Full-Thickness Skin with Mature Hair Follicles Generated from Tissue Culture Expanded Human Cells
Abstract
The goal of regenerative medicine is to reconstruct fully functional organs from tissue culture expanded human cells. In this study, we report a method for human reconstructed skin (hRSK) when starting with human cells. We implanted tissue culture expanded human epidermal and dermal cells into an excision wound on the back of immunodeficient mice. Pigmented skin covered the wound 4 weeks after implantation. Hair shafts were visible at 12 weeks and prominent at 14 weeks. Histologically, the hRSK comprises an intact epidermis and dermis with mature hair follicles, sebaceous glands and most notably, and unique to this system, subcutis. Morphogenesis, differentiation, and maturation of the hRSK mirror the human fetal process. Human antigen markers demonstrate that the constituent cells are of human origin for at least 6 months. The degree of new skin formation is most complete when using tissue culture expanded cells from fetal skin, but it also occurs with expanded newborn and adult cells; however, no appendages formed when we grafted both adult dermal and epidermal cells. The hRSK system promises to be valuable as a laboratory model for studying biological, pathological, and pharmaceutical problems of human skin.
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The mouse is a standard model for investigating skin development and disease in vivo.
“The mouse is a standard model for investigating skin development and disease in vivo”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [12]
Cites
Vascularized and functional human liver from an iPSC-derived organ bud transplant
Takebe, T., Sekine, K., Enomura, M., Koike, H., Kimura, M., Ogaeri, T., Zhang, R.-R., Ueno, Y., Zheng, Y.-W., Koike, N., et al. (2013) · Nature · doi:10.1038/nature12271 · Cited by 2,170 · see citing works
The human keratins: biology and pathology
Moll, R., Divo, M., & Langbein, L. (2008) · Histochemistry and Cell Biology · doi:10.1007/s00418-008-0435-6 · Cited by 1,465 · see citing works
Cytosystems dynamics in self-organization of tissue architecture
Sasai, Y. (2013) · Nature · doi:10.1038/nature11859 · Cited by 475 · see citing works
Humason's Animal tissue techniques
Presnell, J. K., Schreibman, M. P., & Humason, G. L. (1997) · Johns Hopkins University Press eBooks · Cited by 458 · see citing works
Higgins, C. A., Chen, J. C., Cerise, J. E., Jahoda, C. A. B., & Christiano, A. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309970110 · Cited by 396 · see citing works
Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor
Chapman, S., Liu, X., Meyers, C., Schlegel, R., & McBride, A. A. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42297 · Cited by 314 · see citing works
Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches
Toyoshima, K.-E., Asakawa, K., Ishibashi, N., Toki, H., Ogawa, M., Hasegawa, T., Irié, T., Tachikawa, T., Sato, A., Takeda, A., et al. (2012) · Nature Communications · doi:10.1038/ncomms1784 · Cited by 250 · see citing works
Characterization of a new tissue-engineered human skin equivalent with hair
Michel, M., L’Heureux, N., Pouliot, R., Xu, W. L., Auger, F. A., & Germain, L. (1999) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-999-0081-x · Cited by 234 · see citing works
Goodpaster, T. A., Legesse-Miller, A., Hameed, M., Aisner, S. C., Randolph‐Habecker, J., & Coller, H. A. (2007) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.7a7287.2007 · Cited by 165 · see citing works
The embryology and development of human scalp hair
Dawber, R. P. R. (1988) · Clinics in Dermatology · doi:10.1016/0738-081x(88)90059-4 · Cited by 141 · see citing works
Hair follicle regeneration using grafted rodent and human cells
Ehama, R., Ishimatsu-Tsuji, Y., Iriyama, S., Ideta, R., Soma, T., Yano, K., Kawasaki, C., Suzuki, S., Shirakata, Y., Hashimoto, K., et al. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700823 · Cited by 110 · see citing works
Skin: The First Tissue-Engineered Products
Parenteau, N. L. (1999) · Scientific American · doi:10.1038/scientificamerican0499-83 · Cited by 99 · see citing works
Havlíčková, B., Bı́ró, T., Mescalchin, A., Arenberger, P., & Paus, R. (2004) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2004.06184.x · Cited by 83 · see citing works
Terunuma, A., Limgala, R. P., Park, C. J., et al. (2009) · Tissue Engineering Part A · doi:10.1089/ten.tea.2009.0339 · Cited by 72 · see citing works
Thangapazham, R. L., Klover, P. J., Wang, J.-A., et al. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.337 · Cited by 70 · see citing works
A Simplified Procedure to Reconstitute Hair-Producing Skin
Lee, L. F., Jiang, T. X., Garner, W. L., & Chuong, C. (2010) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2010.0477 · Cited by 62 · see citing works
Krugluger, W., Rohrbacher, W., Laciak, K., et al. (2005) · Experimental Dermatology · doi:10.1111/j.0906-6705.2005.00330.x · Cited by 57 · see citing works
Defining hair follicles in the age of stem cell bioengineering
Chuong, C.-M., Cotsarelis, G., & Stenn, K. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700947 · Cited by 56 · see citing works
Self-citationHair Follicle Regeneration in Skin Grafts: Current Concepts and Future Perspectives
Mahjour, S. B., Ghaffarpasand, F., & Wang, H. (2011) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2011.0064 · Cited by 54 · see citing works
Sriwiriyanont, P., Lynch, K. A., Maier, E. A., Hahn, J. M., Supp, D. M., & Boyce, S. T. (2012) · Experimental Dermatology · doi:10.1111/exd.12003 · Cited by 46 · see citing works
Human TSC2-null fibroblast-like cells induce hair follicle neogenesis and hamartoma morphogenesis
Li, S., Thangapazham, R. L., Wang, J.-A., Rajesh, S., Kao, T., Sperling, L. C., Moss, J., & Darling, T. N. (2011) · Nature Communications · doi:10.1038/ncomms1236 · Cited by 45 · see citing works
Mature hair follicles generated from dissociated cells: a universal mechanism of folliculoneogenesis
Zheng, Y., Nace, A., Chen, W., Watkins, K., Sergott, L., Homan, Y., Vandeberg, J. L., Breen, M., & Stenn, K. (2010) · Developmental Dynamics · doi:10.1002/dvdy.22398 · Cited by 36 · see citing works
Self-citationLarouche, D., Cuffley, K., Paquet, C., & Germain, L. (2010) · Tissue Engineering Part A · doi:10.1089/ten.tea.2010.0403 · Cited by 26 · see citing works
Limat, A., Hunziker, T., Breitkreutz, D., et al. (2009) · Skin Pharmacology · doi:10.1159/000211273 · Cited by 18 · see citing works
Human-Based Tissue-Engineered Implants For Plastic And Reconstructive Surgery
Naughton, G. K., & Mansbridge, J. N. (1999) · Clinics in Plastic Surgery · doi:10.1016/s0094-1298(20)32658-4 · Cited by 17 · see citing works
Wood, F. M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-381422-7.10057-4 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Yao, G., Jiang, D., Li, J., Kang, L., Chen, S., Long, Y., Wang, Y., Huang, P., Lin, Y., Cai, W., et al. (2019) · ACS Nano · doi:10.1021/acsnano.9b03912 · Cited by 133 · see citing works
Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells
Lee, J., van der Valk, W. H., Serdy, S. A., Deakin, C., Kim, J., Le, A. P., & Koehler, K. R. (2022) · Nature Protocols · doi:10.1038/s41596-022-00681-y · Cited by 132 · see citing works
Skin organoids: a new human model for developmental and translational research
Lee, J., & Koehler, K. R. (2021) · Experimental Dermatology · doi:10.1111/exd.14292 · Cited by 85 · see citing works
Recreation 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 · see citing works
Hair follicle germs containing vascular endothelial cells for hair regenerative medicine
Kageyama, T., Chun, Y., & Fukuda, J. (2021) · Scientific Reports · doi:10.1038/s41598-020-79722-z · Cited by 50 · see citing works
Xing, F., Yi, W., Fang, M., Su, M., & Lei, T. (2018) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2018.3391 · Cited by 47 · see citing works
“mice (31) to determine whether the same effects of baicalin on Wnt/β-catenin signaling and dPc activity are observed in human-derived cells.”
Yoshida, Y., Soma, T., Matsuzaki, T., & Kishimoto, J. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.06.038 · Cited by 47 · see citing works
Ohyama, M. (2019) · Inflammation and Regeneration · doi:10.1186/s41232-019-0093-1 · Cited by 46 · see citing works
“Past in vivo grafting studies demonstrated that neonatal or fetal KCs were able to regenerate HF or HF-like structures [24, 44, 45].”
BackgroundReconstitution of full-thickness skin by microcolumn grafting
Tam, J., Wang, Y., Vuong, L. N., et al. (2016) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.2174 · Cited by 43 · see citing works
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 41 · see citing works
Weber, E. L., Woolley, T. E., Yeh, C., Ou, K., Maini, P. K., & Chuong, C. (2019) · Experimental Dermatology · doi:10.1111/exd.13891 · Cited by 39 · see citing works
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 38 · see citing works
Su, Y., Wen, J., Zhu, J., Xie, Z., Liu, C. X., Ma, C., Zhang, Q., Xu, X., & Wu, X. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1504-6 · Cited by 36 · see citing works
“However, the regeneration efficiency of human hair follicles is still low, especially for cells derived from adult tissues [17].”
InfluentialSelf-citationWen, L., Miao, Y., Fan, Z., Zhang, J., Guo, Y., Dai, D., Huang, J., Liu, Z., Chen, R., & Hu, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.632882 · Cited by 29 · see citing works
Design of In Vitro Hair Follicles for Different Applications in the Treatment of Alopecia—A Review
Žnidarič, M., Žurga, Ž. M., & Maver, U. (2021) · Biomedicines · doi:10.3390/biomedicines9040435 · Cited by 27 · see citing works
“It often occurs that there are not enough available HFs to cover the patient’s alopecic regions, limiting the number of patients suitable for this kind of treatment [74].”
Li, X., Zhou, Q., Wang, S., Wang, P., Li, J., Xie, Z., Liu, C., Wen, J., & Wu, X. (2020) · Aging · doi:10.18632/aging.103910 · Cited by 22 · see citing works
Self-citationSkin‐on‐a‐chip strategies for human hair follicle regeneration
Jeong, S., Na, Y., Nam, H., & Sung, G. Y. (2022) · Experimental Dermatology · doi:10.1111/exd.14699 · Cited by 24 · see citing works
Zhang, Q., Wen, J., Liu, C. X., Ma, C., Bai, F., Leng, X., Chen, Z., Xie, Z., Mi, J., & Wu, X. (2020) · Stem Cell Research & Therapy · doi:10.1186/s13287-020-01924-z · Cited by 21 · see citing works
Self-citationExpansion Culture of Hair Follicle Stem Cells through Uniform Aggregation in Microwell Array Devices
Hirano, S., Kageyama, T., Yamanouchi, M., Yan, L., Suzuki, K., Ebisawa, K., Kasai, K., & Fukuda, J. (2023) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.2c01141 · Cited by 18 · see citing works
Advances in engineered organoid models of skin for biomedical research
Zeng, D., Li, S., Du, F., Xia, Y., Zhang, J., Yu, S., & Qin, J. (2025) · Burns & Trauma · doi:10.1093/burnst/tkaf016 · Cited by 20 · see citing works
Wu, X., di Vignano, A. T., Zhou, Q., Dziunycz, P., Bai, F., Mi, J., Qin, J., Zu, T., & Hofbauer, G. F. L. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007366 · Cited by 17 · see citing works
Self-citationNakajima, R., Tate, Y., Yan, L., Kageyama, T., & Fukuda, J. (2021) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2021.02.001 · Cited by 16 · see citing works
Sun, Y., Xu, L., Li, Y., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.865983 · Cited by 15 · see citing works
The Patch Assay Reconstitutes Mature Hair Follicles by Culture-Expanded Human Cells
Zhang, Q., Zu, T., Zhou, Q., Wen, J., Leng, X., & Wu, X. (2017) · Regenerative Medicine · doi:10.2217/rme-2017-0017 · Cited by 13 · see citing works
Self-citationBoyce, S. T., & Supp, D. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-801654-1.00011-5 · Cited by 12 · see citing works
An advanced mouse model for human skin wound healing
Wen, J., Li, X., Leng, X., et al. (2016) · Experimental Dermatology · doi:10.1111/exd.13258 · Cited by 12 · see citing works
Self-citationMaterials-based hair follicle engineering: Basic components and recent advances
Lv, Y., Yang, W., Kannan, P. R., Zhang, H., Zhang, R., Zhao, R., & Kong, X. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.101303 · Cited by 12 · see citing works
“Simply implant the cultured and expanded human epidermal and dermal cells into the back wound of immunodeficient mice [170].”
BackgroundDissociated skin cells regenerate hair follicles in a microwound, “The Punch Assay”
Leng, X., Wang, P., Chen, Z., Li, D., Wen, J., Zhang, X., Qian, H., Guo, J., & Wu, X. (2018) · Experimental Dermatology · doi:10.1111/exd.13753 · Cited by 11 · see citing works
Self-citationChang, P., Zhang, W., Wu, M., Zou, R., Song, X., Sun, Q., Gao, J., Zhao, Y., & Liu, Y. (2022) · Macromolecular Bioscience · doi:10.1002/mabi.202100419 · Cited by 9 · see citing works
Liu, G., Li, D., Zhang, L., et al. (2022) · Cells · doi:10.3390/cells11152429 · Cited by 9 · see citing works
Self-citationFabrication of Chimeric Hair Follicles for Skin Tissue Engineering
Lalley, A. L., & Boyce, S. T. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9473-1_13 · Cited by 9 · see citing works
Wang, S., Qian, H., Zhang, L., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.720111 · Cited by 7 · see citing works
Self-citationKageyama, T., Anakama, R., Hamano, S., Tu, S., Migita, Y., Asaba, T., Nanmo, A., Ishikawa, K., Yan, L., Seo, J., et al. (2026) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c01780 · Cited by 6 · see citing works
Cui, X., Wen, J., Li, N., Hao, X., Zhang, S., Zhao, B., Wu, X., & Miao, J. (2022) · Cells · doi:10.3390/cells11193126 · Cited by 6 · see citing works
“Human primary HDFs were derived from the foreskin of children, and were isolated according to our previous publication [17].”
Self-citationLi, N., Yan, X., Cui, X., Zhao, C., Lin, Z., & Miao, J. (2023) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30472 · Cited by 6 · see citing works
“31 Therefore, we tested whether ABO affected the phosphorylation of HP1 γ via mTOR.”
BackgroundGrp94 Inhibitor HCP1 Inhibits Human Dermal Fibroblast Senescence
Cui, X., Hao, X., Wen, J., Zhang, S., Zhao, B., & Miao, J. (2022) · Genes · doi:10.3390/genes13091651 · Cited by 6 · see citing works
“HDFswere obtained from Wu Xunwei’s lab (Jinan, China); they were derived from the foreskin tissue of children [18].”
MethodCui, X., Wang, X., Wen, J., Li, X., Li, N., Hao, X., Zhao, B., Wu, X., & Miao, J. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-03185-4 · Cited by 5 · see citing works
“Cell culture Human primary HDFs were derived from adult foreskins, and were isolated according to our previous publication [19].”
MethodSelf-citationHuman Reconstructed Skin in a Mouse Model
Mi, J., Chen, D., Xu, L., et al. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9473-1_18 · Cited by 5 · see citing works
Self-citationBiofabrication and preclinical evaluation of a large-sized human self-assembled skin substitute
Kawecki, F., Mayrand, D., Ayoub, A., et al. (2020) · Biomedical Materials · doi:10.1088/1748-605x/abbdbe · Cited by 5 · see citing works
Wood, F. M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809880-6.00073-4 · Cited by 4 · see citing works
Li, Z., Huang, S., & Fu, X. (2018) · Elsevier eBooks · doi:10.1016/b978-0-08-101103-4.00017-x · Cited by 4 · see citing works
Advanced medical treatments for hair loss
Kaewmungkun, K., Kaisang, S., Yokhaphachon, N., & Parnpai, R. (2025) · Cell Transplantation · doi:10.1177/09636897251382318 · Cited by 3 · see citing works
“Moreover, Leng et al. 52 reported the generation of 1 hair using 7,000–8,000 skin progenitor cells after injecting 0.5 to 1 × 10 6 cells in the dermal layer of a human skin graft at depths of 1 and 2 mm 53 .”
Influentialkaramivandishi, A., Esmaeili, A., & Taghipour, N. (2024) · Tissue and Cell · doi:10.1016/j.tice.2024.102338 · Cited by 4 · see citing works
Ifediba, M. A., Baetz, N. W., Lambert, L., Benzon, H., Page, V., Anderson, N., Roth, S., Miess, J., Nicolosi, I., Beck, S. E., et al. (2024) · Tissue and Cell · doi:10.1016/j.tice.2024.102403 · Cited by 2 · see citing works
The Hair Follicle as a Wound Healing Promoter and Its Application in Clinical Practice
Jiménez, F., Martínez, M. L., Escario, E., & Izeta, A. (2017) · doi:10.1002/9781119282518.ch12 · Cited by 2 · see citing works
Biofabrication Technologies in Hair Neoformation
Abreu, C. M., Gasperini, L., & Marques, A. P. (2022) · Stem cell biology and regenerative medicine · doi:10.1007/978-3-030-98331-4_12 · Cited by 1 · see citing works
Cui, X., Wen, J., Li, X., Li, N., Hao, X., Zhao, B., Wu, X., & Miao, J. (2021) · Research Square · doi:10.21203/rs.3.rs-216763/v1
Self-citationIntelligent Biomaterials for Organ Regeneration and Tissue Engineering
Liao, Z., Song, J., Zhu, X.-M., Guo, Y., Wang, Y., & Yao, B. (2025) · Springer eBooks · doi:10.1007/978-981-96-8646-9_3
Cui, X., Wang, X., Wen, J., Li, X., Li, N., Hao, X., Zhao, B., Wu, X., & Miao, J. (2022) · Figshare · doi:10.6084/m9.figshare.21303676
Self-citationOuter root sheath cells secrete oxytocin for hair growth promotion and stem cell proliferation
Kageyama, T., Sun, T., Yan, L., Seo, J., Hamano, S., Nanmo, A., & Fukuda, J. (2026) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2026.02.012
- Authors
- Wu, X., Scott, L., Washenik, K., & Stenn, K.
- Affiliations
- Aderans Research Institute, Inc., Marietta, Georgia.
- Venue
- Tissue Engineering Part A
- Publisher
- SAGE Publications
- Published
- 2014-12
- Volume
- 20
- Issue
- 23-24
- Pages
- 3314-3321
- ISSN
- 1937-3341 (ISSN-L)
- 1937-335X
- OpenAlex
- W131060989
- Cited by
- 50
- References
- 26
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 10 · 2021: 8 · 2020: 3 · 2019: 7 · 2018: 5 · 2017: 2 · 2016: 3
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Tissue Engineering Part A (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- epidermal cells, dermal cells, subcutaneous tissue, sebaceous glands, immunodeficient mice, fetal skin, skin morphogenesis, xenotransplantation, skin grafting
- MeSH terms
- Epidermal Cells, Animals, Humans, Male, Skin, Hair Follicle, Dermis, Tissue Engineering, Mice
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