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Laboratory Science JAMES V Laboratory Science JAMES V. J ESTER, PHD, SECTION EDITOR The Corneal Epithelial Stem Cell Niche MARY ANN STEPP, PHD1 AND JAMES D. ZIESKE, PHD2 ABSTRACT In recent years, it has become generally accepted thelium. Stem cells are most simply defined as cells that that the corneal epithelial stem cells are localized in the basal have the capacity to self-renew as well as the ability to gener- cell layer of the limbal epithelium. However, a number of ques- ate differentiated cells.2-6 When adult stem cells are consid- tions remain regarding the number, markers, generation, and ered, a further criterion is added requiring that the cells maintenance of the corneal epithelial stem cells. One of the must self-renew throughout the life span of the animal. key questions concerns what makes up the microenvironment Stem cell research has recently become one of the most or niche that is responsible for allowing the stem cells to re- active areas in biology research; however, to date, no mo- main and function throughout the life of the tissue. This review lecular markers have been recognized that definitively iden- will consider the unique aspects of the limbus and compare tify stem cells. Therefore, stem cells are usually defined by these to what is known about other stem cell niches. a group of common characteristics.2-6 First, stem cells are KEY WORDS corneal epithelium, limbal epithelium, the ultimate precursors for all other cells in a tissue or stem cell, niche, transient amplifying cell, α9 integrin, even in the entire organism. Second, stem cells maintain α-enolase, microenvironment their own population. They are capable of asymmetric cell division, giving rise to one daughter cell that remains a stem cell and a second daughter cell that will go on to I. INTRODUCTION: differentiate. Third, stem cells make up only a small per- WHAT IS A STEM CELL? centage of the total cells in the tissue, ranging from as low lthough it had been speculated for a number of as 0.01% of the cells in bone marrow to 2-4% of the cells years that corneal epithelial cells are repopulated in the small intestine. Fourth, stem cells are relatively un- A by centripetal migration of cells from the limbus differentiated. Fifth, stem cells divide infrequently in vivo, or conjunctiva, it was not until 1986 that Schermer et al1 Sixth, stem cells have progeny that can rapidly replicate in proposed that stem cells localized in the limbus were re- vitro when placed into cell culture. Many recent defini- sponsible for generating and maintaining the corneal epi- tions of stem cells also require that the cells must be multipotent, i.e., they can differentiate into more than one cell type. These definitions state that cells that give rise to Accepted for publication November 2004 only one cell type are termed progenitor cells. According to From the 1Department of Anatomy and Cell Biology, George Washington this strict definition, corneal epithelial stem cells, which University Medical Center, Washington, DC, USA, and 2Schepens Eye Re- search Institute and Department of Ophthalmology, Harvard Medical School, have been reported to give rise only to corneal epithelial Boston, MA, USA cells, would be termed progenitor cells. However, we will Supported by NIH/NEI Grant No. R01 EY13559-03 to MAS and R01 use the less restrictive definition in this review and refer to EY05665 to JDZ. the corneal epithelial precursor cells as stem cells. The authors have no proprietary interest in any concept or product dis- A second classification of cells to be defined are the cussed in this article. progeny of non-stem daughter cells that result from the Single copy reprint requests to Mary Ann Stepp, PhD (address below). asymmetric cell division of a stem cell. These cells are more Corresponding authors: Mary Ann Stepp, PhD, Department of Anatomy committed to differentiation than the stem cell and also and Cell Biology, George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037; Tel: 202-994-0557; Fax 202-994-8885; have a more limited ability to proliferate. They have a range E-mail: [email protected]; and, James D. Zieske, PhD, Schepens Eye Re- of proliferative capacities. The cell that is the immediate search Institute, 20 Staniford Street, Boston, MA 02114; Tel: 617-912-0282; progeny of stem cell division can undergo more rounds of Fax 617-912-0107; E-mail: [email protected] proliferation than the cell that arises after several cell divi- Abbreviations are printed in boldface where they first appear with their sions. Regardless, the primary purpose of these cells is to definitions and are listed in Table 1. increase the number of cells resulting from each stem cell division ultimately resulting in a tissue. These cells have ©2005 Ethis Communications, Inc. The Ocular Surface ISSN: 1542- 0124. Stepp MA, Zieske JD. The corneal epithelial stem cell niche. been traditionally referred to as transient amplifying cell 2005;3(1):15-26. (TAC).1 TACs are also sometimes termed transit cells4 and transit amplifying cells.3 THE OCULAR SURFACE / JANUARY 2005, VOL. 3, NO. 1 / www.theocularsurface.com 15 THE CORNEAL EPITHELIAL STEM CELL NICHE / Stepp and Zieske OUTLINE Table 1. Abbreviations I. Introduction: What is a stem cell? BMP bone morphogenetic protein II. Evidence for the limbal localization of corneal epithelial stem cells CESC corneal epithelial stem cell III. The adult stem cell niche Dpp Decapentaplegic A. The germinal niche of the fly: Role of cell:cell EGF epidermal growth factor contact via cadherins B. Stem cell niches in non-ocular human tissues ESC epidermal stem cell 1. The epidermal stem cell niche: the bulge FGF fibroblast growth factor 2. The gastrointestinal niche: the crypt base GFAP glial fibrillary acidic protein 3. The germinal niche in the adult brain: the subventricular zone and the subgranular zone GISC gastrointestinal stem cell 4. The hematopoietic stem cell niche: the role of GSC germ line stem cell the osteoblast HSC hematopoietic stem cell C. The limbal stem cell niche: a unique microenvironment supporting quiescent corneal IGF insulin-like growth factor epithelial stem cells ISEMF intestinal subepithelial myofibroblast LSC limbal stem cell II. EVIDENCE FOR THE LIMBAL LOCALIZATION LSCD limbal stem cell deficiency OF CORNEAL EPITHELIAL STEM CELLS mRNA messenger RNA Over the past 20 years, research from many laboratories has led to the conclusion that the corneal epithelial stem cells NSC neuronal stem cell are localized in the limbus.7-12 These cells have been termed SGZ subgranular zone both corneal epithelial stem cells (CESC), based on their func- SVZ subventricular zone tion, and limbal stem cells (LSC), based on their localization. We will use the term CESC in this review. TAC transient amplifying cell The first suggestion that the limbus is the source of CESC TGF transforming growth factor was made in 1971 by Davenger and Evensen,13 who showed that, occasionally, pigmented cells were observed to migrate Tn-C Tenacin-C from the limbus into the central cornea. It should be noted, VEGF vascular endothelial growth factor however, that the term stem cell is never used in their report. Centripetal migration of cells from the limbus to central cor- nea has subsequently been documented in animal models.14,15 Schermer et al,1 who demonstrated that the keratin K3 was an expression pattern similar to that of K3. In contrast, sev- localized in all corneal and limbal epithelial cells except the eral proteins are expressed preferentially in the limbal basal limbal basal cells, presented a second line of evidence that cells. These proteins have been scrutinized for their potential the stem cells are localized in the limbus. Coupled with cell for being CESC markers. Included in this group of potential culture studies, Schermer’s report documented that the limbal markers are: 1) metabolic enzymes—α-enolase,26,27 cyto- basal cells were less differentiated than the other corneal epi- chrome oxidase,28 carbonic anhydrase,29 and glucose trans- thelial cells. This report was the first to speculate that the porter I30; 2) growth factor receptors—epithelial growth fac- CESC were localized in the limbus. A third line of evidence is tor receptor,31 TGF-β receptors I and II,32,33 and TrkA34; 3) that limbal basal cells proliferate less frequently than the rest cytoskeleton components—keratin 1935 and vimentin36; 4) of the corneal epithelium. Lavker and coworkers16 demon- cell cycle components—cyclins D and E,37 and p10738; and strated this property by injecting mice with 3H-thymidine 5) others—α9 integrin,39 melanin,40 p63,41 and ATP-bind- and finding that only limbal basal cells retained the label. ing cassette transporter G2.12,42 Fourth, only limbal basal cells are clonogenic in cell culture Most of the proteins considered as potential markers experiments.17-19 Finally, perhaps the strongest evidence, are expressed in numerous basal cells at the limbus; an studies have shown that transplantation of limbal tissue or example is seen in Figure 1, which shows the co-localiza- even cultured limbal basal cells can result in healing of cor- tion of α-enolase and α9-integrin in the adult rat limbus. neal epithelium.20-22 The distribution of these two proteins is partially overlap- As stated above, one piece of evidence that the CESC are ping with some limbal basal cells that express both pro- localized in the limbus is the lack of expression of the differ- teins and others that express more or less of one or the entiation marker K3 in these cells.1 Subsequent to this find- other. This distribution emphasizes the heterogeneity of ing, other proteins, including K12,23 aldehyde dehydroge- cellular phenotypes present at the limbus and is some- nase class 3,24 and connexin-4325 have been shown to have what at odds with the findings that only a small popula- 16 THE OCULAR SURFACE / JANUARY 2005, VOL.
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