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Induced Pluripotent Stem Cells As a Potential Therapeutic Source for Corneal Epithelial Stem Cells

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Induced Pluripotent Stem Cells As a Potential Therapeutic Source for Corneal Epithelial Stem Cells iPSCs for corneal diseases ·Review· Induced pluripotent stem cells as a potential therapeutic source for corneal epithelial stem cells Jie Zhu1, Mark Slevin2,3, Bao-Qiang Guo2,3, Shou-Rong Zhu4 1Queen Mary School, Medical College of Nanchang Citation: Zhu J, Slevin M, Guo BQ, Zhu SR. Induced pluripotent University, Nanchang 330006, Jiangxi Province, China stem cells as a potential therapeutic source for corneal epithelial stem 2School of Healthcare Science, Faculty of Science and cells. Int J Ophthalmol 2018;11(12):2004-2010 Engineering, Manchester Metropolitan University, Chester Street, Manchester M15GD, United Kingdom INTRODUCTION 3Research Institute of Brain Vascular Disease, Weifang Medical luripotent stem cells are primitive cells that are able University, Weifang 261000, Shandong Province, China P to be self-renewing, proliferating indefinitely in their 4Department of Ophthalmology, Affiliated Hospital of Weifang undifferentiated state, and differentiate into different cell [1-2] Medical University, Weifang 261000, Shandong Province, types . They can efficiently differentiate into specific cell China types under defined conditions. Therefore, stem cells have Correspondence to: Bao-Qiang Guo. Research Institute of been regarded as unlimited source of cell transplantation. Brain Vascular Disease, Weifang Medical University, Weifang Over the last decade, stem or progenitor cells transplantation 261000, Shandong Province, China. [email protected]; as a means of replacing tissue have evolved rapidly. There are Shou-Rong Zhu. Department of Ophthalmology, Affiliated distinct kinds of stem cells according to their differentiation Hospital of Weifang Medical University, Weifang 261000, potential. It has already been found that embryonic stem cells Shandong Province, China. [email protected]. (ESCs) and mesenchymal stem cells (MSCs) can directly Received: 2018-08-21 Accepted: 2018-10-12 differentiate into specialized cells, which attracted considerable interest. However, the future use of these cells is still facing challenges, such as immune rejection and ethical debate for Abstract ESCs; the heterogeneity, difficulty of large scale harvest, ● Corneal blindness caused by limbal stem cell deficiency insufficient source, reduced differentiation capability (LSCD) is one of the most common debilitating eye after multiple generations for MSCs, which limit their disorders. Thus far, the most effective treatment for LSCD clinical application. is corneal transplantation, which is often hindered by The discovery of induced pluripotent stem cells (iPSCs) the shortage of donors. Pluripotent stem cell technology is considered as a breakthrough. In 2006, Takahashi and including embryonic stem cells (ESCs) and induced Yamanaka[3] reported that mouse fibroblasts could be induced pluripotent stem cells (iPSCs) have opened new avenues into ESC-like cells and named them “induced pluripotent for treating this disease. iPSCs-derived corneal epithelial stem cells”. iPSCs have self-renewing and multi-directional cells provide an autologous and unlimited source of cells differentiation potential, which are similar to ESCs. for the treatment of LSCD. On the other hand, iPSCs of Differentiated iPSCs generated from the same patient enable LSCD patients can be used for iPSCs-corneal disease their use in autologous transplantation to avoid immune model and new drug discovery. However, prior to clinical [4] rejection and ethical debate . Moreover cells or tissues for trial, the efficacy and safety of these cells in patients with generating iPSCs can be obtained simply and noninvasively. LSCD should be proved. Here we focused on the current Therefore, iPSCs have drawn particular attention to biological status of iPSCs-derived corneal epithelial cells used for scientists and clinicians[5]. cell therapy as well as for corneal disease modeling. Nowadays the work on iPSCs culture focus on the retinal and The challenges and potential of iPSCs-derived corneal retinal cells, which has been revealed a formerly underrated epithelial cells as a choice for clinical treatment in corneal level of intrinsic cellular self-renewing[6]. In recent years disease were also discussed. there has been considerable progress in the study of iPSCs ● KEYWORDS: induced pluripotent stem cells; corneal and corneal diseases. Here we will summarize the recent epithelial cells; limbal stem cell deficiency; disease modeling advancement in iPSCs-derived corneal epithelial cells DOI:10.18240/ijo.2018.12.21 technology and discuss its therapeutic potential for patients with limbal stem cell deficiency (LSCD). The review will also 2004 Int J Ophthalmol, Vol. 11, No. 12, Dec.18, 2018 www.ijo.cn Tel:8629-82245172 8629-82210956 Email:[email protected] highlight the limitations that need to deal with and plausible leading to the reduction or loss of LESCs to some extent and strategies for the application, the advantage of iPSCs-derived the destruction of barrier structures. That may cause corneal disease models to understand the pathophysiology of cornea hazing, corneal epithelium defect, or even blindness, which disorders, as well as the future of clinical trial for iPSCs as cell is clinically termed as LSCD[19-20]. Many disease can cause sources will also be discussed. LSCD, like chemical burn or traumatic injury, inherited corneal LIMBAL STEM CELLS AND CORNEAL EPITHELIAL dystrophy and numerous immune disorders, for example, CELLS Stevens-Johnson syndrome[20]. The development of ocular surface is a dynamic procedure. In Corneal stem epithelial cells are crucial for repair of corneal the next part of the article, we will discuss the development surface. They express different markers during the process of of ocular surface and particular markers, which make proliferation. It is widely believed that the corneal epithelial structures specific. The ocular surface is composed of corneal stem cells belong to unipotent somatic adult stem cells, and epithelium, conjunctival epithelium and tear film. The surface the stem cells are exclusively located in a particular limbal of the cornea is covered by corneal epithelial cells, which structure, which is defined as palisades of Vogt[21]. Limbal are crucial for maintaining normal eye function. Corneal epithelial basal layer lacks the expression of keratins CK3 and epithelial cells are derived from the epidermal layer of the CK12, the terminal differentiation marker of corneal epithelial embryo. When the human embryo is about 9 mm, the lens cells[22]. The study found that when the central corneal bubble differentiates completely from the ectoderm, and epithelium was damaged, the corneal limbus basal cells were then the corneal epithelium differentiates from the ectoderm more active than those in the central region of the epithelium. afterwards. With the continuous development of the embryo, The direction of the cell migration was from the cornea limbus the corneal epithelial cells gradually differentiate and form to the central. Hayashi et al[23] found that the corneal epithelial complete structure[7-8]. The morphology of normal corneal stem cells were gradually replaced by LESCs, which located epithelium is like paving stone. Under normal condition the at the base of the cornea limbus. Although it is hard for the morphological characteristics of corneal epithelium are stable. corneal epithelial stem cells to be classified and separated The dynamic balance of corneal epithelium is important for by just one particular marker, in recent years, ABCG2 and maintaining normal vision and the integrity of ocular surface. P63 (ΔNp63α isoform) has been found expressed in LESCs. Infection, injury or lack of limbus stem cells can lead to However, there is no expression of CK3 and CK12 in these corneal fibrosis[7]. Cell proliferation, morphological changes, cells[24-25]. P63 is a kind of nucleoprotein, which expressed in and the increased expression of mesenchymal markers of the the limbus in the basal layer of the cornea. The expression long-term culture corneal epithelial cells indicated epithelial of P63 in corneal limbic cells is regarded as a marker of to mesenchymal transition[9]. The shape of corneal epithelial proliferation ability for these cells[26]. cells was transformed from cubic into fusiform-like fibroblast. The treatment of LSCD includes drug and surgical therapy. At the same time the connection between epithelial cells Drug therapy such as artificial tear, bandage contact lens was lost[10]. Cytokeratin (CK) 3 and CK 12 were known as and autologous serum eye drop are only applied as adjuvant specific markers of corneal epithelial cells. It was found that therapy, which have been only used in very mild cases[27]. there was connexin 43 in the corneal epithelial cells, which Surgical therapy include amniotic membrane transplantation, could connect them[11]. When the corneal epithelial cells are autologous conjunctival limbal stem cell transplantation, in a transient state of proliferation, expression of connexin allogeneic limbal stem cell transplantation[28-31]. Now, stem 43 is negative[12-13]. CK4 and CK13 were markers of non- cell transplantation is the most optimal method in severe keratinized epithelium[14]. CK15 was the marker of corneal cases and in total LSCD to restore a healthy corneal surface. progenitor cell[15]. In general, connexin 43, CK3, CK12, CK4, Amniotic membrane transplantation, coupled with conjunctival CK13 and CK15 were considered as indicator of corneal epitheliectomy, could be a therapy in partial LSCD[32]. At differentiation[16-17].
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