Skin Stem Cells in Silence, Action, and Cancer

In studying how stem cells make and maintain tissues, nearly every chapter of a cell biology textbook takes on special interest. The field even allows us to venture where no chapters have yet been written. In studying this basic problem, we are continually bombarded by nature's surprises and challenges. Stem cell biology has captured my interest for nearly my entire scientific career. Below, I focus on my laboratory's contributions to this fascinating field, to which so many friends and colleagues have made seminal discoveries equally deserving of this award. In studying how stem cells make and maintain tissues, nearly every chapter of a cell biology textbook takes on special interest. The field even allows us to venture where no chapters have yet been written. In studying this basic problem, we are continually bombarded by nature's surprises and challenges. Stem cell biology has captured my interest for nearly my entire scientific career. Below, I focus on my laboratory's contributions to this fascinating field, to which so many friends and colleagues have made seminal discoveries equally deserving of this award. As a student in physical chemistry, my initial view of biology was that it was a science with too many variables to design a well-controlled experiment. However, the urge to venture into biomedical research was too great, and as a graduate student, I dove into biology head first, never haven taken a biology course in college. At Princeton University, I worked on how bacterial spores become activated to a vegetative state. In retrospect, the parallel to understanding how quiescent stem cells transition to an active tissue-generating mode seems striking. And yet it was not until I heard a lecture by Howard Green, who was then at MIT, that my excitement about stem cells was launched. Green spoke about taking a piece of human skin and identifying cells that he could passage clonally for hundreds of generations without losing their diploidy or their ability to make tissue (Rheinwald and Green, 1975Rheinwald J.G. Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells.Cell. 1975; 6: 331-343Abstract Full Text PDF PubMed Scopus (3915) Google Scholar). Wow! He did not call them stem cells, but in fact, these human keratinocytes fit the definition of stem cells as we know it today. I was passionate to learn more about this system and was excited to be accepted to his laboratory. At the time, Green had begun to exploit for clinical purposes the amazing ability of these long-lived keratinocytes to create sheets of epidermis for the treatment of burn patients (Green, 1991Green H. Cultured cells for the treatment of disease.Sci Am. 1991; 265: 96-102Crossref PubMed Scopus (115) Google Scholar). The highlight of these studies demonstrated that cultured stem cell therapy was successful in saving two children whose body surface was >90% burned. Twenty-five years later, Graziella Pellegrini and Michele De Luca showed that keratinocyte stem cells could be genetically engineered to successfully perform whole-body epidermal replacement for a child suffering from junctional epidermolysis bullosa (Hirsch et al., 2017Hirsch T. Rothoeft T. Teig N. Bauer J.W. Pellegrini G. De Rosa L. Scaglione D. Reichelt J. Klausegger A. Kneisz D. et al.Regeneration of the entire human epidermis using transgenic stem cells.Nature. 2017; 551: 327-332Crossref PubMed Scopus (426) Google Scholar). Collectively, these findings underscore the clinical potential for epidermal stem cells. For my own research, I have always been interested in how stem cells work. What gives them their long-term potential for self-renewal and tissue regeneration during homeostasis and wound repair, and what goes awry when stem cells acquire oncogenic mutations that will lead to malignancy? In Howard's lab, I began by characterizing the main structural proteins, keratins, that these stem cells produced (Fuchs and Green, 1978Fuchs E. Green H. The expression of keratin genes in epidermis and cultured epidermal cells.Cell. 1978; 15: 887-897Abstract Full Text PDF PubMed Scopus (186) Google Scholar). I found that the stem cells expressed K5 and K14, and that these were markers of progenitors of other stratified squamous epithelia. As the stem cells differentiated to make tissue, they displayed distinguishing features: epidermal cells expressed K1 and K10, whereas differentiating esophageal cells expressed other keratins (Fuchs and Green, 1980Fuchs E. Green H. Changes in keratin gene expression during terminal differentiation of the keratinocyte.Cell. 1980; 19: 1033-1042Abstract Full Text PDF PubMed Scopus (822) Google Scholar). When I began at the University of Chicago in 1980, it was at the cusp of DNA recombinant technology. I made a cDNA library to epidermal stem cells and cloned and characterized first the keratin mRNAs and then their genes (Fuchs et al., 1981Fuchs E.V. Coppock S.M. Green H. Cleveland D.W. Two distinct classes of keratin genes and their evolutionary significance.Cell. 1981; 27: 75-84Abstract Full Text PDF PubMed Scopus (200) Google Scholar, Hanukoglu and Fuchs, 1982Hanukoglu I. Fuchs E. The cDNA sequence of a human epidermal keratin: divergence of sequence but conservation of structure among intermediate filament proteins.Cell. 1982; 31: 243-252Abstract Full Text PDF PubMed Scopus (174) Google Scholar, Hanukoglu and Fuchs, 1983Hanukoglu I. Fuchs E. The cDNA sequence of a Type II cytoskeletal keratin reveals constant and variable structural domains among keratins.Cell. 1983; 33: 915-924Abstract Full Text PDF PubMed Scopus (204) Google Scholar, Marchuk et al., 1984Marchuk D. McCrohon S. Fuchs E. Remarkable conservation of structure among intermediate filament genes.Cell. 1984; 39: 491-498Abstract Full Text PDF PubMed Scopus (104) Google Scholar). Illuminating how these protein pairs form heterodimers and assemble into 10 nm cytoskeletal filaments, we then systematically worked our way toward the autosomal dominant blistering disorders, which we showed were caused by mutations in the keratins we had cloned: Epidermolysis bullosa simplex, a disorder of keratins 5 and 14, was rooted in epidermal stem cell fragility (Coulombe et al., 1991Coulombe P.A. Hutton M.E. Vassar R. Fuchs E. A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases.J. Cell Biol. 1991; 115: 1661-1674Crossref PubMed Scopus (167) Google Scholar, Vassar et al., 1991Vassar R. Coulombe P.A. Degenstein L. Albers K. Fuchs E. Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease.Cell. 1991; 64: 365-380Abstract Full Text PDF PubMed Scopus (332) Google Scholar); Epidermolytic hyperkeratosis, a disorder of keratins 1 and 10, was rooted in a skin barrier breach due to loss of integrity of the differentiating skin layers (Cheng et al., 1992Cheng J. Syder A.J. Yu Q.C. Letai A. Paller A.S. Fuchs E. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes.Cell. 1992; 70: 811-819Abstract Full Text PDF PubMed Scopus (289) Google Scholar). The keratin networks provided the stem cells and progeny with the mechanical integrity to withstand the physical traumas to which we subject our skin daily. In the 1990s, we continued to focus on the cytoskeletal, intercellular, and integrin-mediated adhesion of epidermal stem cells, gaining inroads into understanding how stem cells make tissues. Upon my transition to Rockefeller University, we began focusing on the other epithelial stem cells within the skin that give rise to the hair follicles (HFs) and sebaceous and sweat glands. HFs seemed particularly interesting, as in the mouse, they undergo synchronized, cyclical bouts of quiescence, active tissue regeneration, and destruction. As such, they offered a unique opportunity in the stem cell field to explore how stem cells, which fuel these bouts, transition from a quiescent to a tissue-regenerating mode. At the time, Cotsarelis et al., 1990Cotsarelis G. Sun T.T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1900) Google Scholar had posited that the HF stem cells reside in the bulge, an anatomical structure positioned strategically at the base of the non-cycling portion of the resting hair follicle. We engineered a mouse that allowed us to label all the skin epithelial progenitors with a fluorescent histone, and then switch off the gene and trace the dilution of the histone with each cell division. This enabled us to label the layer of less frequently dividing K5/K14+ progenitors within the bulge, purify and characterize them, and document their stemness by picking colonies cultured from single bulge cells and showing that when engrafted, they gave rise to epidermis, sebaceous glands, and HFs (Blanpain et al., 2004Blanpain C. Lowry W.E. Geoghegan A. Polak L. Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.Cell. 2004; 118: 635-648Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar, Tumbar et al., 2004Tumbar T. Guasch G. Greco V. Blanpain C. Lowry W.E. Rendl M. Fuchs E. Defining the epithelial stem cell niche in skin.Science. 2004; 303: 359-363Crossref PubMed Scopus (1636) Google Scholar). Over the past 12 years, we have probed deeper into the biology of these cells and their progeny. Among our major findings is that hair follicle stem cells (HFSCs) spend much of their life in quiescence due to high levels of BMP6 and FGF18 signaling within the inner bulge layer of terminally differentiated cells, which derive from the HFSCs at the end of each hair cycle (Blanpain et al., 2004Blanpain C. Lowry W.E. Geoghegan A. Polak L. Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche.Cell. 2004; 118: 635-648Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar, Hsu et al., 2011Hsu Y.C. Pasolli H.A. Fuchs E. Dynamics between stem cells, niche, and progeny in the hair follicle.Cell. 2011; 144: 92-105Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar). NFATc1 and FOXC1 are two HFSC transcription factors that are downstream of BMP signaling and which function in HFSC quiescence (Horsley et al., 2008Horsley V. Aliprantis A.O. Polak L. Glimcher L.H. Fuchs E. NFATc1 balances quiescence and proliferation of skin stem cells.Cell. 2008; 132: 299-310Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, Lay et al., 2016Lay K. Kume T. Fuchs E. FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential.Proc. Natl. Acad. Sci. USA. 2016; 113: E1506-E1515Crossref PubMed Scopus (92) Google Scholar). With age, BMP signaling and its downstream effectors increase, as HFs spend more time in quiescence (Keyes et al., 2013Keyes B.E. Segal J.P. Heller E. Lien W.H. Chang C.Y. Guo X. Oristian D.S. Zheng D. Fuchs E. Nfatc1 orchestrates aging in hair follicle stem cells.Proc. Natl. Acad. Sci. USA. 2013; 110: E4950-E4959Crossref PubMed Scopus (109) Google Scholar), and when NFATc1 or FOXC1 are HFs undergo many more et al., 2016Lay K. Kume T. Fuchs E. FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential.Proc. Natl. Acad. Sci. USA. 2016; 113: E1506-E1515Crossref PubMed Scopus (92) Google Scholar). the HFSC is the as to in their HFSCs to their potential to have a during their HFSCs the of BMP in to transition to a tissue-regenerating mode. the resting they undergo a of and BMP at the base of the bulge, a as the hair At the transition to the and loss of are in the hair with proliferation et al., M. D. B.E. R. Fuchs E. BMP signaling and its genes hair follicle stem cell Stem 15: Full Text Full Text PDF PubMed Scopus Google Scholar, Greco et al., V. T. Rendl M. M. Pasolli H.A. N. J. Fuchs E. A for stem cell during hair Stem Full Text Full Text PDF PubMed Scopus Google Scholar). is expressed by stem cell and for a these cells become a signaling of the niche et al., Y.C. L. Fuchs E. between skin stem cells and their PubMed Scopus Google Scholar). to the the to BMP and to fuel hair to the bulge to self-renewal and fuel of the of As the follicle the bulge is from the and signaling and it to quiescence At the end of the hair cycle, of these cells will the to form the bulge and hair for the hair The bulge to the hair until it is when it with the In this the stem cells a hair and their ability to in their progeny and in their progeny as of the hair cycle et al., 2011Hsu Y.C. Pasolli H.A. Fuchs E. Dynamics between stem cells, niche, and progeny in the hair follicle.Cell. 2011; 144: 92-105Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, Hsu et al., Y.C. L. Fuchs E. between skin stem cells and their PubMed Scopus Google Scholar). we have on how niche with the stem cell transcription factors to the between stem cell quiescence and We each of the HFSC transcription factors and showed that not NFATc1 and FOXC1 but and are to maintain the HFSCs in their quiescent niche and Fuchs, W.H. Fuchs E. of stem cells by PubMed Scopus Google Scholar, et al., H. Polak L. M. Rendl M. Pasolli H.A. Fuchs E. and are for long-term homeostasis of skin PubMed Scopus Google Scholar, et al., Polak L. Pasolli H.A. Fuchs E. follicle stem cells are and function in skin Stem 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, et al., H. Polak L. Fuchs E. maintains stem cell in hair PubMed Scopus Google Scholar). Upon in and we that all of these transcription factors to that reside within by the at as et al., H. S. M. Oristian D.S. Polak L. M. A. Zheng D. et factors in stem cell and PubMed Scopus Google Scholar). of all the genes expressed by HFSCs are by they of the genes that we know to the stem cell transcription genes and the BMP genes and their and the and their as as a of human skin these for and for BMP studies that when or are is et al., H. Lien W.H. Polak L. J. Zheng D. et of signaling effectors during hair follicle stem cell Stem Full Text Full Text PDF PubMed Scopus Google Scholar). HFSC these are as BMP signaling is and signaling the loss of with the of these HFSC is the of a of to make the hair follicle and hair et al., W.H. Polak L. M. Lay K. Zheng D. Fuchs E. In of hair follicle stem cells by Cell Biol. PubMed Scopus Google Scholar, et al., H. Fuchs E. stem cell 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). The of these to be by signaling and and et al., H. S. M. Oristian D.S. Polak L. M. A. Zheng D. et factors in stem cell and PubMed Scopus Google Scholar). As progenitors to form the of the hair by and by other signaling of BMP and signaling et al., H. Lien W.H. Polak L. J. Zheng D. et of signaling effectors during hair follicle stem cell Stem Full Text Full Text PDF PubMed Scopus Google Scholar, et al., H. Fuchs E. stem cell 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). these findings to how stem cells are to their own transcription factors with the signaling they are on this we have on how stem cells to in their as that which when are in tissue or a skin the these quiescent stem cells to in a The wound and are in a of the of quiescent stem cell transcription factors and the of factors et al., H. S. M. Oristian D.S. Polak L. M. A. Zheng D. et factors in stem cell and PubMed Scopus Google Scholar, et al., M. H. A. Polak L. S. et cell wound and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). the stem cells a of where they a that HF and epidermal tissue is the for HFSCs epidermal the is a as the HFSCs to and epidermal stem cells et al., M. H. A. Polak L. S. et cell wound and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). the as high levels of oncogenic lead to the and of and of and that to be by these transcription factors become activated et al., M. H. A. Polak L. S. et cell wound and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, and Fuchs, M. Fuchs E. stem cells of squamous cell and their by and adhesion Natl. Acad. Sci. USA. 2011; PubMed Scopus Google Scholar, et al., H. D. B.E. Zheng D. Fuchs E. and in squamous cell PubMed Scopus Google Scholar). Two of my Blanpain of and Lowry showed that epidermal and HF stem cells are a of squamous cell in the are the common and when are as a of of head and and they are of the for which are to and In years, we have been the of stem cells in of In we and characterized two populations of stem which in their proliferation our showing that loss of signaling in skin stem cells them to formation et al., G. M. Pasolli H.A. Polak L. Fuchs E. of signaling homeostasis and squamous cell in stratified Full Text Full Text PDF PubMed Scopus Google Scholar), we a where we could and trace the stem cells at the to its other as a and these stem cells, we that the from the and a the the stem cells by their but and to et al., N. Oristian D. Fuchs E. and in squamous cell Full Text Full Text PDF PubMed Scopus Google Scholar). their in et al., N. A. A. I. S. A. 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Fuchs E. in as a of squamous cell PubMed Scopus Google Scholar). exploit a genetic by my lab, which us to a mouse to when skin as a single layer of progenitors that will give rise to the epidermis, sweat and sebaceous glands, and head and et al., S. G. S. Fuchs E. of genetic networks and in mouse PubMed Scopus Google Scholar). the DNA is in of the entire surface their stem cells. in a time, we perform that years to with With the of for and we or genes in the skin stem cells. We have these to the and for skin stem cells in their and et al., H. S. M. Oristian D.S. Polak L. M. A. Zheng D. et factors in stem cell and PubMed Scopus Google Scholar, et al., M. H. A. Polak L. S. et cell wound and 2017; Full Text Full Text PDF PubMed Scopus Google Scholar, et al., S. K. A. S. Polak L. A. S. Fuchs E. skin epithelial stem cells to tissue 2017; PubMed Scopus Google Scholar). will us to our understanding of stem cell biology for to much of our studies have on how stem cells signaling at the we are of other levels of In the past we have in to how stem cells when they an oncogenic frequently in human We that stem cells and of the and a less to this switch is for stem cells to oncogenic and it on a of oncogenic mRNAs with that their to be in the of in protein et al., A. J.G. S. J. D. H. et from 2017; PubMed Scopus Google Scholar). the is frequently in human and the other when levels of mRNAs are patients with the levels the et al., A. J.G. S. J. D. H. et from 2017; PubMed Scopus Google Scholar). findings potential for which we will in the In our studies began with the basic of skin stem cells, first in and then in We then to how progenitors as they in different or and sweat or the progenitors are marked by these keratins and reside at the between the and (Fuchs and Green, 1980Fuchs E. Green H. Changes in keratin gene expression during terminal differentiation of the keratinocyte.Cell. 1980; 19: 1033-1042Abstract Full Text PDF PubMed Scopus (822) Google Scholar, et al., V. D. R. M. T. M. A. Fuchs E. a that governs to the sebaceous Full Text Full Text PDF PubMed Scopus Google Scholar, et al., Polak L. A.S. Pasolli H.A. N. Blanpain C. Fuchs E. of stem cell populations in sweat and reveals in homeostasis and wound Full Text Full Text PDF PubMed Scopus Google Scholar, and Fuchs, M. Fuchs E. stem cells of squamous cell and their by and adhesion Natl. Acad. Sci. USA. 2011; PubMed Scopus Google Scholar, Tumbar et al., 2004Tumbar T. Guasch G. Greco V. Blanpain C. Lowry W.E. Rendl M. Fuchs E. Defining the epithelial stem cell niche in skin.Science. 2004; 303: 359-363Crossref PubMed Scopus (1636) Google distinct have a on their and their and and Fuchs, Fuchs E. and its an between stem cells and their 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). When from their stem cells them to a of tissue regeneration they (Blanpain and Fuchs, C. Fuchs E. Stem cell of epithelial stem cells in tissue PubMed Scopus Google Scholar). with I have that in stem cell even they always lead to The in stem cell research is to be even more with and clinical In I was as a graduate student at Princeton University to have of cell biology who have had a on my own career. the of science and of taking a and to scientific At with Howard Green, I these to my for a cell system where I could human cells where they could but be to and make I the of from all my into my career. This has always been a for in my own that and are as to our as passionate about the science we In many I was to stem cell into the of tissue In the of my I focusing on other I have been to the of our of stem cell I to be a of the and in it was a to as its and colleagues in this will always be to and as as epidermal stem cells. I for been to the for Stem Cell in as is no to be by for I have and this not have been were it not for the and who I have had the to and these but a who have in my at Rockefeller and in the stem cell at at the University of at and at Rendl and at Stem Cell at and at the Stem Cell in at the in at and at Lien at at and Hsu Stem Cell of of and time of my or I always to them but to them in their was the with my first and will be the with in my lab, who I have had the to of and has been and from to This is as much about them as

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