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      Characterization and Prospective of Human Corneal Endothelial Progenitors

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          Abstract

          Corneal endothelial cells play a critical role in maintaining corneal transparency and dysfunction of these cells caused by aging, diseases (such as Fuch's dystrophy), injury or surgical trauma, which can lead to corneal edema and blindness. Due to their limited proliferative capacity in vivo, the only treatment method is via transplantation of a cadaver donor cornea. However, there is a severe global shortage of donor corneas. To circumvent such issues, tissue engineering of corneal tissue is a viable option thanks to the recent discoveries in this field. In this review, we summarize the recent advances in reprogramming adult human corneal endothelial cells into their progenitor status, the expansion methods and characteristics of human corneal endothelial progenitors, and their potential clinical applications as corneal endothelial cell grafts.

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          Most cited references81

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          Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.

          A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- mice. A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.
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            Generation of induced pluripotent stem cells using recombinant proteins.

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              The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus.

              The bmi-1 gene was first isolated as an oncogene that cooperates with c-myc in the generation of mouse lymphomas. We subsequently identified Bmi-1 as a transcriptional repressor belonging to the mouse Polycomb group. The Polycomb group comprises an important, conserved set of proteins that are required to maintain stable repression of specific target genes, such as homeobox-cluster genes, during development. In mice, the absence of bmi-1 expression results in neurological defects and severe proliferative defects in lymphoid cells, whereas bmi-1 overexpression induces lymphomas. Here we show that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence. In these fibroblasts and in bmi-1-deficient lymphocytes, the expression of the tumour suppressors p16 and p19Arf, which are encoded by ink4a, is raised markedly. Conversely, overexpression of bmi-1 allows fibroblast immortalization, downregulates expression of p16 and p19Arf and, in combination with H-ras, leads to neoplastic transformation. Removal of ink4a dramatically reduces the lymphoid and neurological defects seen in bmi-1-deficient mice, indicating that ink4a is a critical in vivo target for Bmi-1. Our results connect transcriptional repression by Polycomb-group proteins with cell-cycle control and senescence.
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                Author and article information

                Journal
                Int J Med Sci
                Int J Med Sci
                ijms
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                1449-1907
                2017
                30 June 2017
                : 14
                : 8
                : 705-710
                Affiliations
                [1 ]Department of Ophthalmology, Yan' An Hospital of Kunming City, Kunming, 650051, China;
                [2 ]Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China;
                [3 ]Shenzhen Eye Hospital, School of Optometry & Ophthalmology of Shenzhen University, Shenzhen Key Laboratory of Department of Ophthalmology, Shenzhen, 518000, China;
                [4 ]Department of Ophthalmology, the Second People's Hospital of Yunnan Province, Kunming, 650021, China;
                [5 ]Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173, USA.
                Author notes
                ✉ Corresponding authors: Ping Guo: Shenzhen Eye Hospital, Zetian Road 18, Room 421, Futian District, Shenzhen, 518000, China. Tel 08613924659029; Fax 08675523959500; Email: 2607212858@ 123456qq.com ; or Yingting Zhu, Ph.D. Research and Development Department, TissueTech, Inc., 7000 SW 97th Avenue, Suite 212, Miami, FL 33173. Telephone: (786) 456-7632; Fax: (305) 274-1297; E-mail: yzhu@ 123456tissuetechinc.com

                * The first three authors contributed equally to this manuscript.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijmsv14p0705
                10.7150/ijms.19018
                5562123
                2c0f765c-63f5-4f62-9802-1e12fde81de9
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 2 January 2017
                : 21 April 2017
                Categories
                Review

                Medicine
                cornea,endothelial,progenitors,tissue engineering.
                Medicine
                cornea, endothelial, progenitors, tissue engineering.

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