Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells
Open accessAbstract
Autologous epidermal cultures restore a functional epidermis on burned patients. Transgenic epidermal grafts do so also in genetic skin diseases such as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells, which can be only partially distinguished from the other clonogenic keratinocytes and cannot be prospectively isolated. Here we report that single-cell transcriptome analysis of primary human epidermal cultures identifies categories of genes clearly distinguishing the different keratinocyte clonal types, which are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells. Holoclone-forming cells display stem cell hallmarks as genes regulating DNA repair, chromosome segregation, spindle organization and telomerase activity. Finally, we identify FOXM1 as a YAP-dependent key regulator of epidermal stem cells. These findings improve criteria for measuring stem cells in epidermal cultures, which is an essential feature of the graft.
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scRNA-seq of human keratinocytes compared to holoclone signatures distinguished epidermal holoclone-forming cells from other epidermal cell states and identified a continuous hierarchical trajectory, showing that holoclone-forming cells generate meroclone- and paraclone-forming cells.
“For instance, scRNA-seq of human KCs was compared to holoclone signatures, and the resulting analyses were able to clearly distinguish epidermal holoclone-forming cells from other epidermal cell states and identify a continuous hierarchical trajectory, showing that holoclone-forming cells generate meroclone- and paraclone-forming cells [67].”
From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [67]
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890 · see citing works
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453 · see citing works
The Molecular Signatures Database Hallmark Gene Set Collection
Liberzon, A., Birger, C., Thorvaldsdóttir, H., Ghandi, M., Mesirov, J. P., & Tamayo, P. (2015) · Cell Systems · doi:10.1016/j.cels.2015.12.004 · Cited by 13,807 · see citing works
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Irizarry, R. A. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.249 · Cited by 10,603 · see citing works
Significance analysis of microarrays applied to the ionizing radiation response
Tusher, V. G., Tibshirani, R., & Chu, G. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091062498 · Cited by 10,568 · see citing works
The single-cell transcriptional landscape of mammalian organogenesis
Cao, J., Spielmann, M., Qiu, X., Huang, X., Ibrahim, D. M., Hill, A. J., Zhang, F., Mundlos, S., Christiansen, L., Steemers, F. J., et al. (2019) · Nature · doi:10.1038/s41586-019-0969-x · Cited by 4,490 · see citing works
p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development
Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C. J., Sharpe, A. H., Caput, D., Crum, C. P., et al. (1999) · Nature · doi:10.1038/19539 · Cited by 2,224 · see citing works
Yang, A., Kaghad, M., Wang, Y., Gillett, E. S., Fleming, M. D., Dötsch, V., Andrews, N. C., Caput, D., & McKeon, F. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80275-0 · Cited by 2,086 · see citing works
p63 is a p53 homologue required for limb and epidermal morphogenesis
Mills, A. A., Zheng, B., Wang, X., Vogel, H. S., Roop, D. R., & Bradley, A. (1999) · Nature · doi:10.1038/19531 · Cited by 1,974 · see citing works
Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data
Dai, M. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni179 · Cited by 1,797 · see citing works
p63 identifies keratinocyte stem cells
Pellegrini, G., Dellambra, E., Golisano, O., Martinelli, E., Fantozzi, I., Bondanza, S., Ponzin, D., McKeon, F., & Luca, M. D. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061032098 · Cited by 1,359 · see citing works
Self-citationThree clonal types of keratinocyte with different capacities for multiplication.
Barrandon, Y., & Green, H. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.8.2302 · Cited by 1,293 · see citing works
Growth of cultured human epidermal cells into multiple epithelia suitable for grafting.
Green, H., Kehinde, O., & Thomas, J. M. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.11.5665 · Cited by 1,251 · see citing works
Permanent Coverage of Large Burn Wounds with Autologous Cultured Human Epithelium
Gallico, G. G., O'Connor, N. E., Compton, C. C., Kehinde, O., & Green, H. (1984) · New England Journal of Medicine · doi:10.1056/nejm198408163110706 · Cited by 1,179 · see citing works
Limbal Stem-Cell Therapy and Long-Term Corneal Regeneration
Rama, P., Matuška, S., Paganoni, G., Spinelli, A. M., Luca, M. D., & Pellegrini, G. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0905955 · Cited by 1,142 · see citing works
Jones, P. H., & Watt, F. M. (1993) · Cell · doi:10.1016/0092-8674(93)90251-k · Cited by 1,100 · see citing works
Telomeres: protecting chromosomes against genome instability
O’Sullivan, R. J., & Karlseder, J. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2848 · Cited by 994 · see citing works
Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification
Fine, J., Bruckner‐Tuderman, L., Eady, R. A. J., Bauer, E. A., Bauer, J. W., Has, C., Heagerty, A., Hintner, H., Hovnanian, A., Jonkman, M. F., et al. (2014) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2014.01.903 · Cited by 934 · see citing works
p63 Is Essential for the Proliferative Potential of Stem Cells in Stratified Epithelia
Senoo, M., Pinto, F., Crum, C. P., & McKeon, F. (2007) · Cell · doi:10.1016/j.cell.2007.02.045 · Cited by 881 · see citing works
A single type of progenitor cell maintains normal epidermis
Clayton, E., Doupé, D. P., Klein, A. M., Winton, D. J., Simons, B. D., & Jones, P. H. (2007) · Nature · doi:10.1038/nature05574 · Cited by 853 · see citing works
Pellegrini, G., Golisano, O., Paterna, P., Lambìase, A., Bonini, S., Rama, P., & Luca, M. D. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.145.4.769 · Cited by 720 · see citing works
Regeneration of the entire human epidermis using transgenic stem cells
Hirsch, T., Rothoeft, T., Teig, N., Bauer, J. W., Pellegrini, G., De Rosa, L., Scaglione, D., Reichelt, J., Klausegger, A., Kneisz, D., et al. (2017) · Nature · doi:10.1038/nature24487 · Cited by 693 · see citing works
Self-citationMavilio, F., Pellegrini, G., Ferrari, S., Nunzio, F. D., Iorio, E. D., Recchia, A., Maruggi, G., Ferrari, G., Provasi, E., Bonini, C., et al. (2006) · Nature Medicine · doi:10.1038/nm1504 · Cited by 668 · see citing works
Distinct contribution of stem and progenitor cells to epidermal maintenance
Mascré, G., Dekoninck, S., Drogat, B., Youssef, K. K., Brohée, S., Sotiropoulou, P. A., Simons, B. D., & Blanpain, C. (2012) · Nature · doi:10.1038/nature11393 · Cited by 567 · see citing works
Actin–microtubule crosstalk in cell biology
Dogterom, M., & Koenderink, G. H. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0067-1 · Cited by 563 · see citing works
Location of stem cells of human hair follicles by clonal analysis
Rochat, A., Kobayashi, K., & Barrandon, Y. (1994) · Cell · doi:10.1016/0092-8674(94)90383-2 · Cited by 532 · see citing works
Alpha 6 beta 4 integrin heterodimer is a component of hemidesmosomes.
Stepp, M. A., Spurr-Michaud, S. J., Tisdale, A. S., Elwell, J., & Gipson, I. K. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.22.8970 · Cited by 483 · see citing works
Aerobic glycolysis tunes YAP/TAZ transcriptional activity
Enzo, E., Santinon, G., Pocaterra, A., Aragona, M., Bresolin, S., Forcato, M., Grifoni, D., Pession, A., Zanconato, F., Guzzo, G., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490379 · Cited by 414 · see citing works
Self-citationRegulation of the master regulator FOXM1 in cancer
Liao, G., Li, X., Zeng, S., Liu, C., Yang, S., Li, Y., Hu, C.-J., & Bai, J. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0266-6 · Cited by 412 · see citing works
Isoforms of ΔNp63 and the migration of ocular limbal cells in human corneal regeneration
Iorio, E. D., Barbaro, V., Ruzza, A., Ponzin, D., Pellegrini, G., & Luca, M. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503437102 · Cited by 407 · see citing works
Pellegrini, G., Ranno, R., Stracuzzi, G., Bondanza, S., Guerra, L., Zambruno, G., Micali, G., & Luca, M. D. (1999) · Transplantation · doi:10.1097/00007890-199909270-00021 · Cited by 369 · see citing works
Self-citationMizuno, T., Murakami, H., Fujii, M., Ishiguro, F., Tanaka, I., Kondo, Y., Akatsuka, S., Toyokuni, S., Yokoi, K., Osada, H., et al. (2012) · Oncogene · doi:10.1038/onc.2012.5 · Cited by 279 · see citing works
Advances in stem cell research and therapeutic development
Luca, M. D., Aiuti, A., Cossu, G., Parmar, M., Pellegrini, G., & Robey, P. G. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0344-z · Cited by 236 · see citing works
Dellambra, E., Golisano, O., Bondanza, S., Siviero, E., Lacal, P. M., Molinari, M., D’Atri, S., & Luca, M. D. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.5.1117 · Cited by 224 · see citing works
Self-citationSingle cell transcriptomics of human epidermis identifies basal stem cell transition states
Wang, S., Drummond, M. L., Guerrero-Juarez, C. F., Tarapore, E., MacLean, A. L., Stabell, A. R., Wu, S. C., Gutierrez, G., That, B. T., Benavente, C. A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18075-7 · Cited by 218 · see citing works
Polarized integrin mediates human keratinocyte adhesion to basal lamina.
Luca, M. D., Tamura, R. N., Kajiji, S. M., Bondanza, S., Rossino, P., Cancedda, R., Marchisio, P. C., & Quaranta, V. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.17.6888 · Cited by 210 · see citing works
Self-citationMechanisms of stretch-mediated skin expansion at single-cell resolution
Aragona, M., Sifrim, A., Malfait, M., Song, Y., Herck, J. V., Dekoninck, S., Gargouri, S., Lapouge, G., Swedlund, B., Dubois, C., et al. (2020) · Nature · doi:10.1038/s41586-020-2555-7 · Cited by 188 · see citing works
Regeneration of Squamous Epithelia from Stem Cells of Cultured Grafts
Luca, M. D., Pellegrini, G., & Green, H. (2005) · Regenerative Medicine · doi:10.2217/17460751.1.1.45 · Cited by 185 · see citing works
FOXM1 (Forkhead box M1) in Tumorigenesis
Wierstra, I. (2013) · Advances in cancer research · doi:10.1016/b978-0-12-407190-2.00016-2 · Cited by 183 · see citing works
Clonal analysis of stably transduced human epidermal stem cells in culture.
Mathor, M. B., Ferrari, G., Dellambra, E., Cilli, M., Mavilio, F., Cancedda, R., & Luca, M. D. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.19.10371 · Cited by 164 · see citing works
Structure of the FoxM1 DNA-recognition domain bound to a promoter sequence
Littler, D. R., Álvarez‐Fernández, M., Stein, A., Hibbert, R. G., Heidebrecht, T., Aloy, P., Medema, R. H., & Anastassis Perrakis, A. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq194 · Cited by 157 · see citing works
Weiler, S. M. E., Pinna, F., Wolf, T., Lutz, T., Geldiyev, A., Sticht, C., Knaub, M., Thomann, S., Bissinger, M., Wan, S., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.02.018 · Cited by 155 · see citing works
Walko, G., Woodhouse, S., Pisco, A. O., Rognoni, E., Liakath‐Ali, K., Lichtenberger, B. M., Mishra, A., Telerman, S. B., Viswanathan, P., Logtenberg, M. E. W., et al. (2017) · Nature Communications · doi:10.1038/ncomms14744 · Cited by 105 · see citing works
Xie, Z., Tan, G., Ding, M., Dong, D., Chen, T., Meng, X., Huang, X., & Tan, Y. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq715 · Cited by 105 · see citing works
Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis
Eisinger-Mathason, T. S. K., Mucaj, V., Biju, K. M., Nakazawa, M. S., Gohil, M., Cash, T. P., Yoon, S. S., Skuli, N., Park, K. M., Gerecht, S., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1420005112 · Cited by 103 · see citing works
Rosa, L. D., Seconetti, A. S., Santis, G. D., Pellacani, G., Hirsch, T., Rothoeft, T., Teig, N., Pellegrini, G., Bauer, J. W., & Luca, M. D. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.055 · Cited by 90 · see citing works
Defining the Design Principles of Skin Epidermis Postnatal Growth
Dekoninck, S., Hannezo, É., Sifrim, A., Miroshnikova, Y. A., Aragona, M., Malfait, M., Gargouri, S., de Neunheuser, C., Dubois, C., Voet, T., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.015 · Cited by 85 · see citing works
Bisson, F., Rochefort, É., Lavoie, A., Larouche, D., Zaniolo, K., Simard‐Bisson, C., Damour, O., Auger, F. A., Guérin, S. L., & Germain, L. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14034684 · Cited by 82 · see citing works
Shaping the actin cytoskeleton using microtubule tips
Basu, R., & Chang, F. (2006) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2006.12.012 · Cited by 78 · see citing works
Hou, Y., Li, W., Sheng, Y., Li, L., Huang, Y., Zhang, Z., Zhu, T., Peace, D. J., Quigley, J. G., Wu, W., et al. (2015) · Nature Immunology · doi:10.1038/ni.3204 · Cited by 78 · see citing works
FOXM1 in sarcoma: role in cell cycle, pluripotency genes and stem cell pathways
Kelleher, F. C., & O’Sullivan, H. (2016) · Oncotarget · doi:10.18632/oncotarget.8669 · Cited by 63 · see citing works
Ustiyan, V., Wert, S. E., Ikegami, M., Wang, I., Kalin, T. V., Whitsett, J. A., & Kalinichenko, V. V. (2012) · Developmental Biology · doi:10.1016/j.ydbio.2012.07.028 · Cited by 61 · see citing works
Actin filament dynamics impacts keratinocyte stem cell maintenance
Nanba, D., Toki, F., Matsushita, N., Matsushita, S., Higashiyama, S., & Barrandon, Y. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201201839 · Cited by 52 · see citing works
Dormant and restless skin stem cells
Rosa, L. D., & Luca, M. D. (2012) · Nature · doi:10.1038/489215a · Cited by 43 · see citing works
Foxm1 controls a pro-stemness microRNA network in neural stem cells
Besharat, Z. M., Abballe, L., Cicconardi, F., Bhutkar, A. J., Grassi, L., Pera, L. L., Moretti, M., Chinappi, M., D’Andrea, D., Mastronuzzi, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-21876-y · Cited by 39 · see citing works
Toward Combined Cell and Gene Therapy for GenodermatosesPreprint
Rosa, L. D., Latella, M. C., Seconetti, A. S., Cattelani, C., Bauer, J. W., Bondanza, S., & Luca, M. D. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035667 · Cited by 36 · see citing works
Self-citationKwok, C. T. D., Leung, M., Qin, J., Qin, Y., Wang, J., Lee, Y. L., & Yao, K. (2016) · Stem Cell Research · doi:10.1016/j.scr.2016.03.007 · Cited by 32 · see citing works
A Cdh1–FoxM1–Apc axis controls muscle development and regeneration
Chen, Z., Li, L., Xu, S., Liu, Z., Zhou, C., Li, Z., Liu, Y., Wu, W., Huang, Y., Kuang, M., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2375-6 · Cited by 31 · see citing works
Ghahramani, A., Donati, G., Luscombe, N. M., & Watt, F. M. (2018) · Genome biology · doi:10.1186/s13059-017-1384-y · Cited by 21 · see citing works
Solberg, N. T., Melheim, M., Strand, M. F., Olsen, P. A., & Krauss, S. J. K. (2019) · Cancers · doi:10.3390/cancers11020164 · Cited by 13 · see citing works
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Research works printed but not linked: 2
- [33]Lam AK FOXM1b, which is present at elevated levels in cancer cells, has a greater transforming potential than FOXM1c Front. Oncol. 2013 3 11 23386997 PMC3560383
- [63]Markowitz D Goff S Bank A Construction and use of a safe and efficient amphotropic packaging cell line Virology 1988 167 400 406 10.1016/S0042-6822(88)90101-8 2462307 · DOI
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Diversity of human skin three-dimensional organotypic cultures
Jia, Y. Y., & Atwood, S. X. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102275 · Cited by 12 · see citing works
- Authors
- Enzo, E., Secone Seconetti, A., Forcato, M., Tenedini, E., Polito, M. P., Sala, I., Carulli, S., Contin, R., Peano, C., Tagliafico, E., Bicciato, S., Bondanza, S., & De Luca, M.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- Azienda Ospedaliero-Universitaria di Modena (IT)
- AstraZeneca (United Kingdom) (GB)
- Institute of Genetic and Biomedical Research (IT)
- ORCID
- Venue
- Nature Communications
- Published
- 2021-05-04
- Volume
- 12
- Issue
- 1
- Pages
- 2505-2505
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8097075
- OpenAlex
- W3158466767
- Cited by
- 66
- References
- 61
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 17 · 2023: 16 · 2022: 11 · 2021: 3
- FWCI
- 13.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- FAR 2019
- Ministero dell'Istruzione, dell'Università e della Ricerca (CTN01_E48C13000140008)
- Regione Emilia-Romagna (E92I16000220005)
- Debra Alto Adige, Lombardia è ricerca
- Topics
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- epidermal stem cells, keratinocytes, clonal heterogeneity, FOXM1, YAP, single-cell transcriptomics, DNA repair, telomerase activity, chromosome segregation, spindle organization, epidermal grafts, junctional epidermolysis bullosa, stem cell proliferation
- MeSH terms
- Cell Self Renewal, Forkhead Box Protein M1, Epidermal Cells, RNA-Seq, YAP-Signaling Proteins, Animals, Cell Adhesion, Cell Line, Cells, Cultured, Multigene Family, Humans, Stem Cells, Transcription Factors, Keratinocytes, Epidermolysis Bullosa, Junctional, Gene Expression Profiling, Microarray Analysis, Chromatin Immunoprecipitation, Adaptor Proteins, Signal Transducing, Mice, Single-Cell Analysis, Transcriptome, Gene Ontology
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