarray experiments Stat Appl Genet Mol Biol 2004 3 Article3 16646809
  36. [39]Benjamini Y Hochberg Y Controlling the false discovery rate: a practical and powerful approach to multiple testing Journal of the Royal Statistical Society Series B 1995 57 289 300

Authors
Yang, R., Zheng, Y., Burrows, M., Liu, S., Wei, Z., Nace, A., Guo, W., Kumar, S., Cotsarelis, G., & Xu, X.
Affiliations
  • University of Pennsylvania (US)
  • New Jersey Institute of Technology (US)
Corresponding author
Xu, Xiaowei
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2014-01-28
Volume
5
Issue
1
Pages
3071-3071
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms4071
PMC
PMC4049184
OpenAlex
W1985780268
Cited by
125
References
40
Citations by year
2026: 6 · 2025: 6 · 2024: 9 · 2023: 5 · 2022: 13 · 2021: 14 · 2020: 14 · 2019: 11 · 2018: 11 · 2017: 11 · 2016: 8 · 2015: 7 · 2014: 10
FWCI
15.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • University of Pennsylvania
  • National Institutes of Health
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR055309, R01AR054593, P30AR057217)
Topics
  • Health Sciences › Medicine › Urology › 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
epithelial stem cells, hair follicle, induced pluripotent stem cells, hair follicle bulge, CD200, CD49f, hair follicle regeneration, hair shaft, root sheath, keratin 15, hair loss, tissue engineering, hair cycle
MeSH terms
Cell Differentiation, Cells, Cultured, Epithelial Cells, Fibroblasts, Humans, Skin, Antigens, CD, Hair Follicle, Tissue Engineering, Integrin alpha6, Pluripotent Stem Cells, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review