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Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery

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

Deadline for manuscript submissions: closed (5 July 2023) | Viewed by 33231

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Special Issue Editors

Prof. Dr. Heli Skottman

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Guest Editor

Eye Regeneration Group, Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere University, 33520 Tampere, Finland
Interests: novel human stem cell-based tools for the retinal and corneal regeneration through cell transplantation and ophthalmic in vitro cell and 3D tissue models for disease modeling and therapy development

Prof. Dr. Sayan Basu

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Guest Editor

Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India
Interests: ocular surface and dry eye disease; scarless corneal wound healing and stem cell therapy and animal models of disease

Special Issue Information

Dear Colleagues,

The eyes are sensory organs endowed with unique features in terms of both structure and function. It is easily accessible and visualized, which is useful both for in vivo diagnostics and topical therapy. It consists of various types of cellular lineages that are embryologically of ectodermal, mesodermal, and endodermal origins. Dysfunction of these different elements, which are crucial to the eye’s structure and function, commonly results in vision-related problems and can even cause blindness. However, these unique features of the eye make it ideally suited for supporting various emerging techniques such as cell therapy, tissue engineering, and gene therapy.

We are pleased to invite all basic and clinic researchers to contribute to our Special Issue on ‘Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery’. In this Special Issue, we propose presenting the most recent updates on research in regenerative ophthalmology and drug discovery, which are at the cusp of clinical translation, starting from the front to the back of the eye. Different cell therapies involving, e.g., limbal, corneal, endothelial and stromal, and conjunctival stem cells have emerged for ocular surface restoration and corneal endothelial disorders. Lacrimal gland regeneration and trabecular meshwork stem cells are evolving technologies for treating dry eye disease and glaucoma, respectively. The retinal tissue of neural origin raised the need to explore newer modalities of therapy such as cells derived from pluripotent stem cells and gene therapy for inherited retinal disorders. The use of biosynthetic corneas, artificial corneal implants, and the development of the bionic eye with artificial intelligence has offered enticing avenues for eyes afflicted with blinding diseases. This Special Issue will summarize the most exciting new therapeutic approaches that could revolutionize the treatment of vision impairment and blindness through disruptive and innovative scientific breakthroughs.

In this Special Issue, both original research articles and reviews are welcome. Research areas may include but are not limited to stem cell-based therapies, novel drug therapies, ocular organoids and gene editing, and related therapeutics. We look forward to receiving your contributions.

Prof. Dr. Heli Skottman
Prof. Dr. Sayan Basu
Guest Editors

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Keywords

ocular regenerative therapy
stem cells, pluripotent stem cells
retinal pigment epithelium
neural retina
cornea
limbal epithelial stem cells
stem cell transplant
gene therapy
drug discovery

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Published Papers (9 papers)

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Research

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20 pages, 2722 KiB

Open AccessArticle

Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells

by Gary S. L. Peh, Francisco Bandeira, Dawn Neo, Khadijah Adnan, Yossa Hartono, Hon Shing Ong, Sacha Naso, Anandalakshmi Venkatraman, José A. P. Gomes, Viridiana Kocaba and Jodhbir S. Mehta

Cells 2023, 12(9), 1307; https://doi.org/10.3390/cells12091307 - 3 May 2023

Cited by 5 | Viewed by 2997

Abstract

(1) Rho-associated coiled-coil protein kinase (ROCK) signaling cascade impacts a wide array of cellular events. For cellular therapeutics, scalable expansion of primary human corneal endothelial cells (CECs) is crucial, and the inhibition of ROCK signaling using a well characterized ROCK inhibitor (ROCKi) Y-27632 had been shown to enhance overall endothelial cell yield. (2) In this study, we compared several classes of ROCK inhibitors to both ROCK-I and ROCK-II, using in silico binding simulation. We then evaluated nine ROCK inhibitors for their effects on primary CECs, before narrowing it down to the two most efficacious compounds—AR-13324 (Netarsudil) and its active metabolite, AR-13503—and assessed their impact on cellular proliferation in vitro. Finally, we evaluated the use of AR-13324 on the regenerative capacity of donor cornea with an ex vivo corneal wound closure model. Donor-matched control groups supplemented with Y-27632 were used for comparative analyses. (3) Our in silico simulation revealed that most of the compounds had stronger binding strength than Y-27632. Most of the nine ROCK inhibitors assessed worked within the concentrations of between 100 nM to 30 µM, with comparable adherence to that of Y-27632. Of note, both AR-13324 and AR-13503 showed better cellular adherence when compared to Y-27632. Similarly, the proliferation rates of CECs exposed to AR-13324 were comparable to those of Y-27632. Interestingly, CECs expanded in a medium supplemented with AR-13503 were significantly more proliferative in (i) untreated vs. AR-13503 (1 μM; * p < 0.05); (ii) untreated vs. AR-13503 (10 μM; *** p < 0.001); (iii) Y-27632 vs. AR-13503 (10 μM; ** p < 0.005); (iv) AR-13324 (1 μM) vs. AR-13503 (10 μM; ** p < 0.005); and (v) AR-13324 (0.1 μM) vs. AR-13503 (10 μM; * p < 0.05). Lastly, an ex vivo corneal wound healing study showed a comparable wound healing rate for the final healed area in corneas exposed to Y-27632 or AR-13324. (4) In conclusion, we were able to demonstrate that various classes of ROCKi compounds other than Y-27632 were able to exert positive effects on primary CECs, and systematic donor-match controlled comparisons revealed that the FDA-approved ROCK inhibitor, AR-13324, is a potential candidate for cellular therapeutics or as an adjunct drug in regenerative treatment for corneal endothelial diseases in humans. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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21 pages, 3881 KiB

Open AccessArticle

Pre-Clinical Evaluation of Efficacy and Safety of Human Limbus-Derived Stromal/Mesenchymal Stem Cells with and without Alginate Encapsulation for Future Clinical Applications

by Mukesh Damala, Abhishek Sahoo, Naveen Pakalapati, Vivek Singh and Sayan Basu

Cells 2023, 12(6), 876; https://doi.org/10.3390/cells12060876 - 11 Mar 2023

Cited by 4 | Viewed by 2849

Abstract

Corneal opacification or scarring is one of the leading causes of blindness worldwide. Human limbus-derived stromal/mesenchymal stem cells (hLMSCs) have the potential of clearing corneal scarring. In the current preclinical studies, we aimed to determine their ability to heal the scarred corneas, in a murine model of corneal scar, and examined their ocular and systemic toxicity after topical administration to rabbit eyes. The hLMSCs were derived from human donor corneas and were cultivated in a clean room facility in compliance with the current good manufacturing practices (cGMP). Before the administration, the hLMSCs were analyzed for their characteristic properties including immunostaining, and were further subjected to sterility and stability analysis. The corneas (right eye) of C57BL/6 mice (n = 56) were stripped of their central epithelium and superficial anterior stroma using a rotary burr (Alger Brush^® II). Few mice were left untreated (n = 8), while few (n = 24) were treated immediately with hLMSCs after debridement (prophylaxis group). The rest (n = 24, scar group) were allowed to develop corneal scarring for 2 weeks and then treated with hLMSCs. In both groups, the treatment modalities included encapsulated (En+) and non-encapsulated (En−) hLMSCs and sham (vehicle) treatment. The follow-up (4 weeks) after the treatment or debridement included clinical photography, fluorescein staining, and optical coherence tomography at regular intervals. All the images and scans were analyzed using ImageJ software to assess the changes in corneal haze, scar area, and the reflectivity ratio of the epithelium to the stroma. The scar area and the scar intensity were found to be decreased in the groups that received hLMSCs. The reflectivity of the stroma was found to be normalized to the baseline levels before the debridement in the eyes that were treated with hLMSCs, relative to the untreated. In the safety study, the central corneas of the left eye of 18 New Zealand rabbits were scraped with a needle and then treated with En+ hLMSCs, En− hLMSCs, and the sham (n = 6 each). Rabbits were then followed up for 4 weeks, during which blood and tear samples were collected at regular intervals. These rabbits were then assessed for changes in the quantities of inflammatory markers (TNF-α, IL-6, and IgE) in the sera and tears, changes in the ocular surface observations such as intraocular pressure (IOP), and the hematological and clinical chemistry parameters. Four weeks later, the rabbits were euthanized and examined histopathologically. No significant changes in conjunctival congestion, corneal clarity, or IOP were noticed during the ophthalmic examination. The level of inflammatory molecules (TNF-α and IL-6 TNF-α) and the hematological parameters were similar in all groups without any significant changes. Histological examination of the internal organs and ocular tissues did not reveal any abnormalities. The results of these studies summarize that the En+ and En− hLMSCs are not harmful to the recipient and potentially restore the transparency of debrided or scarred corneas, indicating that hLMSCs can be assessed for clinical use in humans. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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18 pages, 3023 KiB

Open AccessArticle

A Novel Technique of Amniotic Membrane Preparation Mimicking Limbal Epithelial Crypts Enhances the Number of Progenitor Cells upon Expansion

by Jovana Bisevac, Morten Carstens Moe, Liv Drolsum, Olav Kristianslund, Goran Petrovski and Agate Noer

Cells 2023, 12(5), 738; https://doi.org/10.3390/cells12050738 - 24 Feb 2023

Cited by 2 | Viewed by 1635

Abstract

We aimed to investigate whether a novel technique of human amniotic membrane (HAM) preparation that mimics the crypts in the limbus enhances the number of progenitor cells cultured ex vivo. The HAMs were sutured on polyester membrane (1) standardly, to obtain a flat HAM surface, or (2) loosely, achieving the radial folding to mimic crypts in the limbus. Immunohistochemistry was used to demonstrate a higher number of cells positive for progenitor markers p63α (37.56 ± 3.34% vs. 62.53 ± 3.32%, p = 0.01) and SOX9 (35.53 ± 0.96% vs. 43.23 ± 2.32%, p = 0.04), proliferation marker Ki-67 (8.43 ± 0.38 % vs. 22.38 ± 1.95 %, p = 0.002) in the crypt-like HAMs vs. flat HAMs, while no difference was found for the quiescence marker CEBPD (22.99 ± 2.96% vs. 30.49 ± 3.33 %, p = 0.17). Most of the cells stained negative for the corneal epithelial differentiation marker KRT3/12, and some were positive for N-cadherin in the crypt-like structures, but there was no difference in staining for E-cadherin and CX43 in crypt-like HAMs vs. flat HAMs. This novel HAM preparation method enhanced the number of progenitor cells expanded in the crypt-like HAM compared to cultures on the conventional flat HAM. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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Review

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18 pages, 1119 KiB

Open AccessReview

Single-Cell RNA Sequencing: Opportunities and Challenges for Studies on Corneal Biology in Health and Disease

by Julian A. Arts, Camille Laberthonnière, Dulce Lima Cunha and Huiqing Zhou

Cells 2023, 12(13), 1808; https://doi.org/10.3390/cells12131808 - 7 Jul 2023

Cited by 4 | Viewed by 2449

Abstract

The structure and major cell types of the multi-layer human cornea have been extensively studied. However, various cell states in specific cell types and key genes that define the cell states are not fully understood, hindering our comprehension of corneal homeostasis, related diseases, and therapeutic discovery. Single-cell RNA sequencing is a revolutionary and powerful tool for identifying cell states within tissues such as the cornea. This review provides an overview of current single-cell RNA sequencing studies on the human cornea, highlighting similarities and differences between them, and summarizing the key genes that define corneal cell states reported in these studies. In addition, this review discusses the opportunities and challenges of using single-cell RNA sequencing to study corneal biology in health and disease. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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38 pages, 4316 KiB

Open AccessFeature PaperReview

Corneal Regeneration Using Gene Therapy Approaches

by Subhradeep Sarkar, Priyalakshmi Panikker, Sharon D’Souza, Rohit Shetty, Rajiv R. Mohan and Arkasubhra Ghosh

Cells 2023, 12(9), 1280; https://doi.org/10.3390/cells12091280 - 28 Apr 2023

Cited by 10 | Viewed by 3338

Abstract

One of the most remarkable advancements in medical treatments of corneal diseases in recent decades has been corneal transplantation. However, corneal transplants, including lamellar strategies, have their own set of challenges, such as graft rejection, delayed graft failure, shortage of donor corneas, repeated treatments, and post-surgical complications. Corneal defects and diseases are one of the leading causes of blindness globally; therefore, there is a need for gene-based interventions that may mitigate some of these challenges and help reduce the burden of blindness. Corneas being immune-advantaged, uniquely avascular, and transparent is ideal for gene therapy approaches. Well-established corneal surgical techniques as well as their ease of accessibility for examination and manipulation makes corneas suitable for in vivo and ex vivo gene therapy. In this review, we focus on the most recent advances in the area of corneal regeneration using gene therapy and on the strategies involved in the development of such therapies. We also discuss the challenges and potential of gene therapy for the treatment of corneal diseases. Additionally, we discuss the translational aspects of gene therapy, including different types of vectors, particularly focusing on recombinant AAV that may help advance targeted therapeutics for corneal defects and diseases. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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27 pages, 4767 KiB

Open AccessReview

MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges

by Petros Moustardas, Daniel Aberdam and Neil Lagali

Cells 2023, 12(4), 617; https://doi.org/10.3390/cells12040617 - 14 Feb 2023

Cited by 14 | Viewed by 5424

Abstract

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous cellular signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Once activated through phosphorylation, these MAPKs in turn phosphorylate and activate transcription factors present either in the cytoplasm or in the nucleus, leading to the expression of target genes and, as a consequence, they elicit various biological responses. The aim of this work is to provide a comprehensive review focusing on the roles of MAPK signaling pathways in ocular pathophysiology and the potential to influence these for the treatment of eye diseases. We summarize the current knowledge of identified MAPK-targeting compounds in the context of ocular diseases such as macular degeneration, cataract, glaucoma and keratopathy, but also in rare ocular diseases where the cell differentiation, proliferation or migration are defective. Potential therapeutic interventions are also discussed. Additionally, we discuss challenges in overcoming the reported eye toxicity of some MAPK inhibitors. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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17 pages, 2356 KiB

Open AccessReview

Innovative Therapeutic Approaches for the Treatment of the Ocular Morbidities in Patients with EEC Syndrome

by Vanessa Barbaro, Filippo Bonelli, Stefano Ferrari, Giulia La Vella and Enzo Di Iorio

Cells 2023, 12(3), 495; https://doi.org/10.3390/cells12030495 - 2 Feb 2023

Cited by 2 | Viewed by 2853

Abstract

Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome is caused by heterozygous missense point mutations in the p63 gene, an important transcription factor during embryogenesis and for stem cell differentiation in stratified epithelia. Most of the cases are sporadic, related to de novo mutations arising during early-stage development. Familial cases show an autosomic dominant inheritance. The major cause of visual morbidity is limbal stem cell failure, which develops in the second to third decade of life. Patients often show ocular surface alterations, such as recurrent blepharitis and conjunctivitis, superficial microlesions of the cornea, and spontaneous corneal perforation and ulceration, leading to progressive corneal clouding and eventually visual loss. No definitive cures are currently available, and treatments to alleviate symptoms are only palliative. In this review, we will discuss the proposed therapeutic strategies that have been tested or are under development for the management of the ocular defects in patients affected by EEC syndrome: (i) gene therapy-based approaches by means of Allele-Specific (AS) siRNAs to correct the p63 mutations; (ii) cell therapy-based approaches to replenish the pool of limbal stem cells; and (iii) drug therapy to correct/bypass the genetic defect. However, as the number of patients with EEC syndrome is too limited, further studies are still necessary to prove the effectiveness (and safety) of these innovative therapeutic approaches to counteract the premature differentiation of limbal stem cells. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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31 pages, 4403 KiB

Open AccessReview

Recent Advancements in Molecular Therapeutics for Corneal Scar Treatment

by Anwesha Ghosh, Vijay K. Singh, Vivek Singh, Sayan Basu and Falguni Pati

Cells 2022, 11(20), 3310; https://doi.org/10.3390/cells11203310 - 21 Oct 2022

Cited by 10 | Viewed by 5657

Abstract

The process of corneal wound healing is complex and induces scar formation. Corneal scarring is a leading cause of blindness worldwide. The fibrotic healing of a major ocular wound disrupts the highly organized fibrillar collagen arrangement of the corneal stroma, rendering it opaque. The process of regaining this organized extracellular matrix (ECM) arrangement of the stromal layer to restore corneal transparency is complicated. The surface retention capacity of ocular drugs is poor, and there is a large gap between suitable corneal donors and clinical requirements. Therefore, a more efficient way of treating corneal scarring is needed. The eight major classes of interventions targeted as therapeutic tools for healing scarred corneas include those based on exosomes, targeted gene therapy, microRNAs, recombinant viral vectors, histone deacetylase inhibitors, bioactive molecules, growth factors, and nanotechnology. This review highlights the recent advancements in molecular therapeutics to restore a cornea without scarring. It also provides a scope to overcome the limitations of present studies and perform robust clinical research using these strategies. Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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21 pages, 6615 KiB

Open AccessEditor’s ChoiceReview

Corneal Regeneration Using Adipose-Derived Mesenchymal Stem Cells

by Jorge L. Alió del Barrio, Ana De la Mata, María P. De Miguel, Francisco Arnalich-Montiel, Teresa Nieto-Miguel, Mona El Zarif, Marta Cadenas-Martín, Marina López-Paniagua, Sara Galindo, Margarita Calonge and Jorge L. Alió

Cells 2022, 11(16), 2549; https://doi.org/10.3390/cells11162549 - 16 Aug 2022

Cited by 24 | Viewed by 4798

Abstract

Adipose-derived stem cells are a subtype of mesenchymal stem cell that offers the important advantage of being easily obtained (in an autologous manner) from low invasive procedures, rendering a high number of multipotent stem cells with the potential to differentiate into several cellular lineages, to show immunomodulatory properties, and to promote tissue regeneration by a paracrine action through the secretion of extracellular vesicles containing trophic factors. This secretome is currently being investigated as a potential source for a cell-free based regenerative therapy for human tissues, which would significantly reduce the involved costs, risks and law regulations, allowing for a broader application in real clinical practice. In the current article, we will review the existing preclinical and human clinical evidence regarding the use of such adipose-derived mesenchymal stem cells for the regeneration of the three main layers of the human cornea: the epithelium (derived from the surface ectoderm), the stroma (derived from the neural crest mesenchyme), and the endothelium (derived from the neural crest cells). Full article

(This article belongs to the Special Issue Stem Cell Biotechnology in Ocular Regenerative Medicine and Drug Discovery)

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