Current Trends and Future Perspective of Mesenchymal Stem Cells and Exosomes in Corneal Diseases (original) (raw)
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Mesenchymal Stem Cell-Derived Exosomes in Ophthalmology: A Comprehensive Review
Pharmaceutics
Over the past decade, the field of mesenchymal stem cell (MSC) therapy has exhibited rapid growth. Due to their regenerative, reparatory, and immunomodulatory capacities, MSCs have been widely investigated as therapeutic agents in the cell-based treatment of chronic ophthalmic pathologies. However, the applicability of MSC-based therapy is limited by suboptimal biocompatibility, penetration, and delivery to the target ocular tissues. An emerging body of research has elucidated the role of exosomes in the biological functions of MSCs, and that MSC-derived extracellular vesicles (EVs) possess anti-inflammatory, anti-apoptotic, tissue repairing, neuroprotective, and immunomodulatory properties similar to MSCs. The recent advances in MSCs-derived exosomes can serve as solutions to the challenges faced by MSCs-therapy. Due to their nano-dimensions, MSC-derived exosomes can rapidly penetrate biological barriers and reach immune-privileged organs, allowing for efficient delivery of therape...
Aging, 2020
Induced pluripotent stem cells and mesenchymal stem cells are pluripotent stem cells that represent promising therapies for treating various tissue injuries and wound healing. Exosomes are nanosized extracellular vesicles that have been identified as important mediators of therapeutic functions, which are performed via cell communication. In this study, we compared the efficacy of induced pluripotent stem cells-derived exosomes (iPSCs-Exos) and mesenchymal stem cells-derived exosomes (MSCs-Exos) in treating corneal epithelial defects. The characteristics of the two types of exosomes were not significantly different. Compared to MSCs-Exos, iPSCs-Exos had a better in vitro effect on the proliferation, migration, cell cycle promotion and apoptosis inhibition of human corneal epithelial cells. iPSCs/MSCs-Exos promoted cell regeneration by upregulating cyclin A and CDK2 to drive HCECs to enter the S phase from the G0/G1 phase. In vivo results from a corneal epithelial defect model showed that both iPSCs-Exos and MSCs-Exos accelerated corneal epithelium defect healing while the effects of iPSCs-Exos were much stronger than those of MSCs-Exos. This study demonstrated that iPSCs-Exos had a better therapeutic effect on corneal epithelial defect healing. Thus, a novel potential nanotherapeutic strategy for treating corneal epithelial defects and even more ocular surface disease could be undertaken by using iPSCs-Exos dissolved in eye drops.
Mesenchymal stem cells for treating ocular surface diseases
BMC Ophthalmology, 2015
Mesenchymal stem cells (MSC) have become a promising tool for cell therapy in regenerative medicine. They are readily available, demonstrate powerful differentiation capabilities and present immunosuppressive properties that aid them in surviving from host immune rejection for its great potential use in allograft. Currently clinical trials are underway using MSC, both culture-expanded allogeneic and autologous, for the treatment of a range of diseases not treatable by conventional therapies. A vast array of studies has dedicated towards the use of MSC for treating corneal diseases with very promising outcomes. MSC have successfully differentiated into keratocytes both in vitro and in vivo, and corneal epithelial cells in vitro, but it is uncertain if MSC can assume corneal epithelial cells in vivo. However, to date few studies have unequivocally established the efficacy of MSC for treating corneal endothelial defects. Currently, the diversity in protocols of the isolation and expansion of MSC are hindering to the assessment of cell treatment ability and the further development of treatment regimens. Therefore, future studies should develop international standards for MSC isolation and characterization. In this review, we discuss recent advances in MSC for treating ocular surface diseases.
Advances in Animal and Veterinary Sciences
Background: Corneal ulcer is the discontinuation of the surface epithelial layer of the cornea with variable amounts of the stroma affected. Recent research suggests that Extracellular Vesicles (EVs) of stem cells have the same effects on target cells that their parental stem cells act, these effects are brought on by paracrine signaling involves the release of cytokines and nucleic acids (DNA, mRNA, and miRNA) which may lead to alteration of the gene expression, proliferation, and differentiation of the recipient cells. Methodology: 24 male New Zealand albino rabbits were used in this study, divided randomly into 4 groups (6 rabbits per group), induction of corneal ulcers centrally in groups (I, II) and peripherally in (III, IV). Treated groups are (I, III) using topical lyophilized canine Mesenchymal Stem Cells derived EVs & control groups are (II, IV) using topical normal saline. Result: both treated groups appeared fluorescein negative at the 5th day and are characterized by rapid reepithelization significantly earlier than control groups which were still fluorescein positive. AS-OCT (Anterior Segment Optical Coherence Tomography) showed well-healed epithelium with intact and homogenous stroma on the 5th day in both treated groups, but control groups showed irregular arrangements of epithelial plaques and presented some abnormalities as stromal fibrosis and sub-epithelial cyst formation. Histopathology in both treated groups showed the development of a complete layer of epithelium within 1week which increased in rows at 2nd and 3rd weeks of treatment and the stromal edema decreased with time unlike control groups that showed weak fragmented epithelium development, sub-epithelial hemorrhage and vascularization. These findings prove that EVs have the ability to heal corneal wounds even if in the peripheral parts of the cornea that are deficient in limbal stem cells. Conclusion: In terms of safety, quality, regulatory concerns, and cost, EVs are superior to corneal transplantation and live stem cell therapy.
Investigative ophthalmology & visual science, 2018
Mesenchymal stromal cells (MSCs) have been used therapeutically to modulate inflammation and promote repair. Extracellular vesicles, including exosomes, have been identified as one of the important mediators. This study investigated the effect of human corneal MSC-derived exosomes on corneal epithelial wound healing. Corneal MSCs (cMSCs) were isolated from human cadaver corneas. The secretome was collected after 72 hours and exosomes were isolated using differential ultracentrifugation. Morphology and size of exosomes were examined by electron microscopy and dynamic light scattering. Expression of CD9, CD63, and CD81 by cMSC exosomes was evaluated by western blotting. Cellular uptake of exosomes was studied using calcein-stained exosomes. The effect of exosome on wound healing was measured in vitro using a scratch assay and in vivo after 2-mm epithelial debridement wounds in mice. cMSC exosomes were morphologically round and main population ranged between 40 and 100 nm in diameter. ...
In vitro potential of human mesenchymal stem cells for corneal epithelial regeneration
Regenerative Medicine, 2020
Aim: To determine the potential of mesenchymal stem cells (MSC) for corneal epithelial regeneration in vitro. Materials & methods: Bone marrow MSC (BM-MSC) and adipose tissue MSC were analyzed for corneal epithelial and mesenchymal markers, using limbal stem cells and corneal cells as controls. MSC with better potential were cultured with specific mediums for epithelial induction. Transepithelial electric resistance and wound healing assay with human corneal epithelial cells were performed. Results: BM-MSC showed better potential, increased corneal markers, and higher transepithelial electric resistance values when induced with limbal epithelial culture medium. Induced BM-MSC promoted better wound healing of human corneal epithelial cells by paracrine secretion. Conclusion: BM-MSC has potential for corneal epithelial induction in a protocol compatible with human application.
International Journal of Molecular Sciences, 2021
Corneal endothelial dystrophy is a relevant cause of vision loss and corneal transplantation worldwide. In the present study, we analyzed the effect of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) in an in vitro model of corneal dystrophy, characterized by endoplasmic reticulum stress. The effects of MSC-EVs were compared with those of serum-derived EVs, reported to display a pro-angiogenic activity. MSC-EVs were able to induce a significant down-regulation of the large majority of endoplasmic reticulum stress-related genes in human corneal endothelial cells after exposure to serum deprivation and tunicamycin. In parallel, they upregulated the Akt pathway and limited caspase-3 activation and apoptosis. At variance, the effect of the serum EVs was mainly limited to Akt phosphorylation, with minimal or absent effects on endoplasmic reticulum stress modulation and apoptosis prevention. The effects of MSC-EVs were correlated to the transfer of numerous endoplasmi...
Cells
Severe corneal damage leads to complete vision loss, thereby affecting life quality and impinging heavily on the healthcare system. Current clinical approaches to manage corneal wounds suffer from severe drawbacks, thus requiring the development of alternative strategies. Of late, mesenchymal stromal/stem cell (MSC)-derived extracellular vesicles (EVs) have become a promising tool in the ophthalmic field. In the present study, we topically delivered bone-marrow-derived MSC-EVs (BMSC-EVs), embedded in methylcellulose, in a murine model of alkali-burn-induced corneal damage in order to evaluate their role in corneal repair through histological and molecular analyses, with the support of magnetic resonance imaging. Our data show that BMSC-EVs, used for the first time in this specific formulation on the damaged cornea, modulate cell death, inflammation and angiogenetic programs in the injured tissue, thus leading to a faster recovery of corneal damage. These results were confirmed on ca...
Exploring the Mesenchymal Stem Cell Secretome for Corneal Endothelial Proliferation
Stem Cells International
Ex vivo grown human corneal endothelial cells (HCEnC) are a new emerging treatment option to treat visually impaired patients aimed at alleviating the current global donor shortage. Expanding HCEnC is still challenging, and obtaining cells in sufficient quantities is a limiting factor. It is already known that conditioned medium obtained from bone marrow mesenchymal stem cells can stimulate the proliferation of endothelial cells. The aim of this study was to take this work a step further to identify some of the underlying factors responsible. We confirmed the stimulatory effect of the mesenchymal stem cell secretome seen previously and separated the exosomes from the soluble proteins using size exclusion chromatography. We demonstrated the presence of exosomes and soluble proteins in the early and late fractions, respectively, with transmission electron microscopy and protein assays. Proliferation studies demonstrated that growth stimulation could be reproduced with the later protei...