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      Profile of biological characterizations and clinical application of corneal stem/progenitor cells

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          Abstract

          Corneal stem/progenitor cells are typical adult stem/progenitor cells. The human cornea covers the front of the eyeball, which protects the eye from the outside environment while allowing vision. The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role. Corneal stem/progenitor cells include mainly corneal epithelial stem cells, corneal endothelial cell progenitors and corneal stromal stem cells. Since the discovery of corneal epithelial stem cells (also known as limbal stem cells) in 1971, an increasing number of markers for corneal stem/progenitor cells have been proposed, but there is no consensus regarding the definitive markers for them. Therefore, the identification, isolation and cultivation of these cells remain challenging without a unified approach. In this review, we systematically introduce the profile of biological characterizations, such as anatomy, characteristics, isolation, cultivation and molecular markers, and clinical applications of the three categories of corneal stem/progenitor cells.

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          Most cited references204

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          Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

          Kazutoshi Takahashi, Shinya Yamanaka (2006)
          Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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            Induction of pluripotent stem cells from adult human fibroblasts by defined factors.

            Kazutoshi Takahashi, Koji TANABE, Mari Ohnuki … (2007)
            Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.
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              Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells

              TT Sun, J. A. Schermer, S Galvin (1986)
              In this paper we present keratin expression data that lend strong support to a model of corneal epithelial maturation in which the stem cells are located in the limbus, the transitional zone between cornea and conjunctiva. Using a new monoclonal antibody, AE5, which is highly specific for a 64,000-mol-wt corneal keratin, designated RK3, we demonstrate that this keratin is localized in all cell layers of rabbit corneal epithelium, but only in the suprabasal layers of the limbal epithelium. Analysis of cultured corneal keratinocytes showed that they express sequentially three major keratin pairs. Early cultures consisting of a monolayer of "basal" cells express mainly the 50/58K keratins, exponentially growing cells synthesize additional 48/56K keratins, and postconfluent, heavily stratified cultures begin to express the 55/64K corneal keratins. Cell separation experiments showed that basal cells isolated from postconfluent cultures contain predominantly the 50/58K pair, whereas suprabasal cells contain additional 55/64K and 48/56K pairs. Basal cells of the older, postconfluent cultures, however, can become AE5 positive, indicating that suprabasal location is not a prerequisite for the expression of the 64K keratin. Taken together, these results suggest that the acidic 55K and basic 64K keratins represent markers for an advanced stage of corneal epithelial differentiation. The fact that epithelial basal cells of central cornea but not those of the limbus possess the 64K keratin therefore indicates that corneal basal cells are in a more differentiated state than limbal basal cells. These findings, coupled with the known centripetal migration of corneal epithelial cells, strongly suggest that corneal epithelial stem cells are located in the limbus, and that corneal basal cells correspond to "transient amplifying cells" in the scheme of "stem cells----transient amplifying cells----terminally differentiated cells."
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                Author and article information

                Contributors
                Pei-Xi Ying
                Min Fu
                Chang Huang
                Zhi-Hong Li
                Qing-Yi Mao
                Sheng Fu
                Xu-Hui Jia
                Yu-Chen Cao
                Li-Bing Hong
                Li-Yang Cai
                Xi Guo
                Ru-Bing Liu
                Fan-ke Meng
                Guo-Guo Yi
                Journal
                Journal ID (nlm-ta): World J Stem Cells
                Journal ID (publisher-id): WJSC
                Title: World Journal of Stem Cells
                Publisher: Baishideng Publishing Group Inc
                ISSN (Electronic): 1948-0210
                Publication date (Print): 26 November 2022
                Publication date (Electronic): 26 November 2022
                Volume: 14
                Issue: 11
                Pages: 777-797
                Affiliations
                Department of Ophthalmology, Zhujiang Hospital, The Second Clinical School, Southern Medical University, Guangzhou 510280, Guangdong Province, China
                Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
                Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200030, China
                NHC Key Laboratory of Myopia, Fudan University, Shanghai 200030, China
                Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200030, China
                Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Shock and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510550, Guangdong Province, China
                The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
                Hengyang Medical School, The University of South China, Hengyang 421001, Hunan Province, China
                The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
                The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
                The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
                The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
                Medical College of Rehabilitation, Southern Medical University, Guangzhou 510515, Guangdong Province, China
                The Second Clinical School, Southern Medical University, Guangzhou 510515, Guangdong Province, China
                Emergency Department, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
                Department of Ophthalmology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China. yigg@ 123456mail.sysu.edu.cn
                Author notes

                Author contributions: Ying PX, Mao QY, Huang C, Fu M, and Yi GG designed the research study; Jia XH, Cao YC, Hong LB, Cai LY, Guo X, Liu RB, Meng FK, Fu M, and Yi GG provided help and advice; Ying PX, Fu M, Mao QY, Huang C, Li ZH, and Fu S wrote the manuscript; all authors have read and approved the final manuscript.

                Corresponding author: Guo-Guo Yi, MMed, Attending Doctor, Department of Ophthalmology, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Guangzhou 510655, Guangdong Province, China. yigg@ 123456mail.sysu.edu.cn

                Article
                Other ID: jWJSC.v14.i11.pg777
                DOI: 10.4252/wjsc.v14.i11.777
                PMC ID: 9724387
                SO-VID: 6b9e1cee-97d0-4d63-b4e6-491b2fd35dfc
                Copyright © ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
                License:

                This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                Date received : 21 August 2022
                Date revision received : 8 November 2022
                Date accepted : 23 November 2022
                Categories
                Subject: Review

                Keywords: corneal epithelial stem cells,corneal endothelium stem cells,corneal stromal stem cells,bioengineering,gene markers
                Data availability:
                Keywords: corneal epithelial stem cells, corneal endothelium stem cells, corneal stromal stem cells, bioengineering, gene markers

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