Stem Cells and the Niche: A Dynamic Duo
2010; Elsevier BV; Volume: 6; Issue: 2 Linguagem: Inglês
10.1016/j.stem.2010.01.011
ISSN1934-5909
Autores Tópico(s)Cancer Cells and Metastasis
ResumoStem cell niches are dynamic microenvironments that balance stem cell activity to maintain tissue homeostasis and repair throughout the lifetime of an organism. The development of strategies to monitor and perturb niche components has provided insight into the responsive nature of the niche and offers a framework to uncover how disruption of normal stem cell niche function may contribute to aging and disease onset and progression. Additional work in the identification of genetic factors that regulate the formation, activity, and size of stem cell niches will facilitate incorporation of the niche into stem cell-based therapies and regenerative medicine. Stem cell niches are dynamic microenvironments that balance stem cell activity to maintain tissue homeostasis and repair throughout the lifetime of an organism. The development of strategies to monitor and perturb niche components has provided insight into the responsive nature of the niche and offers a framework to uncover how disruption of normal stem cell niche function may contribute to aging and disease onset and progression. Additional work in the identification of genetic factors that regulate the formation, activity, and size of stem cell niches will facilitate incorporation of the niche into stem cell-based therapies and regenerative medicine. Stem cell niches are discrete and dynamic functional domains that influence stem cell behavior to govern tissue homeostasis under diverse physiological (development and aging) and pathological (injury and disease) conditions. The niche must be flexible in order to coordinate stem cell behavior with homeostasis and repair; however, the plasticity of a niche may be co-opted in cancer and chronic disease. Here, we review experimental data highlighting the relationships between stem cells and their niches, advances in imaging technologies that permit characterization of niches in vivo, and factors regulating niche involvement in tissue regeneration and cancer. In 1978, R. Schofield proposed that proliferative, hematopoietic cells derived from the spleen (spleen colony-forming cells, CFU-S) displayed decreased proliferative potential when compared to hematopoietic stem cells from the bone marrow because they were no longer in association with a complement of cells, a “niche,” which supports long-term stem cell activity (Schofield, 1978Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell.Blood Cells. 1978; 4: 7-25PubMed Google Scholar). This idea that specialized environments within tissues can preserve proliferative potential and block maturation of adult stem cells was the first description of the stem cell niche hypothesis. Implicit in this model is the prediction that removal of stem cells from the niche results in loss of stem cell identity, self-renewal capacity, and the onset of differentiation. As such, the niche would provide a mechanism to precisely balance the production of stem cells and progenitor cells to maintain tissue homeostasis. Therefore, a stem cell niche is not defined solely by the presence of stem cells but also by the ability to regulate stem cell behavior. Characterization of somatic support cells that produce factors necessary for the maintenance of germline stem cells (GSCs) in C. elegans and Drosophila provided examples of discrete “niches” (Kiger et al., 2001Kiger A.A. Jones D.L. Schulz C. Rogers M.B. Fuller M.T. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue.Science. 2001; 294: 2542-2545Crossref PubMed Scopus (363) Google Scholar, Kimble and White, 1981Kimble J.E. White J.G. On the control of germ cell development in Caenorhabditis elegans.Dev. Biol. 1981; 81: 208-219Crossref PubMed Scopus (287) Google Scholar, Tulina and Matunis, 2001Tulina N. Matunis E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling.Science. 2001; 294: 2546-2549Crossref PubMed Scopus (343) Google Scholar, Xie and Spradling, 2000Xie T. Spradling A.C. A niche maintaining germ line stem cells in the Drosophila ovary.Science. 2000; 290: 328-330Crossref PubMed Scopus (407) Google Scholar) and, consequently, paradigms for the identification and characterization of stem cell niches in vertebrates. Development of functional assays to verify stem cell identity, characterize niche support cells, and technologies to visualize stem cell-niche cell interactions in vivo have enabled a better understanding of how stem cell niche dynamics are regulated in physiological and pathological processes. Lineage-tracing techniques and serial transplantation assays have confirmed the presence of stem cell populations in many tissues. Consequently, these methods have also aided in characterizing putative niches. In Drosophila, clonal analysis relies upon mitotic recombination to initiate marker expression in a random mitotic cell and all of its subsequent daughter cells (Harrison and Perrimon, 1993Harrison D.A. Perrimon N. Simple and efficient generation of marked clones in Drosophila.Curr. Biol. 1993; 3: 424-433Abstract Full Text PDF PubMed Google Scholar, Lee and Luo, 1999Lee T. Luo L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis.Neuron. 1999; 22: 451-461Abstract Full Text Full Text PDF PubMed Google Scholar). This method has been used to identify a number of stem cell populations in tissues as diverse as the nervous system, gonads, and digestive tract (Figure 1) (Decotto and Spradling, 2005Decotto E. Spradling A.C. The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals.Dev. Cell. 2005; 9: 501-510Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, Fox and Spradling, 2009Fox D.T. Spradling A.C. The Drosophila hindgut lacks constitutively active adult stem cells but proliferates in response to tissue damage.Cell Stem Cell. 2009; 5: 290-297Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, Gönczy and DiNardo, 1996Gönczy P. DiNardo S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis.Development. 1996; 122: 2437-2447PubMed Google Scholar, Margolis and Spradling, 1995Margolis J. Spradling A. Identification and behavior of epithelial stem cells in the Drosophila ovary.Development. 1995; 121: 3797-3807PubMed Google Scholar, Micchelli and Perrimon, 2006Micchelli C.A. Perrimon N. 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Within mammalian tissues, uptake and long-term retention of bromo-deoxyuridine (BrdU) or incorporation of fluorescently labeled histone H2B during DNA synthesis have been used as a marker for slowly cycling (“label-retaining”) putative stem cells. However, improved lineage-tracing strategies utilizing Cre recombinase have facilitated locating stem/progenitor cell populations in vivo (Table 1), providing insight into ongoing debates regarding the nature of stem cell populations within tissues such as the digestive system and skin.Table 1Assays Used to Determine Stem Cell Identity and Niche ComponentsOrganismTissueStem Cell PopulationStem Cell Functional AssayNiche Support Cells/ComponentsNiche Cell FactorsKey ReferencesC. elegansgonadgerm line stem cellspatial organizationdistal tip cellNKimble, 1981Kimble J. Alterations in cell lineage following laser ablation of cells in the somatic gonad of Caenorhabditis elegans.Dev. Biol. 1981; 87: 286-300Crossref PubMed Scopus (265) Google ScholarD. melanogasterovarygerm line stem celllineage analysiscap cells,terminal filament,escort stem cellsBMPMargolis and Spradling, 1995Margolis J. Spradling A. Identification and behavior of epithelial stem cells in the Drosophila ovary.Development. 1995; 121: 3797-3807PubMed Google Scholar, Xie and Spradling, 1998Xie T. Spradling A.C. decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary.Cell. 1998; 94: 251-260Abstract Full Text Full Text PDF PubMed Scopus (340) Google ScholarD. melanogasterovaryescort stem celllineage analysiscap cells?JAK-STATDecotto and Spradling, 2005Decotto E. Spradling A.C. The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals.Dev. Cell. 2005; 9: 501-510Abstract Full Text Full Text PDF PubMed Scopus (151) Google ScholarD. melanogasterovaryfollicle stem celllineage analysisbasement membrane, cap cells, escort cellsHH, BMPMargolis and Spradling, 1995Margolis J. Spradling A. Identification and behavior of epithelial stem cells in the Drosophila ovary.Development. 1995; 121: 3797-3807PubMed Google ScholarD. melanogastertestisgerm line stem celllineage analysishub cells, somatic cyst stem cellsBMP, JAK-STATKiger et al., 2001Kiger A.A. Jones D.L. Schulz C. Rogers M.B. Fuller M.T. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue.Science. 2001; 294: 2542-2545Crossref PubMed Scopus (363) Google Scholar, Tulina and Matunis, 2001Tulina N. Matunis E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling.Science. 2001; 294: 2546-2549Crossref PubMed Scopus (343) Google ScholarD. melanogastertestissomatic cyst stem celllineage analysishub cells, germline stem cellsJAK-STATGönczy and DiNardo, 1996Gönczy P. DiNardo S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis.Development. 1996; 122: 2437-2447PubMed Google Scholar, Leatherman and Dinardo, 2008Leatherman J.L. Dinardo S. Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal.Cell Stem Cell. 2008; 3: 44-54Abstract Full Text Full Text PDF PubMed Scopus (107) Google ScholarD. melanogastermidgutintestinal stem celllineage analysisbasement membrane, enterocytes?N, Wg, JAK-Stat, InsulinMicchelli and Perrimon, 2006Micchelli C.A. Perrimon N. Evidence that stem cells reside in the adult Drosophila midgut epithelium.Nature. 2006; 439: 475-479Crossref PubMed Scopus (326) Google Scholar, Ohlstein and Spradling, 2006Ohlstein B. Spradling A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells.Nature. 2006; 439: 470-474Crossref PubMed Scopus (337) Google Scholar)D. melanogasterhindguthindgut stem celllineage analysisbasement membrane?WgFox and Spradling, 2009Fox D.T. Spradling A.C. The Drosophila hindgut lacks constitutively active adult stem cells but proliferates in response to tissue damage.Cell Stem Cell. 2009; 5: 290-297Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, Takashima et al., 2008Takashima S. Mkrtchyan M. Younossi-Hartenstein A. Merriam J.R. Hartenstein V. The behavior of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling.Nature. 2008; 454: 651-655Crossref PubMed Scopus (78) Google ScholarM. musculusbloodhematopoietic stem cellsingle cell transplantosteoblasts, osteoclasts, vascular, perivascular cellsWnt, N, ANG1, OPN, CXCL12reviewed in Weissman et al., 2001Weissman I.L. Anderson D.J. Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations.Annu. Rev. Cell Dev. Biol. 2001; 17: 387-403Crossref PubMed Scopus (523) Google Scholar, Wagers, 2005Wagers A.J. Stem cell grand SLAM.Cell. 2005; 121: 967-970Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, Garrett and Emerson, 2009Garrett R.W. Emerson S.G. 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A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis.Science. 2007; 317: 1722-1726Crossref PubMed Scopus (194) Google ScholarM. musculusneuralneural stem celllineage analysis, in vitro culturevascular, ependymal cells, astrocytesWnt, SHH, FGF, VEGF, NPalmer et al., 2000Palmer T.D. Willhoite A.R. Gage F.H. Vascular niche for adult hippocampal neurogenesis.J. Comp. Neurol. 2000; 425: 479-494Crossref PubMed Scopus (1098) Google Scholar Open table in a new tab For example, intestinal stem cells in mammals had been proposed to reside at the +4 position (four cells above Paneth cells), based on the observation that these cells incorporated and retained BrdU (Potten et al., 1974Potten C.S. Kovacs L. Hamilton E. Continuous labelling studies on mouse skin and intestine.Cell Tissue Kinet. 1974; 7: 271-283PubMed Google Scholar). However, recent lineage-tracing analysis and in vitro culturing techniques provided convincing evidence that crypt base columnar cells (CBCs) that express leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) behave as stem cells in intestinal crypts (Barker et al., 2007Barker N. van Es J.H. Kuipers J. Kujala P. van den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007Crossref PubMed Scopus (1393) Google Scholar, Sato et al., 2009Sato T. Vries R.G. Snippert H.J. van de Wetering M. Barker N. Stange D.E. van Es J.H. Abo A. Kujala P. Peters P.J. Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265Crossref PubMed Scopus (667) Google Scholar). In the murine small intestine, CBCs are intercalated between Paneth cells and are in direct contact with a basement membrane at the base of the intestinal crypt (Chang et al., 1974Chang L.R. Chen T.S. Huang K.C. Electrolyte transport across the mouse small intestine.Proc. Soc. Exp. Biol. Med. 1974; 145: 1220-1224Crossref PubMed Google Scholar). Using a Cre-inducible knockin allele of Lgr5, lineage tracing demonstrated that Lgr5+ cells were responsible for the maintenance of the entire villus and capable of long term (>12 month) self-renewal (Barker et al., 2007Barker N. van Es J.H. Kuipers J. Kujala P. van den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007Crossref PubMed Scopus (1393) Google Scholar). In addition, single dissociated Lgr5+ crypt cells cultured in vitro generated crypt-villus organoid structures resembling intestinal epithelium and contained the appropriate differentiated cell types (Sato et al., 2009Sato T. Vries R.G. Snippert H.J. van de Wetering M. Barker N. Stange D.E. van Es J.H. Abo A. Kujala P. Peters P.J. Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265Crossref PubMed Scopus (667) Google Scholar). Lgr5 is a Wnt target gene, and components of the Wnt signaling pathway are required for intestinal stem cell maintenance (Korinek et al., 1998Korinek V. Barker N. Moerer P. van Donselaar E. Huls G. Peters P.J. Clevers H. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4.Nat. Genet. 1998; 19: 379-383Crossref PubMed Scopus (914) Google Scholar). Mutations in APC or β-catenin are sufficient to induce colon carcinoma (Korinek et al., 1997Korinek V. 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Genet. 2008; 40: 915-920Crossref PubMed Scopus (472) Google Scholar). Bmi1 and Lgr5 label cells at different locations within the intestinal crypts with distinct cellular morphologies; therefore, it is possible that these cell types may constitute overlapping stem cell populations. It was long assumed that neighboring myofibroblasts acted as support cells within the crypts to provide a stromal niche for the intestinal stem cells. However, the ability of isolated stem cells to generate organized, crypt-like structures in vitro suggests that the stem cells are not absolutely dependent upon these fibroblasts for maintenance (Sato et al., 2009Sato T. Vries R.G. Snippert H.J. van de Wetering M. Barker N. Stange D.E. van Es J.H. Abo A. Kujala P. Peters P.J. Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265Crossref PubMed Scopus (667) Google Scholar). Given the proximity of Paneth cells to Lgr5+ CBC cells and the fact that they are a likely source of Wnt (Gregorieff et al., 2005Gregorieff A. Pinto D. Begthel H. Destrée O. Kielman M. Clevers H. Expression pattern of Wnt signaling components in the adult intestine.Gastroenterology. 2005; 129: 626-638Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar), this cell type could easily act to support the adjacent stem cell population. If so, the ability of CBC cells to generate differentiated cells that then act as a niche component (Sato et al., 2009Sato T. Vries R.G. Snippert H.J. van de Wetering M. Barker N. Stange D.E. van Es J.H. Abo A. Kujala P. Peters P.J. Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265Crossref PubMed Scopus (667) Google Scholar) would be similar to ability of somatic stem cells in the Drosophila testis, which give rise to differentiated cells that are an integral component of the testis niche (Voog et al., 2008Voog J. D'Alterio C. Jones D.L. Multipotent somatic stem cells contribute to the stem cell niche in the Drosophila testis.Nature. 2008; 454: 1132-1136Crossref PubMed Scopus (69) Google Scholar). As Lgr5 appears to be a marker for epithelial stem cells in a number of tissues (Barker et al., 2010Barker N. Huch M. Kujala P. van de Wetering M. Snippert H. van Es J. Sato T. Stange D.E. Begthel H. van den Born M. et al.Lgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-lived Gastric Units In Vitro.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, Jaks et al., 2008Jaks V. Barker N. Kasper M. van Es J.H. Snippert H.J. Clevers H. Toftgård R. Lgr5 marks cycling, yet long-lived, hair follicle stem cells.Nat. Genet. 2008; 40: 1291-1299Crossref PubMed Scopus (330) Google Scholar), it will be interesting to determine whether cells that are functionally equivalent to Paneth cells exist within these niches. Genetic labeling experiments have also aided in the identification of stem cell populations within the skin. The epidermis, hair follicles, and sebaceous glands are maintained by stem cell populations that reside in at least three distinct microenvironments: the basal layer of the interfollicular epidermis (IFE), the follicular bulge, and the base of the sebaceous gland. Epidermal stem cells in the IFE, which normally contribute to epidermal homeostasis, reside in nests near the basement membrane (Jones and Watt, 1993Jones P.H. Watt F.M. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression.Cell. 1993; 73: 713-724Abstract Full Text PDF PubMed Google Scholar) and have been identified using clonal marking strategies (Clayton et al., 2007Clayton E. Doupé D.P. Klein A.M. Winton D.J. Simons B.D. Jones P.H. A single type of progenitor cell maintains normal epidermis.Nature. 2007; 446: 185-189Crossref PubMed Scopus (326) Google Scholar, Ghazizadeh and Taichman, 2005Ghazizadeh S. Taichman L.B. Organization of stem cells and their progeny in human epidermis.J. Invest. Dermatol. 2005; 124: 367-372Crossref PubMed Scopus (71) Google Scholar). The complete nature of the epidermal niche is not known, although the basement membrane likely provides positional information and proliferative cues (Lechler and Fuchs, 2005Lechler T. Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin.Nature. 2005; 437: 275-280Crossref PubMed Scopus (454) Google Scholar). Stem cells residing in the bulge region of the outer root sheath of the hair follicle have been identified using long-term label retention (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 (1158) 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 (1056) Google Scholar) and lineage-tracing strategies (Jaks et al., 2008Jaks V. Barker N. Kasper M. van Es J.H. Snippert H.J. Clevers H. Toftgård R. Lgr5 marks cycling, yet long-lived, hair follicle stem cells.Nat. 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These slow-cycling stem cells are specified early in development and are capable of contributing to the epidermis upon injury, as well as the sebaceous gland (Nowak et al., 2008Nowak J.A. Polak L. Pasolli H.A. Fuchs E. Hair follicle stem cells are specified and function in early skin morphogenesis.Cell Stem Cell. 2008; 3: 33-43Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Based on molecular markers and proliferation capacity, bulge-derived stem cells are distinct from cells that reside in the hair germ (Greco et al., 2009Greco V. Chen T. Rendl M. Schober M. Pasolli H.A. Stokes N. Dela Cruz-Racelis J. Fuchs E. A two-step mechanism for stem cell activation during hair regeneration.Cell Stem Cell. 2009; 4: 155-169Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar), which are activated prior to each new hair cycle and are also capable of contributing to the bulge (Ito et al., 2004Ito M. Kizawa K. Hamada K. Cotsarelis G. Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen.Differentiation. 2004; 72: 548-557Crossref PubMed Scopus (103) Google Scholar). Due to the dynamic nature of the stem cell niche in the hair follicle, both temporal (hair cycle stage or time after injury) and spatial information (location of stem cell population in relation to bulge or near wound edge) likely coordinate interactions between the distinct populations of stem cells in the bulge and hair germ (Greco et al., 2009Greco V. Chen T. Rendl M. Schober M. Pasolli H.A. Stokes N. Dela Cruz-Racelis J. Fuchs E. A two-step mechanism for stem cell activation during hair regeneration.Cell Stem Cell. 2009; 4: 155-169Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Dermal papilla (DP) cells are specialized, mesenchymal cells that lie at the base of the hair follicle and are marked by expression of the serine protease, Corin (Enshell-Seijffers et al., 2008Enshell-Seijffers D. Lindon C. Morgan B.A. The serine protease Corin is a novel modifier of the Agouti pathway.Development. 2008; 135: 217-225Crossref PubMed Scopus (43) Google Scholar). DP cells are capable of promoting hair follicle formation in skin epidermis in vitro (Jahoda et al., 1984Jahoda C.A. Horne K.A. Oliver R.F. Induction of hair growth by implantation of cultured dermal papilla cells.Nature. 1984; 311: 560-562Crossref PubMed Google Scholar) and clearly provide signals to activate the hair germ, as well as bulge stem cells (Greco et al., 2009Greco V. Chen T. Rendl M. Schober M. Pasolli H.A. Stokes N. Dela Cruz-Racelis J. Fuchs E. A two-step mechanism for stem cell activation during hair regeneration.Cell Stem Cell. 2009; 4: 155-169Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar); therefore, DP cells are likely a component of the hair follicle stem cell niche. In addition to lineage tracing strategies, single-cell transplantation assays have confirmed stem cell identity and function in a number of tissues (Table 1). Isolation of prospective stem cells is accomplished using fluorescence-activated cell sorting (FACS) based upon expression of cell surface marker combinations and/or dye-exclusion properties, followed by transplantation of these cells into live tissues, typically manipulated so as to be devoid of endogenous stem cells. The fluid nature of the hematopoietic system has aided in the isolation of hematopoietic stem cells (HSC) that can be identified by numerous cell surface markers (Wilson et al., 2008Wilson A. Laurenti E. Oser G. van der Wath R.C. Blanco-Bose W. Jaworski M. Offner S. Dunant C.F. Eshkind L. Bockamp E. et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (521) Google Scholar) (reviewed in Wagers, 2005Wagers A.J. Stem cell grand SLAM.Cell. 2005; 121: 967-970Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, Weissman et al., 2001Weissman I.L. Anderson D.J. Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations.Annu. Rev. Cell Dev. Biol. 2001; 17: 387-403Crossref PubMed Scopus (523) Google Scholar). However, isolation of cells by FACS in conjunction with transplantation has also led to the identification of stem cells from solid tissues, including those from testis, muscle, breast, and prostate (Cerletti et al., 2008Cerletti M. Jurga S. Witc
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