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The Modulation of Stem and Progenitor Cells in Retinal and Ocular Biology

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 13509

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Special Issue Editor

Prof. Dr. Volker Enzmann

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Guest Editor

Dept. of Ophthalmology, University of Bern, Bern, Switzerland
Interests: Müller cells, Stem cells, Retinal degeneration, Retinal regeneration, AMD

Special Issue Information

Dear Colleagues,

Vision is one of the most valuable senses in humans and diseases of ocular structures affect the life of millions of people worldwide. Potential treatments for such devastating events have been widely investigated. However, an effective treatment has not been found, especially for advanced stages of degenerative diseases. Therefore, cell-based therapy is being pursued as a potential alternative. In this regard, modulation of the biology of ocular stem and progenitor cells is a pivotal step to understand and employ its potential for new therapeutic approaches. In the center of investigations are neural stem as well as Müller cells, which behave as progenitor cells upon injury in some vertebrates. Additionally, limbal stem cells represent a source for corneal renewal and repair. Nevertheless, the implementation of other concepts, exogenous as well as endogenous, are also accepted. In this special issue, we will focus on experimental stem cell-based therapeutical approaches and summarize progress in treatment of retinal degenerative disease. Thereby, the physiological and pathophysiological basics behind the visual system will be covered, as will the hurdles towards a successful transition in the clinic.

Prof. Dr. Volker Enzmann
Guest Editor

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Keywords

ocular biology

retinal degeneration

regeneration

stem cells

progenitor cells

müller cells

Published Papers (5 papers)

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Research

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22 pages, 6010 KiB

Open AccessArticle

ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation

by Berbang Meshko, Thomas L. A. Volatier, Karina Hadrian, Shuya Deng, Yanhong Hou, Mark Andreas Kluth, Christoph Ganss, Markus H. Frank, Natasha Y. Frank, Bruce Ksander, Claus Cursiefen and Maria Notara

Cells 2023, 12(13), 1731; https://doi.org/10.3390/cells12131731 - 27 Jun 2023

Cited by 1 | Viewed by 1506

Abstract

The limbus, the vascularized junction between the cornea and conjunctiva, is thought to function as a barrier against corneal neovascularization. However, the exact mechanisms regulating this remain unknown. In this study, the limbal epithelial stem cell (LESC) marker ABCB5 was used to investigate the role of LESCs in corneal neovascularization. In an ABCB5KO model, a mild but significant increase of limbal lymphatic and blood vascular network complexity was observed in developing mice (4 weeks) but not in adult mice. Conversely, when using a cornea suture model, the WT animals exhibited a mild but significant increase in the number of lymphatic vessel sprouts compared to the ABCB5KO, suggesting a contextual anti-lymphangiogenic effect of ABCB5 on the limbal vasculature during development, but a pro-lymphangiogenic effect under inflammatory challenge in adulthood. In addition, conditioned media from ABCB5-positive cultured human limbal epithelial cells (ABCB5+) stimulated human blood and lymphatic endothelial cell proliferation and migration. Finally, a proteomic analysis demonstrated ABCB5+ cells have a pro(lymph)angiogenic as well as an anti-inflammatory profile. These data suggest a novel dual, context-dependent role of ABCB5+ LESCs, inhibiting developmental but promoting inflammatory (lymph)angiogenesis in adulthood and exerting anti-inflammatory effects. These findings are of high clinical relevance in relation to LESC therapy against blindness. Full article

(This article belongs to the Special Issue The Modulation of Stem and Progenitor Cells in Retinal and Ocular Biology)

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18 pages, 4537 KiB

Open AccessArticle

Recognizing the Differentiation Degree of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cells Using Machine Learning and Deep Learning-Based Approaches

by Chung-Yueh Lien, Tseng-Tse Chen, En-Tung Tsai, Yu-Jer Hsiao, Ni Lee, Chong-En Gao, Yi-Ping Yang, Shih-Jen Chen, Aliaksandr A. Yarmishyn, De-Kuang Hwang, Shih-Jie Chou, Woei-Chyn Chu, Shih-Hwa Chiou and Yueh Chien

Cells 2023, 12(2), 211; https://doi.org/10.3390/cells12020211 - 4 Jan 2023

Cited by 5 | Viewed by 3318

Abstract

Induced pluripotent stem cells (iPSCs) can be differentiated into mesenchymal stem cells (iPSC-MSCs), retinal ganglion cells (iPSC-RGCs), and retinal pigmental epithelium cells (iPSC-RPEs) to meet the demand of regeneration medicine. Since the production of iPSCs and iPSC-derived cell lineages generally requires massive and time-consuming laboratory work, artificial intelligence (AI)-assisted approach that can facilitate the cell classification and recognize the cell differentiation degree is of critical demand. In this study, we propose the multi-slice tensor model, a modified convolutional neural network (CNN) designed to classify iPSC-derived cells and evaluate the differentiation efficiency of iPSC-RPEs. We removed the fully connected layers and projected the features using principle component analysis (PCA), and subsequently classified iPSC-RPEs according to various differentiation degree. With the assistance of the support vector machine (SVM), this model further showed capabilities to classify iPSCs, iPSC-MSCs, iPSC-RPEs, and iPSC-RGCs with an accuracy of 97.8%. In addition, the proposed model accurately recognized the differentiation of iPSC-RPEs and showed the potential to identify the candidate cells with ideal features and simultaneously exclude cells with immature/abnormal phenotypes. This rapid screening/classification system may facilitate the translation of iPSC-based technologies into clinical uses, such as cell transplantation therapy. Full article

(This article belongs to the Special Issue The Modulation of Stem and Progenitor Cells in Retinal and Ocular Biology)

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17 pages, 28469 KiB

Open AccessArticle

P-Cadherin Is Expressed by Epithelial Progenitor Cells and Melanocytes in the Human Corneal Limbus

by Naresh Polisetti, Lyne Sharaf, Gottfried Martin, Günther Schlunck and Thomas Reinhard

Cells 2022, 11(12), 1975; https://doi.org/10.3390/cells11121975 - 20 Jun 2022

Cited by 8 | Viewed by 2541

Abstract

Interactions between limbal epithelial progenitor cells (LEPC) and surrounding niche cells, which include limbal mesenchymal stromal cells (LMSC) and melanocytes (LM), are essential for the maintenance of the limbal stem cell niche required for a transparent corneal surface. P-cadherin (P-cad) is a critical stem cell niche adhesion molecule at various epithelial stem cell niches; however, conflicting observations were reported on the presence of P-cad in the limbal region. To explore this issue, we assessed the location and phenotype of P-cad⁺ cells by confocal microscopy of human corneoscleral tissue. In subsequent fluorescence-activated cell sorting (FACS) experiments, we used antibodies against P-cad along with CD90 and CD117 for the enrichment of LEPC, LMSC and LM, respectively. The sorted cells were characterized by immunophenotyping and the repopulation of decellularized limbal scaffolds was evaluated. Our findings demonstrate that P-cad is expressed by epithelial progenitor cells as well as melanocytes in the human limbal epithelial stem cell niche. The modified flow sorting addressing P-cad as well as CD90 and CD117 yielded enriched LEPC (CD90⁻CD117⁻P-cad⁺) and pure populations of LMSC (CD90⁺CD117⁻P-cad⁻) and LM (CD90⁻CD117⁺P-cad⁺). The enriched LEPC showed the expression of epithelial progenitor markers and better colony-forming ability than their P-cad⁻ counterparts. The cultured LEPC and LM exhibited P-cad expression at intercellular junctions and successfully repopulated decellularized limbal scaffolds. These data suggest that P-cad is a critical cell–cell adhesion molecule, connecting LEPC and LM, which may play an important role in the long-term maintenance of LEPC at the limbal stem cell niche; moreover, these findings led to further improvement of cell enrichment protocols to enhance the yield of LEPC. Full article

(This article belongs to the Special Issue The Modulation of Stem and Progenitor Cells in Retinal and Ocular Biology)

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17 pages, 8517 KiB

Open AccessArticle

CRISPR/Cas9-Mediated Models of Retinitis Pigmentosa Reveal Differential Proliferative Response of Müller Cells between Xenopus laevis and Xenopus tropicalis

by Karine Parain, Sophie Lourdel, Alicia Donval, Albert Chesneau, Caroline Borday, Odile Bronchain, Morgane Locker and Muriel Perron

Cells 2022, 11(5), 807; https://doi.org/10.3390/cells11050807 - 25 Feb 2022

Cited by 9 | Viewed by 2682

Abstract

Retinitis pigmentosa is an inherited retinal dystrophy that ultimately leads to blindness due to the progressive degeneration of rod photoreceptors and the subsequent non-cell autonomous death of cones. Rhodopsin is the most frequently mutated gene in this disease. We here developed rhodopsin gene editing-based models of retinitis pigmentosa in two Xenopus species, Xenopus laevis and Xenopus tropicalis, by using CRISPR/Cas9 technology. In both of them, loss of rhodopsin function results in massive rod cell degeneration characterized by progressive shortening of outer segments and occasional cell death. This is followed by cone morphology deterioration. Despite these apparently similar degenerative environments, we found that Müller glial cells behave differently in Xenopus laevis and Xenopus tropicalis. While a significant proportion of Müller cells re-enter into the cell cycle in Xenopus laevis, their proliferation remains extremely limited in Xenopus tropicalis. This work thus reveals divergent responses to retinal injury in closely related species. These models should help in the future to deepen our understanding of the mechanisms that have shaped regeneration during evolution, with tremendous differences across vertebrates. Full article

(This article belongs to the Special Issue The Modulation of Stem and Progenitor Cells in Retinal and Ocular Biology)

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Review

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26 pages, 1575 KiB

Open AccessReview

Therapeutic Strategies for Restoring Perturbed Corneal Epithelial Homeostasis in Limbal Stem Cell Deficiency: Current Trends and Future Directions

by Faisal Masood, Jin-Hong Chang, Anosh Akbar, Amy Song, Wen-Yang Hu, Dimitri T. Azar and Mark I. Rosenblatt

Cells 2022, 11(20), 3247; https://doi.org/10.3390/cells11203247 - 16 Oct 2022

Cited by 9 | Viewed by 2598

Abstract

Limbal stem cells constitute an important cell population required for regeneration of the corneal epithelium. If insults to limbal stem cells or their niche are sufficiently severe, a disease known as limbal stem cell deficiency occurs. In the absence of functioning limbal stem cells, vision-compromising conjunctivalization of the corneal epithelium occurs, leading to opacification, inflammation, neovascularization, and chronic scarring. Limbal stem cell transplantation is the standard treatment for unilateral cases of limbal stem cell deficiency, but bilateral cases require the use of cultured non-limbal autologous stem cell or allogeneic limbal stem cell transplantation. Herein we review the current therapeutic utilization of limbal stem cells. We also describe several limbal stem cell markers that impact their phenotype and function and discuss the possibility of modulating limbal stem cells and other sources of stem cells to facilitate the development of novel therapeutic interventions. We finally consider several hurdles for widespread adoption of these proposed methodologies and discuss how they can be overcome to realize vision-restoring interventions. Full article

(This article belongs to the Special Issue The Modulation of Stem and Progenitor Cells in Retinal and Ocular Biology)

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