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• W2067077881 abstract "Corneal epithelium is a self-renewing tissue. Recent studies indicate that corneal epithelial stem cells reside preferentially in the basal layer of peripheral cornea in the limbal zone, rather than uniformly in the entire corneal epithelium. This idea is supported by a unique limbal/corneal expression pattern of the K3 keratin marker for corneal-type differentiation; the preferential distribution of the slow-cycling (label-retaining) cells in the limbus; the superior proliferative capacity of limbal cells as compared with central corneal epithelial cells in vitro and in vivo; and the ability of limbal basal cells to rescue/reconstitute severely damaged or completely depleted corneal epithelium upon transplantation. The limbal/stem cell concept provides explanations for several paradoxical properties of corneal epithelium including the predominance of tumor formation in the limbal zone, the centripetal migration of peripheral corneal cells toward the central cornea, and the “mature-looking” phenotype of the corneal basal cells. The limbal stem cell concept has led to a better understanding of the strategies that a stratified squamous epithelium uses in repair, to a new classification of various anterior surface epithelial diseases, to a repudiation of the classical idea of “conjunctival transdifferentiation”, and to a new surgical procedure called limbal stem cell transplantation. Corneal epithelium is a self-renewing tissue. Recent studies indicate that corneal epithelial stem cells reside preferentially in the basal layer of peripheral cornea in the limbal zone, rather than uniformly in the entire corneal epithelium. This idea is supported by a unique limbal/corneal expression pattern of the K3 keratin marker for corneal-type differentiation; the preferential distribution of the slow-cycling (label-retaining) cells in the limbus; the superior proliferative capacity of limbal cells as compared with central corneal epithelial cells in vitro and in vivo; and the ability of limbal basal cells to rescue/reconstitute severely damaged or completely depleted corneal epithelium upon transplantation. The limbal/stem cell concept provides explanations for several paradoxical properties of corneal epithelium including the predominance of tumor formation in the limbal zone, the centripetal migration of peripheral corneal cells toward the central cornea, and the “mature-looking” phenotype of the corneal basal cells. The limbal stem cell concept has led to a better understanding of the strategies that a stratified squamous epithelium uses in repair, to a new classification of various anterior surface epithelial diseases, to a repudiation of the classical idea of “conjunctival transdifferentiation”, and to a new surgical procedure called limbal stem cell transplantation. Stem cells are a subpopulation of cells capable of extensive self-renewal that upon division gives rise to progeny (transit amplifying or TA cells) that have limited renewal capability (Potten and Loeffler, 1990Potten C.S. Loeffler M. Stem cells: Attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt.Development. 1990; 110: 1001-1020Crossref PubMed Google Scholar). Additionally, stem cells divide relatively infrequently in mature tissues and are structurally and biochemically primitive. In cases of tissue injury, stem cells can proliferate to repopulate the tissue. The TA cell divides more frequently than the stem cell and ultimately all of the TA cells differentiate in the scheme of “stem cell→TA cell→terminally differentiated cell” (Lavker and Sun, 2000Lavker R.M. Sun T-T. Epidermal stem cells: Properties, markers, and location.Proc Nat Acad Sci USA. 2000; 97: 13473-13475Crossref PubMed Scopus (342) Google Scholar;Potten and Booth, 2002Potten C.S. Booth C. Keratinocyte stem cells: A commentary.J Invest Dermatol. 2002; 119: 888-899Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). The unique properties of stem cells allow their identification in various tissues (reviewed inMiller et al., 1993Miller S.J. Lavker R.M. Sun T-T. Keratinocyte stem cells of cornea, skin and hair follicle: Common and distinguishing features.Semin Dev Biol. 1993; 4: 217-240Crossref Scopus (47) Google Scholar). In many cases the identification of stem cells provide new insights into the growth and differentiation properties of the tissue in question. In the case of corneal epithelium, this tissue has long been known to have several unusual and puzzling features. For example, almost all corneal epithelial neoplasias are associated with the peripheral cornea in a rim called the limbus, which represents the transitional zone between the transparent cornea and the white conjunctiva (Waring et al., 1984Waring G.O. Roth A.M. Ekins M.B. Clinical and pathologic description of 17 cases of corneal intraepithelial neoplasia.Am J Ophthalmol. 1984; 97: 547-559Abstract Full Text PDF PubMed Scopus (103) Google Scholar). Another well known and peculiar feature of corneal epithelium is that the peripheral corneal epithelial cells seem to be able to migrate centripetally toward the center of the cornea (Davanger and Evensen, 1971Davanger M. Evensen A. Role of the pericorneal papillary structure in renewal of corneal epithelium.Nature. 1971; 229: 560-561Crossref PubMed Scopus (480) Google Scholar;Buck, 1979Buck R.C. Cell migration in repair of mouse corneal epithelium.Invest Opthalmol Vis Sci. 1979; 18: 767-784PubMed Google Scholar). In addition, the basal cells of central cornea are more mature looking than the basal cells of all other stratified squamous epithelia (Kuwabara et al., 1976Kuwabara T. Perkins D.G. Cogan D.G. Sliding of the epithelium in experimental corneal wounds.Invest Opthalmol. 1976; 15: 4-14PubMed Google Scholar;Buck, 1979Buck R.C. Cell migration in repair of mouse corneal epithelium.Invest Opthalmol Vis Sci. 1979; 18: 767-784PubMed Google Scholar;Srinivasan and Eakins, 1979Srinivasan B.D. Eakins K.E. The reepithelialization of rabbit cornea following single and multiple denudation.Exp Eye Res. 1979; 29: 595-600Crossref PubMed Scopus (20) Google Scholar). While studying the growth and differentiation of rabbit corneal epithelial cells in vivo and in cell culture, Sun and coworkers discovered in the early to mid-1980s that corneal epithelial cells synthesized two major tissue-restricted keratins called K3 and K12 (Moll et al., 1982Moll R. Franke W.W. Schiller D.L. the catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells.Cell. 1982; 31: 11-24Abstract Full Text PDF PubMed Scopus (4374) Google Scholar;Tseng et al., 1982Tseng S.C. Jarvinen M.J. Nelson W.G. Huang J.W. Woodcock-Mitchell J. Sun T-T. Correlation of specific keratins with different types of epithelial differentiation: Monoclonal antibody studies.Cell. 1982; 30: 361-372Abstract Full Text PDF PubMed Scopus (503) Google Scholar;Sun et al., 1984Sun T-T. Eichner R. Schermer A. Cooper D. Nelson W.G. Weiss R.A. Classification, expression, and possible mechanisms of evolution of mammalian epithelial keratins: A unifying model.in: Levine A. Topp W. Woude G Vance Watson J.D. A Unifying Model. New York, Cold Spring Harbor1984: 169-176Google Scholar;Schermer et al., 1986Schermer A. Galvin S. Sun T-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells.J Cell Biol. 1986; 103: 49-62Crossref PubMed Scopus (1158) Google Scholar). Using a monoclonal antibody AE5 to examine the expression of K3 in cultured rabbit corneal epithelial cells (Figure 1),Schermer et al., 1986Schermer A. Galvin S. Sun T-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells.J Cell Biol. 1986; 103: 49-62Crossref PubMed Scopus (1158) Google Scholar noted that K3 was associated with the upper, more differentiated, cell layers, indicating that K3 was a marker for an advanced stage of corneal epithelial differentiation. When the expression of the K3 keratin was examined in vivo, it was observed that this keratin was also expressed in the upper cell layers in corneal epithelium in the limbal zone; this was consistent with the concept that K3 was a marker for an advanced stage of differentiation. Unexpectedly, however, K3 was found to express uniformly in central rabbit corneal epithelium (i.e., even the supposedly undifferentiated basal cells of central corneal epithelium express the K3 differentiation marker). This uniform expression suggests that, although the basal cells in the limbal zone were undifferentiated, those of the central corneal epithelium are more differentiated as far as the expression of the K3 marker is concerned. This finding, coupled with several other biological considerations (see below), ledSchermer et al., 1986Schermer A. Galvin S. Sun T-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells.J Cell Biol. 1986; 103: 49-62Crossref PubMed Scopus (1158) Google Scholar to propose that corneal epithelial stem cells were not uniformly dispersed across the entire corneal epithelial basal layer, as had been thought; instead, these stem cells were concentrated in the peripheral limbal zone (Figure 2).Figure 2The limbal stem cell concept. Panel (a) depicts the expression of the K3 keratin marker for an advanced stage of corneal-type differentiation in the limbal and corneal epithelium. In Panel (b), corneal epithelial stem cells are proposed to be situated in the basal layer of the limbal epithelium. The TA cells (stem cell progeny) migrate centripetally towards the central cornea(Schermer et al., 1986Schermer A. Galvin S. Sun T-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells.J Cell Biol. 1986; 103: 49-62Crossref PubMed Scopus (1158) Google Scholar; reproduced by copyright permission of the Rockefeller Press).View Large Image Figure ViewerDownload (PPT) Strong support for the limbal stem cell concept has come from several approaches. The observation that slow-cycling cells were restricted to the limbal basal layer provided compelling evidence in support of the limbal/corneal stem cell hypothesis (Figure 3;Cotsarelis et al., 1989Cotsarelis G. Cheng S.Z. Dong G. Sun T-T. Lavker R.M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: Implications on epithelial stem cells.Cell. 1989; 57: 201-209Abstract Full Text PDF PubMed Scopus (1096) Google Scholar). One of the most reliable ways to identify epithelial stem cells in vivo takes advantage of the fact that these cells are relatively slow cycling, and thus can be identified experimentally as “label-retaining cells” (LRC) (Bickenbach, 1981Bickenbach J.R. Identification and behavior of label-retaining cells in oral mucosa and skin.J Dent Res. 1981; 60: 1611-1620Crossref PubMed Google Scholar;Bickenbach and Mackenzie, 1984Bickenbach J.R. Mackenzie B.D.S. Identification and behavior of label-retaining cells in hamster epithelia.J Invest Dermatol. 1984; 82: 618-622Abstract Full Text PDF PubMed Scopus (110) Google Scholar;Morris et al., 1985Morris R.J. Fischer S.M. Slaga T.J. Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations.J Invest Dermatol. 1985; 84: 277-281Abstract Full Text PDF PubMed Scopus (143) Google Scholar). To detect the slow-cycling cells, one can perfuse a tissue continuously with tritiated thymidine (3H-T) or bromodeoxyuridine (BrdU) to label as many dividing cells as possible, including some of the occasionally dividing stem cells. During a chase period, which is typically 4–8 wk, the rapidly dividing TA cells lose most of their labels due to dilution whereas the slow-cycling stem cells still retain their label; this way some of the stem cells can be detected experimentally as the LRC. Application of this labeling technique to mouse corneal epithelium revealed that central corneal epithelium contained no LRC; such cells were found exclusively in the basal layer of peripheral corneal epithelium in the limbal area (Cotsarelis et al., 1989Cotsarelis G. Cheng S.Z. Dong G. Sun T-T. Lavker R.M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: Implications on epithelial stem cells.Cell. 1989; 57: 201-209Abstract Full Text PDF PubMed Scopus (1096) Google Scholar;Wei et al., 1995Wei Z.G. Cotsarelis G. Sun T-T. Lavker R.M. Label-retaining cells are preferentially located in fornical epithelium: Implications on conjunctival epithelial homeostasis.Invest Ophthalmol Vis Sci. 1995; 36: 236-246PubMed Google Scholar;Lehrer et al., 1998Lehrer M.S. Sun T-T. Lavker R.M. Strategies of epithelial repair: Modulation of stem cell and transit amplifying cell proliferation.J Cell Sci. 1998; 111: 2867-2875Crossref PubMed Google Scholar). Further support of the limbal stem cell concept has come from cell and explant culture studies showing that limbal cells have a higher in vitro proliferative potential than central corneal epithelial cells (Ebato et al., 1988Ebato B. Friend J. Thoft R.A. Comparison of limbal and peripheral human corneal epithelium in tissue culture.Invest Ophthalmol Vis Sci. 1988; 29: 1533-1537PubMed Google Scholar;Wei et al., 1993Wei Z.G. Wu R.L. Lavker R.M. Sun T-T. In vitro growth and differentiation of rabbit bulbar, fornix, and palpebral conjunctival epithelia. Implications on conjunctival epithelial transdifferentiation and stem cells.Invest Ophthalmol Vis Sci. 1993; 34: 1814-1828PubMed Google Scholar;Pellegrini et al., 1999Pellegrini G. Golisano O. Paterna P. Lambiase A. Bonini S. Rama P. DeLuca M. Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface.J Cell Biol. 1999; 145: 769-782Crossref PubMed Scopus (575) Google Scholar). In vivo experiments have demonstrated that when limbal and corneal epithelia were continuously stimulated with phorbol myristate, limbal epithelium maintained a significantly greater proliferative response than the corneal epithelium (Lavker et al., 1998Lavker R.M. Wei Z-G. Sun T-T. Phorbol ester preferentially stimulates mouse fornical conjunctival and limbal epithelial cells to proliferate in vivo.Invest Ophthalmol Vis Sci. 1998; 39: 101-107Google Scholar), thus providing additional support to the idea that limbal cells have a greater proliferative capacity than corneal epithelial cells. An interesting and previously not well-understood phenomenon about corneal epithelium is that its squamous cell carcinomas, which are particularly abundant in cattle and are known as “cancer eye” (Anderson, 1991Anderson D.E. Genetic study of eye cancer in cattle.J Hered. 1991; 82: 21-26Crossref PubMed Scopus (18) Google Scholar), are predominantly associated with the limbus. A similar preponderance of a limbal origin of corneal epithelial tumors exists in humans (Waring et al., 1984Waring G.O. Roth A.M. Ekins M.B. Clinical and pathologic description of 17 cases of corneal intraepithelial neoplasia.Am J Ophthalmol. 1984; 97: 547-559Abstract Full Text PDF PubMed Scopus (103) Google Scholar). Since stem cells are considered to be the origin of most tumors (Reya et al., 2001Reya T. Morrison S.J. Clarke M.F. Weissman I.L. Stem cells, cancer, and cancer stem cells.Nature. 2001; 414: 105-111Crossref PubMed Scopus (7394) Google Scholar) and since the limbal epithelium is enriched in stem cells, it makes sense that tumors originate from this region. Perhaps some of the most striking biological data in support of the limbal stem cell concept are the transplantation studies pioneered by Tseng and colleagues, who demonstrated that limbal stem cells can be used to reconstitute the entire corneal epithelium (Figure 4;Kenyon and Tseng, 1989Kenyon K.R. Tseng S.C. Limbal autograft transplantation for ocular surface disorders.Ophthalmology. 1989; 96: 709-722Abstract Full Text PDF PubMed Scopus (820) Google Scholar;Tseng, 1989Tseng S.C.G. Concept and application of limbal stem cells.Eye. 1989; 3: 141-157Crossref PubMed Scopus (496) Google Scholar,Tseng, 2000Tseng S.C. Significant impact of limbal epithelial stem cells.Int J Opthalmol. 2000; 48: 79-81Google Scholar). This procedure, known as limbal stem cell transplantation, has restored the eyesight of many patients and is being practiced by ophthalmologists all over the world (Tan et al., 1996Tan D.T. Ficker L.A. Buckley R.J. Limbal transplantation.Ophthalmology. 1996; 103: 29-36Abstract Full Text PDF PubMed Scopus (197) Google Scholar;Pellegrini et al., 1997Pellegrini G. Traverso C.E. Franzi A.T. Zingirian M. Cancedda R. De Luca M. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium.Lancet. 1997; 349: 990-993Abstract Full Text Full Text PDF PubMed Scopus (1043) Google Scholar;Tsubota, 1997Tsubota K. Corneal epithelial stem-cell transplantation.Lancet. 1997; 349: 990-993Abstract Full Text Full Text PDF PubMed Google Scholar;Tsai et al., 2000Tsai R.J. Li L.M. Chen J.K. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells.N Engl J Med. 2000; 343: 86-93Crossref PubMed Scopus (815) Google Scholar;Lemp, 2002Lemp M.A. What's new in ophthalmic surgery.J Am Coll Surg. 2002; 195: 361-363Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). In their ground-breaking paper,Kenyon and Tseng, 1989Kenyon K.R. Tseng S.C. Limbal autograft transplantation for ocular surface disorders.Ophthalmology. 1989; 96: 709-722Abstract Full Text PDF PubMed Scopus (820) Google Scholar noted that limbal transplantation, in cases of severe ocular surface injury caused by chemical and thermal burns, resulted in rapid corneal re-epithelialization with an optically smooth, stable surface that did not subsequently erode or persistently breakdown. These findings clearly demonstrated that the limbal epithelium can be used to restore the lost stem cell population. The next advance in limbal transplantation was the successful use of limbal allografts, in conjunction with immunosuppression, to restore eyesight in patients with severe corneal epithelial damage (Tsai and Tseng, 1994Tsai R.J. Tseng S.C. Human allograft limbal transplantation for corneal surface reconstruction.Cornea. 1994; 13: 389-400Crossref PubMed Scopus (317) Google Scholar). This technique reduces the risk of causing limbal cell deficiency in the healthy donor eye after the removal of a relatively large limbal autograft (Chen and Tseng, 1990Chen J.J. Tseng S.C. Corneal epithelial wound healing in partial limbal deficiency.Invest Ophthalmol Vis Sci. 1990; 31: 1301-1314PubMed Google Scholar,Chen and Tseng, 1991Chen J.J. Tseng S.C. Abnormal corneal epithelial wound healing in partial-thickness removal of limbal epithelium.Invest Ophthalmol Vis Sci. 1991; 32: 2219-2233PubMed Google Scholar). Another way to minimize the damage of the donor eye is to expand, under in vitro cell culture conditions, human limbal epithelial cells for the purpose of transplantation (Lindberg et al., 1993Lindberg K. Brown M.E. Chaves H.V. Kenyan K.R. Rheinwald J.G. In vitro propagation of human ocular surface epithelial cells for transplantation.Invest Ophthalmol Vis Sci. 1993; 34: 2672-2679PubMed Google Scholar).Pellegrini et al., 1997Pellegrini G. Traverso C.E. Franzi A.T. Zingirian M. Cancedda R. De Luca M. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium.Lancet. 1997; 349: 990-993Abstract Full Text Full Text PDF PubMed Scopus (1043) Google Scholar were the first to demonstrate that such in vitro expanded limbal cells can be successfully transplanted to the severely damaged eye with subsequent restoration of the corneal surface and vision. More recently, it has been reported that human amniotic membrane provides a substrate that not only supports the in vitro propagation of limbal stem cells, but also has a striking anti-inflammatory effect on the recipient site. Limbal stem cells propagated this way have been used successfully in patients with a variety of ocular surface disorders (Kim and Tseng, 1995Kim J.C. Tseng S.C. Transplantation of preserved human amniotic membrane for surface reconstruction in severely damaged rabbit corneas.Cornea. 1995; 14: 473-484Crossref PubMed Google Scholar;Tseng et al., 1998Tseng S.C. Prabhasawat P. Barton K. Gray T. Meller D. Amniotic membrane transplantation with or without limbal autografts for corneal surface reconstruction in patients with limbal stem cell deficiency.Arch Ophthalmol. 1998; 116Crossref PubMed Scopus (598) Google Scholar;Schwab et al., 2000Schwab I.R. Reyes M. Isseroff R.R. Successful transplantation of bioengineered tissue replacements in patients with ocular surface disease.Cornea. 2000; 19: 421-426Crossref PubMed Scopus (336) Google Scholar;Tsai et al., 2000Tsai R.J. Li L.M. Chen J.K. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells.N Engl J Med. 2000; 343: 86-93Crossref PubMed Scopus (815) Google Scholar;Koizumi et al., 2001Koizumi N. Inatomi T. Suzuki T. Sotozono C. Kinoshita S. Cultivated corneal epithelial stem cell transplantation in ocular surface disorders.Ophthalmology. 2001; 108: 1569-1574Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar). Since the term corneal epithelial stem cell was first used in 1986, the concept of corneal epithelial stem cells residing in the limbus has spawned a fast-growing field of research. Unlike other epithelial stem cells that are physically adjacent to their progeny thus complicating their analysis (see papers on epidermal and hair follicular stem cells in this volume), limbal stem cells are well separated from their progeny cells. Therefore, the corneal/limbal epithelium, as a model system, offers unique advantages for studying the properties of stem cells versus their progeny TA cells and terminally differentiated cells (Schermer et al., 1986Schermer A. Galvin S. Sun T-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells.J Cell Biol. 1986; 103: 49-62Crossref PubMed Scopus (1158) Google Scholar;Cotsarelis et al., 1989Cotsarelis G. Cheng S.Z. Dong G. Sun T-T. Lavker R.M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: Implications on epithelial stem cells.Cell. 1989; 57: 201-209Abstract Full Text PDF PubMed Scopus (1096) Google Scholar;Lehrer et al., 1998Lehrer M.S. Sun T-T. Lavker R.M. Strategies of epithelial repair: Modulation of stem cell and transit amplifying cell proliferation.J Cell Sci. 1998; 111: 2867-2875Crossref PubMed Google Scholar;Lavker and Sun, 2000Lavker R.M. Sun T-T. Epidermal stem cells: Properties, markers, and location.Proc Nat Acad Sci USA. 2000; 97: 13473-13475Crossref PubMed Scopus (342) Google Scholar). For example, the manner in which stem cell and TA cell proliferation is modulated during corneal epithelial repair has provided information on the strategies that a stratified squamous epithelium adopts to expand during wound healing. Using a double-labeling technique that permits the detection of two or more rounds of DNA synthesis in a given cell, we demonstrated that a large number of normally slow-cycling limbal epithelial stem cells could be induced to replicate in response to a single physical or chemical perturbation of the central corneal epithelium (Lehrer et al., 1998Lehrer M.S. Sun T-T. Lavker R.M. Strategies of epithelial repair: Modulation of stem cell and transit amplifying cell proliferation.J Cell Sci. 1998; 111: 2867-2875Crossref PubMed Google Scholar). In addition, we showed that corneal epithelial TA cells, located in unperturbed peripheral cornea, replicate at least twice and have a relatively long cell cycle time of about 72 h. When induced to proliferate, however, these TA cells can reduce their cell cycle time and undergo additional cell divisions. In contrast, corneal epithelial TA cells can usually divide only once prior to becoming post-mitotic even after TPA stimulation, suggesting a reduced proliferative capacity. These results indicate that corneal epithelium uses three strategies to expand its cell population during wound healing: (i) recruitment of stem cells to produce more TA cells; (ii) increasing the number of times a TA cell can replicate; and (iii) increasing the efficiency of TA cell replication by shortening the cell cycle time (Figure 5;Lehrer et al., 1998Lehrer M.S. Sun T-T. Lavker R.M. Strategies of epithelial repair: Modulation of stem cell and transit amplifying cell proliferation.J Cell Sci. 1998; 111: 2867-2875Crossref PubMed Google Scholar). Similar repair strategies may be used by epidermis and other stratified squamous epithelia. Many other important basic questions about the properties of corneal epithelial stem cells have been studied intensively, including basement membrane heterogeneity (Kolega et al., 1989Kolega J. Manabe M. Sun T.T. Basement membrane heterogeneity and variation in corneal epithelial differentiation.Differentiation. 1989; 42: 54-63Crossref PubMed Scopus (85) Google Scholar;Ljubimov et al., 1995Ljubimov A.V. Burgeson R.E. Betkowski R.J. Michael A.F. Sun T-T. Kenney M.C. Human corneal basement membrane heterogeneity: Topographical differences in the expression of type IV collagen and laminin isoforms.Lab Invest. 1995; 72: 461-473PubMed Google Scholar), growth factor regulation (Kruse and Volcker, 1997Kruse F.E. Volcker H.E. Stem cells, wound healing, growth factors, and angiogenesis in the cornea.Curr Opin Ophthalmol. 1997; 8: 46-54Crossref PubMed Scopus (34) Google Scholar), differential growth modulation of the stem cells versus transit amplifying cells (Lavker et al., 1998Lavker R.M. Wei Z-G. Sun T-T. Phorbol ester preferentially stimulates mouse fornical conjunctival and limbal epithelial cells to proliferate in vivo.Invest Ophthalmol Vis Sci. 1998; 39: 101-107Google Scholar;Lehrer et al., 1998Lehrer M.S. Sun T-T. Lavker R.M. Strategies of epithelial repair: Modulation of stem cell and transit amplifying cell proliferation.J Cell Sci. 1998; 111: 2867-2875Crossref PubMed Google Scholar), and molecular regulation of the corneal epithelium-specific keratin genes (Figure 6;Wu et al., 1993Wu R.L. Galvin S. Wu S.K. Xu C. Blumenberg M. Sun T.T. A 300 bp 5′-upstream sequence of a differentiation-dependent rabbit K3 keratin gene can serve as a keratinocyte-specific promoter.J Cell Sci. 1993; 105: 303-316PubMed Google Scholar;Chen et al., 1997Chen T-T. Wu R.L. Castro-Munozledo F. Sun T-T. Regulation of K3 keratin gene transcription by Sp1 and AP-2 in differentiating rabbit corneal epithelial cells.Mol Cell Biol. 1997; 17: 3056-3064Crossref PubMed Scopus (104) Google Scholar). Impressive clinical advances have taken advantage of the limbal stem cell concept, including limbal stem cell transplantation and a new way of classifying the anterior ocular epithelial deficiencies and abnormalities (Holland and Schwartz, 1996Holland E. Schwartz G. The evolution of epithelial transplantation for severe ocular surface disease and a proposed classification system.Cornea. 1996; 15: 549-556Crossref PubMed Scopus (186) Google Scholar). In addition, in vitro and in vivo studies have demonstrated that corneal/limbal epithelium and conjunctival epithelium belong to two distinct lineages, thus refuting the classical concept of conjunctival transdifferentiation (Kruse et al., 1990Kruse F.E. Chen J.J.Y. Tsai R.J.F. Tseng S.C.G. Conjunctival transdifferentiation is due to the incomplete removal of limbal basal epithelium.Invest Ophthalmol Vis Sci. 1990; 31: 1903-1913PubMed Google Scholar;Chen et al., 1994Chen W.Y. Mui M.M. Kao W.W. Lui C.Y. Tseng S.C. Conjunctival epithelial cells do not transdifferentiate in organotypic cultures: Expression of K12 keratin is restricted to corneal epithelium.Curr Eye Res. 1994; 13: 765-768Crossref PubMed Scopus (116) Google Scholar;Moyer et al., 1996Moyer P.D. Kaufman A.H. Zhang Z. Kao C.W. Spaulding A.G. Kao W.W. Conjunctival epithelial cells can resurface denuded cornea, but do not transdifferentiate to express cornea-specific keratin 12 following removal of limbal epithelium in mouse.Differentiation. 1996; 60: 31-38Crossref PubMed Scopus (48) Google Scholar;Wei et al., 1996Wei Z.G. Sun T-T. Lavker R.M. Rabbit conjunctival and corneal epithelial cells belong to two separate lineages.Invest Ophthalmol Vis Sci. 1996; 37: 523-533PubMed Google Scholar). The corneal epithelial stem cell concept has enhanced our understanding of the biology, biochemistry, and diseases of anterior ocular epithelia. Many challenges still face epithelial stem cell biologists, however. For example, the generation of stem cell-specific surface markers will greatly facilitate the physical isolation and molecular characterization of stem cells. Some of the currently available markers for limbal stem cells, e.g., enolase (Zieske et al., 1992Zieske J.D. Bukusoglu G. Yankauckas M.A. Wasson M.E. Keutmann H.T. Alpha-enolase is restricted to basal cells of stratified squamous epithelium.Dev Biol. 1992; 151: 18-26Crossref PubMed Scopus (68) Google Scholar) and p63 (Pellegrini et al., 2001Pellegrini G. Dellambra E. Golisano O. et al.p63 identifies keratinocyte stem cells.Proc Natl Acad Sci USA. 2001; 98: 3156-3161Crossref PubMed Scopus (1124) Google Scholar) are expressed not only by limbal basal cells, but also by a majority of basal cells of various stratified squamous epithelia making them unlikely to be stem cell specific. Another important area is the characterization of the microenvironment that forms the stem cell niche. One of the first examples of biochemical heterogeneity between limbal and corneal epithelial basal cells was the K3 keratin data, which demonstrated the suprabasal expression of K3 keratin in the limbal zone, but uniform expression in corneal epithelium (Schermer et al., 1986Schermer A. Galvin S. Sun T-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells.J Cell Biol. 1986; 103: 49-62Crossref PubMed Scopus (1158) Google Scholar). Subsequently, other proteins including K12 keratin that forms a “keratin pair” with K3 keratin (Liu et al., 1993Liu C.Y. Zhu G. Westerhausen L.A. Converse R. Kao C.W. Sun T-T. Kao W.W. Cornea-specific expression of K12 keratin during mouse development.Curr Eye Res. 1993; 12: 963-974Crossref PubMed Scopus (103) Google Scholar;Wu et al., 1994Wu R.L. Chen T-T. Sun T-T. Functional importance of an Sp1- and an NFkB-related nuclear protein in a keratinocyte-specific promoter of rabbit K3 keratin gene.J Biol Chem. 1994; 269: 28450-28459Abstract Full Text PDF PubMed Google Scholar;Zhu et al., 1994Zhu G. Ishizaki M. Haseba T. Wu R.L. Sun T-T. Kao W.W. Expression of K12 kertin in alkali-burned rabbit corneas.Curr Eye Res. 1994; 11: 875-887Crossref Scopus (25) Google Scholar), isocitrate dehydrogenase (Sun et al., 1999Sun L. Sun T-T. Lavker R.M. Identification of a cytosolic NADP+-dependent isocitrate dehydrogenase that is preferentially expressed in bovine corneal epithelium: A corneal epithelial crystallin.J Biol Chem. 1999; 274: 17334-17341Crossref PubMed Scopus (56) Google Scholar) and calcium-linked epithelial differentiation protein (Sun et al., 2000Sun L. Sun T-T. Lavker R.M. CLED: A calcium-linked protein associated with early epithelial differentiation.Exp Cell Res. 2000; 259: 96-106Crossref PubMed Scopus (26) Google Scholar) also showed a similar limbal versus corneal epithelial expression pattern. This differential expression of proteins in the limbal versus corneal basal cells may be in part due to basement membrane heterogeneity. Using a monoclonal antibody AE27,Kolega et al., 1989Kolega J. Manabe M. Sun T.T. Basement membrane heterogeneity and variation in corneal epithelial differentiation.Differentiation. 1989; 42: 54-63Crossref PubMed Scopus (85) Google Scholar demonstrated strong staining of the corneal epithelial basement membrane zone and heterogenous staining of the limbal basement membrane zone. Interestingly, limbal basal cells in contact with those areas of the basement membrane that were strongly AE27 positive, expressed K3, whereas those cells resting on basement membrane that was AE27 negative or weak did not express K3 (Kolega et al., 1989Kolega J. Manabe M. Sun T.T. Basement membrane heterogeneity and variation in corneal epithelial differentiation.Differentiation. 1989; 42: 54-63Crossref PubMed Scopus (85) Google Scholar). This result strongly suggests basement membrane composition can influence K3 expression. Additional evidence for basement membrane heterogeneity was provided byLjubimov et al., 1995Ljubimov A.V. Burgeson R.E. Betkowski R.J. Michael A.F. Sun T-T. Kenney M.C. Human corneal basement membrane heterogeneity: Topographical differences in the expression of type IV collagen and laminin isoforms.Lab Invest. 1995; 72: 461-473PubMed Google Scholar who showed that laminin chains α-2 and β-2 were present in limbal basement membrane but not in central corneal basement membrane. More recently, tissue recombination studies have demonstrated that the K3-negative phenotype of the limbal basal cells is mediated through the limbal stroma/basement membrane (Espana et al., 2003Espana E.M. Di Pascuale M. Grueterich M. Solomon A. Tseng S.C.G. Keratolimbal allograft for corneal surface reconstruction.Eye. 2003; 18: 406-417Crossref Scopus (69) Google Scholar). Together, these data suggest that the regulation of the expression of many corneal differentiation-dependent genes may be influenced by (horizontal) basement membrane heterogeneity. Although such basement membrane heterogeneity undoubtedly contributes to the limbal and corneal epithelial phenotypes, many other mesenchymal signaling molecules are likely to be involved in maintaining the “stemness” of limbal stem cells. Some recent data suggest that amniotic membrane can support the replication of limbal stem cells and therefore provides an experimental stem cell niche (Grueterich et al., 2003Grueterich M. Espana E.M. Tseng S.C.G. Ex vivo expansion of limbal stem cells: Amniotic membrane serving as a stem cell niche.Surv Ophthalmol. 2003; 48: 631-646Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Further studies are needed to better understand the biochemical and cellular basis of this process." @default.
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• W2067077881 title "Corneal Epithelial Stem Cells: Past, Present, and Future" @default.
• W2067077881 cites W1588777732 @default.
• W2067077881 cites W1610415263 @default.
• W2067077881 cites W1964228231 @default.
• W2067077881 cites W1964273402 @default.
• W2067077881 cites W1968506175 @default.
• W2067077881 cites W1974536947 @default.
• W2067077881 cites W1975135735 @default.
• W2067077881 cites W1979066673 @default.
• W2067077881 cites W1979623069 @default.
• W2067077881 cites W1995201215 @default.
• W2067077881 cites W1997733450 @default.
• W2067077881 cites W2014888598 @default.
• W2067077881 cites W2016693266 @default.
• W2067077881 cites W2023020722 @default.
• W2067077881 cites W2023468388 @default.
• W2067077881 cites W2036607348 @default.
• W2067077881 cites W2037451360 @default.
• W2067077881 cites W2043541388 @default.
• W2067077881 cites W2049918761 @default.
• W2067077881 cites W2052530372 @default.
• W2067077881 cites W2057514048 @default.
• W2067077881 cites W2063639875 @default.
• W2067077881 cites W2068459844 @default.
• W2067077881 cites W2071110385 @default.
• W2067077881 cites W2073814456 @default.
• W2067077881 cites W2075024160 @default.
• W2067077881 cites W2092087562 @default.
• W2067077881 cites W2094008821 @default.
• W2067077881 cites W2096604029 @default.
• W2067077881 cites W2097375886 @default.
• W2067077881 cites W2102085111 @default.
• W2067077881 cites W2109382289 @default.
• W2067077881 cites W2112816709 @default.
• W2067077881 cites W2115975363 @default.
• W2067077881 cites W2118854821 @default.
• W2067077881 cites W2119226652 @default.
• W2067077881 cites W2120636006 @default.
• W2067077881 cites W2123744978 @default.
• W2067077881 cites W2126332265 @default.
• W2067077881 cites W2126917358 @default.
• W2067077881 cites W2128078747 @default.
• W2067077881 cites W2132984034 @default.
• W2067077881 cites W2135701285 @default.
• W2067077881 cites W2148459495 @default.
• W2067077881 cites W2150960871 @default.
• W2067077881 cites W2163674890 @default.
• W2067077881 cites W2165759868 @default.
• W2067077881 cites W2168211018 @default.
• W2067077881 cites W2182752233 @default.
• W2067077881 cites W4231479655 @default.
• W2067077881 cites W2129087492 @default.
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