Stammzellen und ihre Bedeutung in der Dermatologie

Zusammenfassung

Die Hauthomeostase wird von epidermalen Stammzellen gesichert, welche sich selbsterneuern und Tochterzellen generieren, die eine terminale Differenzierung ausweisen. Mehrere spezialisierte Hautstammzellenpopulationen sind bereits nachgewiesen worden. Genetische Markierungsstudien wiesen multipotente Stammzellen im Haarfollikel auf, welche die Regeneration der Haarfollikel unterstützen, aber für den Aufbau der interfollikulären Epidermis nicht verantwortlich sind. Die Letztere besitzt eine eigene Stammzellpopulation. Bei Gefährdung der Hautintegrität, z. B. nach Verbrennung, übernehmen jedoch Haarfollikelstammzellen die epidermale Regeneration. Andererseits sind die Zellen der Wulstregion, die ersten adulten Hautstammzellen, die identifiziert wurden, fähig, Haarfollikel, interfollikuläre Epidermis und Talgdrüsen zu bilden. Außerdem können sich aus Zellen der Wulstregion – mindestens in den Haarfollikeln der Maus – auch nichtepitheliale Zellen entwickeln, welche auf einen abstammungsunabhängigen, pluripotenten Charakter der Wulstregion hinweisen. Multipotente Zellen (hautabstammende Progenitorzellen) sind in der menschlichen Dermis vorhanden. Dermale Stammzellen stellen 0,3 % der Vorhautfibroblasten dar. Progenitorzellen existieren auch in den Talgdrüsen und sind in der Lage, sowohl Talgdrüsenzellen als auch Zellen der interfollikulären Epidermis zu generieren. Die unterschiedliche Selbsterneuerung und Abstammungsdifferenzierung der Stammzellen der Haut machen diese Zellen für die regenerative Medizin, die Gewebeersatzforschung, die Gentherapie und die zellbasierte Therapie mit autologen adulten Stammzellen attraktiv.

Abstract

Skin integrity is maintained by epidermal stem cells, which self-renew and generate daughter cells that undergo terminal differentiation. Existence of several distinct skin stem cell populations has been reported. Genetic labelling studies detected multipotent stem cells of the hair follicle, which support regeneration of hair follicles but is not responsible for maintaining interfollicular epidermis. The latter exhibits a distinct stem cell population. However, whenever skin integrity is severely compromised, e. g. after burns, hair follicle stem cells remodel epidermal regeneration. On the other hand, bulge cells, the first adult stem cells of the skin to have been identified, are capable of forming hair follicles, interfollicular epidermis and sebaceous glands. In addition – at least in mouse hair follicles – they can also give rise to non-epithelial cells, indicating a lineage-independent pluripotent character. Multipotent cells (skin-derived precursor cells) are present in human dermis. Dermal stem cells represent 0.3 % among human dermal foreskin fibroblasts. A resident pool of progenitor cells exists within the sebaceous glands, which is able to differentiate into both sebocytes and interfollicular epidermis. The self-renewal and multi-lineage differentiation of skin stem cells make these cells attractive for regenerative medicine, tissue repair, gene therapy and cell-based therapy with autologous adult stem cells.

Literatur

• 1 Hübner K, Fuhrmann G, Christenson L K, Kehler J, Reinbold R, De La Fuente R, Wood J, Strauss 3rd J F, Boiani M, Schöler H R. Derivation of oocytes from mouse embryonic stem cells.  Science. 2003;  300 1251-1256
• 2 Thomson J A, Itskovitz-Eldor J, Shapiro S S, Waknitz M A, Swiergiel J J, Marshall V S, Jones J M. Embryonic stem cell lines derived from human blastocysts.  Science. 1998;  282 1145-1147
• 3 Adjaye J, Huntriss J, Herwig R, BenKahla A, Brink T C, Wierling C, Hultschig C, Groth D, Yaspo M L, Picton H M, Gosden R G, Lehrach H. Primary differentiation in the human blastocyst: comparative molecular portraits of inner cell mass and trophectoderm cells.  Stem Cells. 2005;  23 1514-1525
• 4 Martin G R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.  Proc Natl Acad Sci USA. 1981;  78 7634-7638
• 5 Smith A G, Heath J K, Donaldson D D, Wong G G, Moreau J, Stahl M, Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides.  Nature. 1988;  336 688-690
• 6 Schnieke A E, Kind A J, Ritchie W A, Mycock K, Scott A R, Ritchie M, Wilmut I, Colman A, Campbell K H. Human factor IX transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts.  Science. 1997;  278 2130-2133
• 7 Mitalipov S M, Zhou Q, Byrne J A, Ji W Z, Norgren R B, Wolf D P. Reprogramming following somatic cell nuclear transfer in primates is dependent upon nuclear remodeling.  Hum Reprod. 2007;  22 2232-2242
• 8 Sharpless N E, DePinho R A. How stem cells age and why this makes us grow old.  Nat Rev Mol Cell Biol. 2007;  8 703-713
• 9 Moore K A, Lemischka I R. Stem cells and their niches.  Science. 2006;  311 1880-1885
• 10 Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.  Cell. 2007;  131 861-872
• 11 Yu J, Vodyanik M A, Smuga-Otto K, Antosiewicz-Bourget J, Frane J L, Tian S, Nie J, Jonsdottir G A, Ruotti V, Stewart R, Slukvin I I, Thomson J A. Induced pluripotent stem cell lines derived from human somatic cells.  Science. 2007;  318 1917-1920
• 12 Hanna J, Wernig M, Markoulaki S, Sun C W, Meissner A, Cassady J P, Beard C, Brambrink T, Wu L C, Townes T M, Jaenisch R. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.  Science. 2007;  318 1920-1923
• 13 Fuchs E. Skin stem cells: rising to the surface.  J Cell Biol. 2008;  180 273-284
• 14 Levy V, Lindon C, Zheng Y, Harfe B D, Morgan B A. Epidermal stem cells arise from the hair follicle after wounding.  Dev Cell. 2007;  9 855-861
• 15 Ito 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;  72 548-557
• 16 Niemann C, Watt F M. Designer skin: lineage commitment in postnatal skin.  Trends Cell Biol. 2002;  12 185-192
• 17 Potten C S. The epidermal proliferative unit: the possible role of the central basal cell.  Cell Tissue Kinet. 1974;  7 77-88
• 18 Clayton E, Doupe 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;  446 185-189
• 19 Jones 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;  73 713-724
• 20 Li A, Simmons P J, Kaur P. Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype.  Proc Natl Acad Sci USA. 1998;  95 3902-3907
• 21 Lowell S, Jones P, LeRoux I, Dunne J, Watt F M. Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters.  Curr Biol. 2000;  10 491-500
• 22 Ohyama M, Terunuma A, Tock C L, Radonovich M F, Pise-Masison C A, Hopping S B, Brady J N, Udey M C, Vogel J C. Characterization and isolation of stem cell-enriched human hair follicle bulge cells.  J Clin Invest. 2006;  116 249-260
• 23 Legg J, Lensen U B, Broad S, Leigh I, Watt F M. Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis.  Development. 2003;  130 6049-6063
• 24 Jensen K B, Watt F M. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence.  Proc Natl Acad Sci USA. 2006;  103 11 958-11 963
• 25 Tiede S, Kloepper J E, Bodo E, Tiwari S, Kruse C, Paus R. Hair follicle stem cells: Walking the maze.  Eur J Cell Biol. 2007;  86 355-376
• 26 Paus R, Foitzik K. In search of the ‘‘hair cycle clock’’: a guided tour.  Differentiation. 2004;  72 489-511
• 27 Cotsarelis 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 1329-1337
• 28 Fuchs E, Horsley V. More than one way to skin ….  Genes & Devel. 2008;  22 976-985
• 29 Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris R J, Cotsarelis G. Stem cells of the hair follicle contribute to wound repair but not to homeostasis of the epidermis.  Nat Med. 2005;  11 1351-1354
• 30 Lyle S, Christofidou-Solomidou M, Liu Y, Elder D E, Albelda S, Cotsarelis G. Human hair follicle bulge cells are biochemically distinct and possess an epithelial stem cell phenotype.  J Invest Dermatol Symp Proc. 1999;  4 296-301
• 31 Cotsarelis G. Epithelial stem cells: a folliculocentric view.  J Invest Dermatol. 2006;  126 459-468
• 32 Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells.  Cell. 2001;  104 233-245
• 33 Liu Y, Lyle S, Yang Z, Cotsarelis G. Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge.  J Invest Dermatol. 2003;  121 963-968
• 34 Hoffman R M. The pluripotency of hair follicle stem cells.  Cell Cycle. 2006;  5 232-233
• 35 Roh C, Tao Q, Photopoulos C, Lyle S. In vitro differences between keratinocyte stem cells and transitamplifying cells of the human hair follicle.  J Invest Dermatol. 2005;  125 1099-1105
• 36 Lyle S, Christofidou-Solomidou M, Liu Y, Elder D E, 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 3179-3188
• 37 vanGenderen C, Okamura R M, Farinas I, Quo R G, Parslow T G, Bruhn L, Grosschedl R. Development of several organs that require inductive epithelial–mesenchymal interactions is impaired in LEF-1-deficient mice.  Genes Dev. 1994;  8 2691-2703
• 38 Gat U, DasGupta R, Degenstein L, Fuchs E. De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin.  Cell. 1998;  95 605-614
• 39 O’Shaughnessy R F, Yeo W, Gautier J, Jahoda C AB, Christiano A M. The WNT signalling modulator, wise, is expressed in an interaction-dependent manner during hair-follicle cycling.  J Invest Dermatol. 2004;  123 613-621
• 40 Nguyen H, Rendl M, Fuchs E. Tcf3 governs stem cell features and represses cell fate determination in skin.  Cell. 2006;  127 171-183
• 41 Artuc M, Steckelings U M, Henz B M. Mast cell-fibroblast interactions: human mast cells as source and inducers of fibroblast and epithelial growth factors.  J Invest Dermatol. 2002;  118 391-395
• 42 Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing.  J Invest Dermatol. 2007;  127 998-1008
• 43 Stark H J, Willhauck M J, Mirancea N, Boehnke K, Nord I, Breitkreutz D, Pavesio A, Boukamp P, Fusenig N E. Authentic fibroblast matrix in dermal equivalents normalises epidermal histogenesis and dermoepidermal junction in organotypic co-culture.  Eur J Cell Biol. 2004;  83 631-645
• 44 Chen F G, Zhang W J, Bi D, Liu W, Wei X, Chen F F, Zhu L, Cui L, Cao Y. Clonal analysis of nestin(-) vimentin(+) multipotent fibroblasts isolated from human dermis.  J Cell Sci. 2007;  120 2875-2883
• 45 Toma J G, Akhavan M, Fernandes K J, Barnabé-Heider F, Sadikot A, Kaplan D R, Miller F D. Isolation of multipotent adult stem cells from the dermis of mammalian skin.  Nat Cell Biol. 2001;  3 778-784
• 46 Biernaskie J A, McKenzie I A, Toma J G, Miller F D. Isolation of skin-derived precursors (SKPs) and differentiation and enrichment of their Schwann cell progeny.  Nat Protoc. 2006;  1 2803-2812
• 47 Bucala R, Spiegel L A, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.  Mol Med. 1994;  1 71-81
• 48 Quan T E, Cowper S, Wu S P, Bockenstedt L K, Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood.  Int J Biochem Cell Biol. 2004;  36 598-606
• 49 Shi C M, Cheng T M. Differentiation of dermis-derived multipotent cells into insulin-producing pancreatic cells in vitro.  World J Gastroenterol. 2004;  10 2550-2552
• 50 Tobin D J, Gunin A, Magerl M, Paus R. Plasticity and cytokinetic dynamics of the hair follicle mesenchyme during the hair growth cycle: implications for growth control and hair follicle transformations.  J Invest Dermatol Symp Proc. 2003;  8 80-86
• 51 Jahoda C AB, Reynolds A J. Hair follicle dermal sheath cells: unsung participants in wound healing.  Lancet. 2001;  358 1445-1448
• 52 Jahoda C AB, Whitehouse C J, Reynolds A J, Hole N. Hair follicle dermal cells differentiate into adipogenic and osteogenic lineages.  Exp Dermatol. 2003;  12 849-859
• 53 Kumamoto T, Shalhevet D, Matsue H, Mummert M E, Ward B R, Jester J V, Takashima A. Hair follicles serve as local reservoirs of skin mast cell precursors.  Blood. 2003;  102 1654-1660
• 54 DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation.  Development. 1999;  126 4557-4568
• 55 Richardson G D, Arnott E C, Whitehouse C J, Lawrence C M, Reynolds A J, Hole N, Jahoda C AB. Plasticity of rodent and human hair follicle dermal cells: implications for cell therapy and tissue engineering.  J Invest Dermatol Symp Proc. 2005;  10 180-183
• 56 Fernandes K J, McKenzie I A, Mill P, Smith K M, Akhavan M, Barnabe-Heider F, Biernaskie J, Junek A, Kobayashi N R, Toma J G, Kaplan D R, Labosky P A, Rafuse V, Hui C C, Miller F D. A dermal niche for multipotent adult skin-derived precursor cells.  Nat Cell Biol. 2004;  6 1082-1093
• 57 Zouboulis C C. Acne and sebaceous gland function.  Clin Dermatol. 2004;  22 360-366
• 58 Watt F M, Lo Celso C, Silva-Vargas V. Epidermal stem cells: an update. Curr. Opin.  Genetics Develop. 2006;  16 518-524
• 59 Niemann C, Unden A B, Lyle S, Zouboulis C C, Toftgård R, Watt F M. Indian hedgehog and beta-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis.  Proc Natl Acad Sci USA. 2003;  100 (suppl 1) 11873-11880
• 60 Lo Celso C, Berta M A, Braun K M, Frye M, Lyle S, Zouboulis C C, Watt F M. Characterisation of bipotential epidermal progenitors derived from human sebaceous gland: contrasting roles of c-Myc and beta-catenin.  Stem Cells. 2008;  26 1241-1252
• 61 Selleri S, Seltmann H, Gariboldi S, Shirai Y F, Balsari A, Zouboulis C C, Rumio C. Doxorubicin-induced alopecia is associated with sebaceous gland differentiation.  J Invest Dermatol. 2006;  126 711-720
• 62 Braun K M, Niemann C, Jensen U B, Sundberg J P, Silva-Vargas V, Watt F M. Manipulation of stem cell proliferation and lineage commitment: Visualisation of label-retaining cells in wholemounts of mouse epidermis.  Development. 2003;  130 5241-5255
• 63 Horsley V, O’Carroll D, Tooze R, Ohinata Y, Saitou M, Obukhanych T, Nussenzweig M, Tarakhovsky A, Fuchs E. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland.  Cell. 2006;  126 597-609
• 64 Allen M, Grachtchouk M, Sheng H, Grachtchouk V, Wang A, Wei L, Liu J, Ramirez A, Metzger D, Chambon P, Jorcano J, Dlugosz A. Hedgehog signaling regulates sebaceous gland development.  Am J Pathol. 2003;  163 2173-2178
• 65 Takeda H, Lyle S, Lazar A JF, Zouboulis C C, Smyth I, Watt F M. Human sebaceous tumours harbour inactivating mutations in LEF1.  Nat Med. 2006;  12 395-397
• 66 Han G, Li A G, Liang Y Y, Owens P, He W, Lu S, Yoshimatsu Y, Wang D, Ten Dijke P, Lin X, Wang X J. Smad7-induced beta-catenin degradation alters epidermal appendage development.  Dev Cell BL. 2006;  11 301-312