Abstract

Degenerative ocular disorders, glaucoma, cataracts and age-related macular degeneration, are major contributors to global blindness and visual impairment. Other conditions, such as limbal stem cell deficiency, dry eye disease and retinitis pigmentosa, lead to significant ocular distress and progressive vision loss, profoundly affecting patients’ quality of life. Conventional therapies primarily focus on symptom management and slowing disease progression, offering limited potential for tissue restoration. In recent years, stem cell therapy and regenerative medicine have emerged as promising strategies to address these limitations. Mesenchymal Stem Cells (MSCs) induced Pluripotent Stem Cells (iPSCs) and other progenitor cells have demonstrated the capacity to differentiate into ocular-specific cell types, modulate inflammation, secrete neurotrophic factors and promote tissue repair. Preclinical studies and early clinical trials have shown encouraging results in corneal regeneration, retinal repair and optic nerve protection, highlighting the translational potential of these therapies. Despite these advances, challenges remain, including optimizing cell sourcing, delivery methods, immune compatibility and long-term safety. This review provides a comprehensive overview of current stem cell-based approaches in ophthalmology, discussing underlying mechanisms, preclinical and clinical evidence and future directions for regenerative interventions aimed at restoring visual function. Stem cell therapy offers a transformative approach with the potential to shift ophthalmic care from palliative management to true tissue regeneration, offering hope for patients with previously untreatable ocular disorders.

Keywords: Ophthalmology; Stem Cell; Stem Cell Therapy; Clinical Trial; Secretome

Definition of Mesenchymal Stem Cells

Stem Cells (SCs) are specialized cells characterized by self-renewal and the capacity to differentiate into one or more lineages with varying potency [1]. Stem cell-based strategies have become central to regenerative medicine because they can, in principle, replace damaged cells or modulate hostile tissue microenvironments. Embryonic Stem Cells (ESCs) originally derived from the inner cell mass of pre-implantation blastocysts, are pluripotent and can generate derivatives of all three germ layers [2,3]. Their self-renewal capacity, pluripotency and relative genomic stability make them attractive candidates for cellular therapies [4]. However, ethical considerations and translational constraints have limited their clinical adoption.

Induced pluripotent stem cells (iPSCs) are generated by reprogramming somatic cells through overexpression of transcription factors (Oct4, Sox2, Klf4 and c-Myc), yielding cells that closely resemble ESCs in differentiation potential and self-renewal  [5-7]. Despite strong therapeutic promise, concerns persist regarding genetic and epigenetic stability, tumorigenic risk and manufacturing standardization, particularly when scaled for clinical use.

Mesenchymal stem/stromal cells (MSCs) were initially described as fibroblast-like, plastic-adherent colony-forming cells isolated from bone marrow, capable of differentiating into mesodermal lineages [8]. MSCs are now recognized as multipotent stromal populations present in many adult tissues and perivascular niches [9]. Their translational appeal is driven by relative ease of isolation and expansion, limited ethical concerns and potent immunomodulatory and trophic effects that extend beyond classical “replacement” biology.

Because MSCs are heterogeneous and lack a single definitive marker, the International Society for Cellular Therapy (ISCT) proposed minimal criteria: plastic adherence; expression of CD73, CD90 and CD105; absence of CD14, CD34, CD45 and HLA-DR; and trilineage differentiation into adipocytes, chondrocytes and osteoblasts in-vitro. Importantly, these criteria support phenotypic identification, but do not fully capture functional potency, which varies by tissue source, donor factors, culture conditions and manufacturing protocols.

Secretome of Mesenchymal Stem Cells

MSCs can be isolated from multiple tissues, including bone marrow, adipose tissue, placenta, dental pulp, synovium, endometrium and other sources [10]. Under defined conditions they can exhibit differentiation capacity across mesodermal and, more controversially, non-mesodermal lineages. Clinically, however, the predominant therapeutic rationale for MSCs in many indications has shifted from durable differentiation to paracrine signaling and immunomodulation.

Over the past two decades, autologous and allogeneic MSC-based interventions have been explored for inflammatory and degenerative diseases. MSCs may modulate immune responses and promote tissue repair by reshaping local cytokine environments, increasing regulatory cell populations and supporting cell survival under stress [11]. Nonetheless, cell-based therapies raise translational concerns including ectopic tissue formation, immune incompatibility, pro-tumor signaling in permissive settings, pulmonary microvascular trapping after systemic delivery and inconsistent potency across products.

These limitations have driven interest in MSC secretome as a cell-free therapeutic alternative. The MSC secretome includes soluble factors (cytokines, chemokines, growth factors, immunoregulatory mediators) and Extracellular Vesicles (EVs), potentially enabling more standardized dosing and safety testing, easier storage/administration and reduced risks associated with living cell persistence [12]. Preclinical and early clinical studies have evaluated MSC secretome approaches across multiple disease areas, with reported benefits in musculoskeletal repair, dermatologic disorders and degenerative conditions [13]. However, secretome effects appear highly context-dependent: depending on microenvironmental cues, secretome components may promote tissue protection or contribute to pathological remodeling, underscoring the need for controlled manufacturing and indication-specific evaluation [14].

EVs are commonly classified by size and biogenesis [15]. Small EVs (often termed exosomes, ~30-200 nm) typically express markers such as CD63, CD9, CD81, TSG101, Alix and flotillin and carry proteins, lipids and nucleic acids (including miRNAs) capable of modulating recipient cell pathways [15]. Medium EVs (microvesicles/ectosomes, ~200-1000 nm) bud from the plasma membrane and share overlapping cargo profiles; large EVs include apoptotic bodies and oncosomes, the latter associated with cancer cell-derived biomarkers [16]. For ocular applications, EV-based delivery is increasingly investigated as a strategy to harness MSC paracrine benefits while reducing surgical burden and long-term cell persistence risks.

Ophthalmological Diseases and the Rationale for Regeneration

Visual impairment affects more than two billion people globally [17]. Age-related conditions and refractive errors account for a substantial share and epidemiologic projections indicate increases in glaucoma and Age-related Macular Degeneration (AMD) over coming decades, alongside rising cataract burden with population aging [18]. Many chronic eye diseases progress silently for years (e.g., glaucoma) and delayed presentation is compounded by low public awareness, misattribution to “normal aging”, and limited access to routine screening [19,20]. Modifiable lifestyle risk factors (smoking, metabolic disease, nutritional deficiency and UV exposure) contribute to multiple ocular pathologies and remain important targets for prevention strategies [21,22].

Despite major therapeutic advances, many ophthalmic disorders remain limited by irreversible loss of specialized retinal or optic nerve cells and by chronic inflammatory and oxidative microenvironments that drive progressive degeneration. Regenerative medicine aims to restore structure and function by promoting cell survival, replacing lost cells and/or modulating pathological tissue environments. Approaches include gene therapy, scaffolds, soluble factors, tissue engineering and cell-based or cell-free interventions.

Multiple cell platforms have been investigated in ophthalmology, including MSCs, ESCs/iPSCs, retinal progenitor cells and Retinal Pigment Epithelium (RPE)-directed therapies. In this review, we focus on MSC-based interventions and related regenerative strategies for ocular disease, emphasizing mechanisms of action, delivery considerations, clinical evidence quality and translational barriers rather than providing an extended description of conventional therapies.

Mesenchymal Stem Cells in Retinal and Optic Nerve Disease

Retinal degenerative diseases (including glaucoma-associated optic neuropathy, retinitis pigmentosa, AMD and diabetic retinopathy) are leading causes of vision loss and blindness. In many of these conditions, conventional therapies primarily slow progression or treat complications, but do not restore lost neuronal or photoreceptor populations. MSCs are proposed as therapeutic candidates due to immunomodulatory activity, secretion of neurotrophic factors, anti-apoptotic effects and the potential, still debated in-vivo, for limited differentiation toward retinal-like phenotypes [23].

However, the clinical evidence base for MSCs in ophthalmology remains heterogeneous and largely early-phase. Variability in MSC source (bone marrow, adipose, umbilical cord/Wharton’s jelly), manufacturing and expansion protocols, dosing, delivery route and outcome definitions complicates cross-study comparisons. Moreover, several studies report improvements that may be transient, emphasizing the need to evaluate durability beyond short follow-up windows (typically 6-12 months in many early reports). These considerations should shape interpretation of the current literature.

Preclinical work suggests MSCs can protect retinal ganglion cells, reduce inflammatory injury and support axon regeneration in optic nerve injury models [24,25]. MSCs and MSC-derived factors have been associated with expression of retinal markers in-vitro, but whether functional integration and stable neuronal replacement occurs in-vivo remains insufficiently demonstrated in most models [26]. Safety data from broader clinical fields suggest no definitive association with malignancy or mortality in aggregate analyses, yet ocular delivery introduces distinct risks that require dedicated discussion [28].

Why the Retina is a Suitable Target for MSC-Based Strategies?

The retina provides unique advantages for regenerative interventions:

1. Direct visualization through transparent optical media and precise multimodal imaging enables early detection of adverse events and objective monitoring
2. Partial immune privilege behind the blood-eye barrier may support survival of transplanted materials
3. Standardized animal models facilitate mechanistic and proof-of-concept testing
4. Ophthalmic microsurgical techniques enable targeted delivery to specific retinal compartments

At the same time, the immune-privileged environment does not eliminate risk and perturbation of ocular compartments can induce inflammation, fibrosis or Proliferative Vitreoretinopathy (PVR), particularly with intravitreal or surgical approaches.

Delivery Options and Comparative Risks

MSCs can be delivered systemically (intravenous) or locally (intravitreal, subretinal or periocular routes) (Table 1). Delivery route strongly influences both efficacy and safety profiles.

Subretinal delivery can position cells or cell products near the outer retina and RPE and bypass the inner limiting membrane barrier that restricts intravitreal integration [29,30]. However, subretinal injection often requires vitrectomy and surgical expertise, with risks including retinal tears, detachment and inadvertent dispersion of cells into the vitreous cavity. Importantly, minimizing vitreous disruption may reduce the risk of PVR, but this remains a key safety consideration whenever intraocular surgery is performed [31].

Table 1: Comparison of MSC delivery routes for retinal and optic nerve indications.

Intravitreal delivery is less invasive and widely used for anti-VEGF injections; it can be performed outpatient and may be more relevant for inner retinal targets. Nonetheless, the internal limiting membrane limits retinal integration and intravitreal cell persistence or aggregation raises theoretical risks of traction, inflammation and fibrosis in susceptible settings [32]. Systemic delivery may be limited by pulmonary trapping and restricted ocular access due to the blood-retinal barrier, potentially reducing effective delivery to target tissues while increasing systemic exposure.

Fig. 1 summarizes the major mechanistic domains through which MSCs are proposed to exert therapeutic benefit in retinal disease. Importantly, most evidence supports a predominantly paracrine mode of action rather than stable structural integration of transplanted cells into functional retinal circuitry. Immunomodulation is mediated through soluble factors such as PGE2 and IDO and through downstream effects on regulatory T-cells and macrophage polarization. Neuroprotection appears linked to secretion of trophic factors and attenuation of TLR4-associated inflammatory cascades. Antioxidative effects may involve activation of AKT-dependent survival signaling and enhancement of endogenous antioxidant responses, while angiogenic modulation may be beneficial in ischemic microvascular degeneration but potentially detrimental in proliferative neovascular stages. The relative dominance of these mechanisms is likely disease-stage dependent (Table 2-6).

Figure 1: Principal paracrine mechanisms by which mesenchymal stem cells exert therapeutic effects in retinal and optic nerve diseases.

Table 2: Clinical studies of MSC-based therapy for Retinitis Pigmentosa.

Table 3: MSC-based strategies for Glaucoma (Preclinical + Clinical separated).

Table 4: Human clinical studies (Glaucoma).

Table 5: MSC-based strategies for diabetic retinopathy preclinical in-vivo studies.

Table 6: Preclinical in-vitro studies (DR / BRB / angiogenesis).

Strategies for Treating Retinal Diseases with MSCs

Immunomodulation and Immune Re-programming

Conventional immunosuppression for ocular inflammatory disease (e.g., corticosteroids and systemic immunosuppressants) can be effective but carries systemic and ocular adverse effects. MSCs have been proposed as alternatives or adjuncts because they can suppress multiple immune effector pathways and promote regulatory immune phenotypes [33,34].

Mechanistically, MSCs act largely through secreted mediators that influence T-cells, B-cells, NK cells, macrophages and dendritic cells [35]. Key pathways include COX2, PGE2, IL-6, dependent signaling and Indoleamine 2,3-Dioxygenase (IDO) induction in inflammatory milieus [36]. MSC apoptosis followed by macrophage efferocytosis has been proposed as an immunoregulatory mechanism, with downstream IDO-mediated suppression contributing to reduced immune activation [37,38]. MSCs also support expansion of regulatory T-cells, polarization toward M2-like macrophages and promotion of tolerogenic dendritic phenotypes while inhibiting NK cell proliferation [39].

Cell-free MSC products may also reduce inflammatory recruitment signals. For example, MSC-derived exosomes have been associated with downregulation of MCP-1, a chemokine involved in monocyte recruitment [40]. In inflammatory models, intravitreal MSC administration has been associated with reduced expression of cytokines such as IL-1β, TNF-α and IFN-γ and decreased macrophage infiltration [41,42]. Importantly, many mechanistic findings are derived from animal models with acute inflammatory induction; translation to chronic human retinal degenerations requires cautious interpretation.

Neuroprotection and Neuronal Survival Pathways

MSC neuroprotective activity is commonly attributed to trophic support and inflammation control rather than durable neuronal replacement. MSCs can reduce retinal apoptosis, preserve inner retinal thickness and mitigate neuroinflammation partly through modulation of innate immune signaling such as TLR4-linked pathways, alongside suppression of TNF-α, IL-1β, oxidative stress mediators and reactive oxygen species [43]. MSCs secrete neurotrophic factors including NGF, GDNF, CNTF, bFGF and BDNF, which collectively support retinal neuron survival and stress resistance [44]. Conditioned medium studies suggest photoreceptor survival benefits in-vitro, supporting a paracrine mechanism. In-vivo, subretinal MSC injection has been associated with preservation of photoreceptor layers in genetic degeneration models [47]. However, whether transplanted MSCs functionally integrate as retinal neurons remains insufficiently established; many studies detect marker expression without demonstrating synaptic integration and sustained function. Early clinical reports (e.g., in retinitis pigmentosa and optic neuropathies) suggest potential functional improvements but interpretation is limited when studies are open-label, non-randomized, underpowered or have short follow-up. Future trials should standardize endpoints (BCVA, microperimetry, ERG, OCT metrics), include masking/sham controls where feasible and assess durability beyond 12 months [45,46].

Angiogenesis: Repair vs Pathologic Neovascularization

Pathologic neovascularization contributes to complications such as vitreous hemorrhage and tractional retinal detachment. Ocular vascular disease includes ischemia-driven retinal neovascularization (e.g., DR, ROP, vein occlusions) and subretinal neovascularization common in AMD and high myopia [48].

MSCs can secrete angiogenic mediators (VEGF, FGF, HGF, TGF-β1, IGF-1) that may support vascular repair in ischemic settings [49]. Conversely, the same pro-angiogenic profile could theoretically exacerbate pathological neovascularization depending on disease stage and microenvironment. Therefore, pro-angiogenic MSC effects should be interpreted as stage-dependent and may be more appropriate for early microvascular degeneration and pericyte loss than for active proliferative neovascular phases. In DR, hyperglycemia drives oxidative stress, microvascular degeneration, pericyte dysfunction and inflammation. MSCs may reduce ROS and inflammatory mediators and potentially support pericyte-like functions while promoting neurotrophic support [54,55]. However, much of this evidence is preclinical; clinical translation requires careful safety monitoring for proliferative responses.

Oxidative Stress and Antioxidant Defense

Oxidative stress is implicated in retinal degeneration through ROS-mediated damage, inflammation and cellular dysfunction. MSCs may mitigate oxidative injury via free radical scavenging, enhancement of endogenous antioxidant systems, mitochondrial support (including mitochondrial transfer in some models) and activation of survival pathways [56]. Mechanistically, evidence across systems points to pathways such as AKT-linked cytoprotection and downstream antioxidant responses (commonly discussed with NRF2-associated transcriptional programs in broader literature), although the specific causal chain should be clearly linked to retinal models when stated. Overexpression of Stanniocalcin-1 (STC1) has been associated with increased survival of oxidatively stressed cells [57]. In ocular models, adipose-derived MSCs delivered subretinally have been reported to protect RPE and photoreceptors under oxidative stress [58]. Overall, MSC-mediated antioxidant effects likely interact with immunomodulation and trophic support rather than acting as a single isolated pathway.

Conventional Therapies: Brief Context and Limitations

Conventional therapies remain essential for managing major retinal diseases, but most approaches do not replace lost neurons or photoreceptors and often require repeated treatments or invasive procedures. For retinitis pigmentosa, gene-based strategies (including ASOs, genome editing such as CRISPR/Cas9 and optogenetic approaches) represent important advances, especially when targeting specific mutations or restoring light sensitivity in surviving retinal cells [59-63]. Nutritional supplements (vitamin A, lutein, DHA) and pharmacologic approaches (including calcium channel modulation) have shown variable and sometimes conflicting evidence and generally do not provide restorative therapy [64,65].

For glaucoma, treatment focuses on intraocular pressure reduction through topical medications, laser trabeculoplasty and surgical interventions including MIGS and filtering/tube procedures [66-84]. These modalities slow progression but do not regenerate retinal ganglion cells or reverse optic nerve damage.

For diabetic retinopathy and DME, systemic metabolic control and ocular treatments (anti-VEGF, steroids, laser, vitrectomy in selected cases) have strong evidence for reducing vision loss and managing complications, but long-term burden, incomplete responses and progression in some patients persist [85-117]. These limitations motivate regenerative approaches aimed at neurovascular protection and microenvironmental modulation. Rationale for inclusion in this review: Conventional therapies are summarized here solely to define the unmet need that MSC-based and regenerative strategies seek to address, rather than to provide a comprehensive therapeutic manual.

Emerging MSC-Based Therapies for DR (Keep, but make analytical)

Recent studies suggest MSC-derived EVs may provide cell-free strategies for DR by reducing oxidative stress, inflammation and apoptosis in diabetic models. For example, MSC-sEV delivery of NEDD4 has been associated with reduced retinal oxidative stress and apoptosis in diabetic rats [153]. Human umbilical cord MSC-derived sEVs have also shown anti-inflammatory and anti-apoptotic activity in rat DR models, with microRNA-18b implicated through MAP3K1 targeting [154]. Additionally, adipose-derived MSCs may preserve pro-angiogenic repair capacity under high glucose conditions and restore endothelial angiogenesis via secreted factors [155]. While these studies are promising, most are preclinical and outcomes may depend heavily on EV isolation methods, dosing, biodistribution and disease stage. Translation requires standardized manufacturing, clear primary endpoints and long-term ocular safety evaluation.

Safety, Regulatory and Translational Challenges

Although MSC approaches are often described as “safe,” intraocular and periocular delivery raises distinct risks that should be explicitly addressed:

• Proliferative Vitreoretinopathy (PVR) and fibrosis: Intraocular manipulation and cell presence in the vitreous may increase risk of traction, membrane formation and retinal detachment in susceptible contexts. Risk may vary by delivery route, product type (cells vs EVs) and surgical disruption
• Ectopic tissue formation and inappropriate differentiation: Particularly relevant for living cell products; risk is influenced by manufacturing controls and local microenvironment signals
• Tumorigenicity and long-term surveillance: While many studies report no signal of malignancy in short follow-up, long-term surveillance is limited and genomic instability risks differ by product type (e.g., iPSCs vs MSCs)
• Immune reactions and inflammation: Even “immune-privileged” ocular compartments can mount inflammatory responses and allogeneic products may carry additional immunologic considerations
• Product heterogeneity: MSC source (BM-MSC vs UC-MSC vs AD-MSC), donor characteristics, passage number, cryopreservation, potency assays and contamination controls are major determinants of reproducibility
• Regulatory and ethical concerns: The field is complicated by unregulated “stem cell clinics” offering ocular injections without rigorous evidence, which has contributed to safety incidents and public mistrust. High-quality clinical translation requires adherence to regulated manufacturing and clinical trial oversight (FDA/EMA-aligned pathways and local regulatory equivalents)

Evidence Hierarchy and Critical Appraisal

Current clinical evidence for MSC-based ophthalmic therapies is predominantly early-phase and frequently limited by:

• Small sample sizes
• Non-randomized designs
• Open-label protocols
• Inconsistent endpoints
• Short follow-up (commonly 6-12 months)
• Variable manufacturing/dosing/delivery protocols

Accordingly, the literature should be framed as preliminary, with an explicit statement that robust phase III randomized controlled trials remain limited or lacking in most indications and that reported functional improvements may be transient or influenced by bias without masking/sham controls. This critical framing will directly address the reviewer’s “descriptive vs analytical” concern.

Conclusion

Mesenchymal stem cells and MSC-derived products, particularly extracellular vesicles, represent promising regenerative strategies for ophthalmic disease through immunomodulatory, neuroprotective, antioxidant and microenvironment-stabilizing effects. However, the strength of clinical evidence remains preliminary in many indications due to small early-phase studies, heterogeneity in product manufacturing and delivery and limited long-term follow-up. Future progress will depend on standardized potency and safety assays, rigorous controlled trial designs with durable functional endpoints and clear regulatory pathways that distinguish validated therapies from unregulated interventions. With these advances, MSC-based approaches may evolve from experimental interventions into reproducible, safe adjuncts or, in select contexts, transformative therapies, for preserving and restoring vision.

Conflict of Interest

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial or non-profit sectors.

Data Availability Statement

Data can be made available upon reasonable request.

Ethical Statement                                                

Written informed consent was obtained from the patient for publication of this case report and accompanying images. Institutional ethics approval was deemed exempt for a single case report according to institutional guidelines.

Informed Consent Statement

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Authors’ Contributions

All authors contributed equally to this paper.

References

1. Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin. 2013;34(6):747-54.
2. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154-6.
3. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145-7.
4. Yoon SW, Kim DK, Kim KP, Park KS. Rad51 regulates cell cycle progression by preserving G2/M transition in mouse embryonic stem cells. Stem Cells Dev. 2014;23(22):2700-11.
5. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-76.
6. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-72.
7. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26(1):101-6.
8. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393-5.
9. Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301-13.
10. Falzarano MS, Ferlini A. Urinary stem cells as tools to study genetic disease: overview of the literature. J Clin Med. 2019;8(5):627.
11. Jasim SA, Yumashev AV, Abdelbasset WK, Margiana R, Markov A, Suksatan W, et al. Shining the light on clinical application of mesenchymal stem cell therapy in autoimmune diseases. Stem Cell Res Ther. 2022;13(1):101.
12. Kahmini FR, Shahgaldi S. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles as novel cell-free therapy for treatment of autoimmune disorders. Exp Mol Pathol. 2021;118:104566.
13. Fan Y, Li Z, He Y. Exosomes in the pathogenesis, progression and treatment of osteoarthritis. Bioengineering (Basel). 2022;9(3):99.
14. Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Mesenchymal stem cell-derived extracellular vesicles: Challenges in clinical applications. Front Cell Dev Biol. 2020;8:149.
15. Cn S, Md H. Extracellular vesicles in type 1 diabetes: A versatile tool. Bioengineering (Basel). 2022;9(3).
16. Meehan B, Rak J, Di Vizio D. Oncosomes-large and small: What are they, where they came from? J Extracell Vesicles. 2016;5.
17. Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al. Global causes of blindness and distance vision impairment 1990-2020: A systematic review and meta-analysis. Lancet Glob Health. 2017;5(12):e1221-34.
18. Arena R, McNeil A, Sagner M, Hills AP. The current global state of key lifestyle characteristics: health and economic implications. Prog Cardiovasc Dis. 2017;59(5):422-9.
19. Irving EL, Harris JD, Machan CM, Robinson BE, Hrynchak PK, Leat SJ, et al. Value of routine eye examinations in asymptomatic patients. Optom Vis Sci. 2016;93(7):660-6.
20. Kirag N, Temel AB. The effect of an eye health promotion program on the health protective behaviors of primary school students. J Educ Health Promot. 2018;7:37.
21. Nita M, Grzybowski A. Smoking and eye pathologies: A systemic review. Part I. Anterior eye segment pathologies. Curr Pharm Des. 2017;23(4):629-38.
22. Ang MJ, Afshari NA. Cataract and systemic disease: a review. Clin Exp Ophthalmol. 2021;49(2):118-27.
23. Holan V, Palacka K, Hermankova B. Mesenchymal stem cell-based therapy for retinal degenerative diseases: Experimental models and clinical trials. Cells. 2021;10(3):588.
24. Jones MK, Lu B, Girman S, Wang S. Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases. Prog Retin Eye Res. 2017;58:1-27.
25. Chen M, Xiang Z, Cai J. The anti-apoptotic and neuroprotective effects of human umbilical cord blood mesenchymal stem cells on acute optic nerve injury is transient. Brain Res. 2013;1532:63-75.
26. Hermankova B, Kossl J, Javorkova E, Bohacova P, Hajkova M, Zajicova A, et al. The identification of interferon-γ as a key supportive factor for retinal differentiation of murine mesenchymal stem cells. Stem Cells Dev. 2017;26(19):1399-408.
27. Wang Y, Han ZB, Ma J, Zuo C, Geng J, Gong W, et al. A toxicity study of multiple-administration human umbilical cord mesenchymal stem cells in cynomolgus monkeys. Stem Cells Dev. 2012;21(9):1401-8.
28. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. Safety of cell therapy with mesenchymal stromal cells: A systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559.
29. Holan V, Hermankova B, Krulova M, Zajicova A. Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells: A clue to stem cell-based therapy. World J Stem Cells. 2019;11(11):957-67.
30. Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: Follow-up of two open-label phase 1/2 studies. Lancet. 2015;385(9967):509-16.
31. Tzameret A, Sher I, Belkin M, Treves AJ, Meir A, Nagler A, et al. Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy. Exp Eye Res. 2014;118:135-44.
32. Chen M, Chen Q, Sun X, Shen W, Liu B, Zhong X, et al. Generation of retinal ganglion-like cells from reprogrammed mouse fibroblasts. Invest Ophthalmol Vis Sci. 2010;51(11):5970-8.
33. Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther. 2011;2(4):34.
34. Skrahin A, Ahmed RK, Ferrara G, Rane L, Poiret T, Isaikina Y, et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: An open-label phase 1 safety trial. Lancet Respir Med. 2014;2(2):108-22.
35. Lu Y, Liu J, Liu Y, Qin Y, Luo Q, Wang Q, et al. TLR4 plays a crucial role in MSC-induced inhibition of NK cell function. Biochem Biophys Res Commun. 2015;464(2):541-7.
36. Djouad F, Charbonnier LM, Bouffi C, Louis-Plence P, Bony C, Apparailly F, et al. IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS One. 2010;5:e14247.
37. Galleu A, Riffo-Vasquez Y, Trento C, Lomas C, Dolcetti L, Cheung TS, et al. Apoptosis in mesenchymal stromal cells induces in-vivo recipient-mediated immunomodulation. Sci Transl Med. 2017;9(416):7828.
38. Kean TJ, Lin P, Caplan AI, Dennis JE. MSCs: Delivery routes and engraftment, cell-targeting strategies and immune modulation. Stem Cells Int. 2013;2013:732742.
39. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: Sensors and switchers of inflammation. Stem Cells. 2013;31(10):2042-6.
40. Yu B, Shao H, Su C, Jiang Y, Chen X, Bai L, et al. Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep. 2016;6:34562.
41. Perez VL, Caspi RR. Immune mechanisms in inflammatory and degenerative eye disease. Trends Immunol. 2015;36(6):354-63.
42. Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. The immunomodulatory potential of mesenchymal stem cells in a retinal inflammatory environment. Stem Cell Rev Rep. 2019;15(3):392-402.
43. Ji S, Xiao J, Liu J, Tang S. Human umbilical cord mesenchymal stem cells attenuate ocular hypertension-induced retinal neuroinflammation via toll-like receptor 4 pathway. Stem Cells Int. 2019;2019:9274585.
44. Sun J, Mandai M, Kamao H, Hashiguchi T, Shikamura M, Kawamata S, et al. Protective effects of human iPS-derived retinal pigmented epithelial cells compared with human mesenchymal stromal cells and human neural stem cells on degenerating retina in rd1 mice. Stem Cells. 2015;33(5):1543-53.
45. Özmert E, Arslan U. Management of retinitis pigmentosa by Wharton’s jelly-derived mesenchymal stem cells: prospective analysis of 1-year results. Stem Cell Res Ther. 2020;11(1):353.
46. Weiss JN, Levy S, Benes SC. Stem cell ophthalmology treatment study: Bone marrow derived stem cells in the treatment of non-arteritic ischemic optic neuropathy. Stem Cell Investig. 2017;4:94.
47. Arnhold S, Absenger Y, Klein H, Addicks K, Schraermeyer U. Transplantation of bone marrow-derived mesenchymal stem cells rescue photoreceptor cells in dystrophic retina of rhodopsin knockout mouse. Graefes Arch Clin Exp Ophthalmol. 2007;245(3):414-22.
48. Ishibazawa A, Nagaoka T, Yokota H, Takahashi A, Omae T, Song YS, et al. Characteristics of retinal neovascularization in proliferative diabetic retinopathy imaged by optical coherence tomography angiography. Invest Ophthalmol Vis Sci. 2016;57(14):6247-55.
49. Kim KS, Park JM, Kong T, Kim C, Bae SH, Kim HW, et al. Retinal angiogenesis effects of TGF-β1 and paracrine factors secreted from human placental stem cells in response to a pathological environment. Cell Transplant. 2016;25(6):1145-57.
50. Zhang W, Liu H, Rojas M, Caldwell RW, Caldwell RB. Efficacy and safety of autologous bone marrow mesenchymal stem cell transplantation in patients with diabetic retinopathy. Cell Physiol Biochem. 2018;49(1):40-52.
51. Gaddam S, Periasamy R, Gangaraju R. Adult stem cell therapeutics in diabetic retinopathy. Int J Mol Sci. 2019;20(19):4876.
52. Elshaer SL, Evans W, Pentecost M, Lenin R, Periasamy R, Jha KA, et al. Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2Akita mouse. Stem Cell Res Ther. 2018;9(1):322.
53. Yang J, Li Y, Chan L. Induced pluripotent stem cells and outer retinal disease. Stem Cells Int. 2016;2016:2850873.
54. Li X, Xie X, Lian W, Shi R, Han S, Zhang H, et al. Preconditioning of adipose tissue-derived mesenchymal stem cells with deferoxamine increases production of pro-angiogenic, neuroprotective and anti-inflammatory factors. PLoS One. 2017;12:e0178011.
55. Fiori A, Terlizzi V, Kremer H, Gebauer J, Hammes HP, Harmsen MC, et al. Mesenchymal stromal/stem cells as potential therapy in diabetic retinopathy. Immunobiology. 2018;223(12):729-43.
56. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014;20(7):1126-67.
57. Ohkouchi S, Block GJ, Katsha AM, Kanehira M, Ebina M, Kikuchi T, et al. Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1. Mol Ther. 2012;20(2):417-23.
58. Barzelay A, Weisthal Algor S, Niztan A, Katz S, Benhamou M, Nakdimon I, et al. Adipose-derived mesenchymal stem cells migrate and rescue RPE in the setting of oxidative stress. Stem Cells Int. 2018;2018:9682856.
59. Dias MF, Joo K, Kemp JA, Fialho SL, da Silva Cunha A, Woo SJ, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives. Prog Retin Eye Res. 2018;63:107-31.
60. Prado DA, Acosta-Acero M, Maldonado RS. Gene therapy beyond Luxturna: A new horizon of the treatment for inherited retinal disease. Curr Opin Ophthalmol. 2020;31(3):147-54.
61. Diakatou M, Manes G, Bocquet B, Meunier I, Kalatzis V. Genome editing as a treatment for the most prevalent causative genes of autosomal dominant retinitis pigmentosa. Int J Mol Sci. 2019;20(10):2542.
62. Doudna JA, Charpentier E. Genome editing: the new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096.
63. Peddle CF, MacLaren RE. The application of CRISPR/Cas9 for the treatment of retinal diseases. Yale J Biol Med. 2017;90(4):533-41.
64. Saari JC. Vitamin A and vision. Subcell Biochem. 2016;81:231-59.
65. Perusek L, Maeda T. Vitamin A derivatives as treatment options for retinal degenerative diseases. Nutrients. 2013;5(7):2646-66.
66. Ostler E, Rhee D, Burney E, Sozeri Y. Advances in medical therapy for glaucoma. Curr Opin Ophthalmol. 2021;32(2):129-33.
67. Faiq MA, Wollstein G, Schuman JS, Chan KC. Cholinergic nervous system and glaucoma: from basic science to clinical applications. Prog Retin Eye Res. 2019;72:100767.
68. Brooks AM, Gillies WE. Ocular beta-blockers in glaucoma management: Clinical pharmacological aspects. Drugs Aging. 1992;2(3):208-21.
69. Zimmerman TJ. Topical ophthalmic beta blockers: a comparative review. J Ocul Pharmacol. 1993;9(4):373-84.
70. Stein JD, Khawaja AP, Weizer JS. Glaucoma in adults-screening, diagnosis and management: A review. JAMA. 2021;325(2):164-74.
71. Samples JR, Singh K, Lin SC, Francis BA, Hodapp E, Jampel HD, et al. Laser trabeculoplasty for open-angle glaucoma: A report by the American Academy of Ophthalmology. Ophthalmology. 2011;118(11):2296-302.
72. Freitas AL, Ushida M, Almeida I, Dias DT, Dorairaj S, Kanadani FN, et al. Selective laser trabeculoplasty as an initial treatment option for open-angle glaucoma. Ophthalmology. 2016;123(2):263-70.
73. Tsang S, Cheng J, Lee JW. Developments in laser trabeculoplasty. Curr Opin Ophthalmol. 2015;26(2):134-9.
74. Babighian S, Caretti L, Tavolato M, Cian R, Galan A. Excimer laser trabeculotomy vs 180 degrees selective laser trabeculoplasty in primary open-angle glaucoma: a 2-year randomized controlled trial. Eye (Lond). 2010;24(4):632-8.
75. Vinod K, Gedde SJ, Feuer WJ, Panarelli JF, Chang TC, Chen PP, et al. Practice preferences for glaucoma surgery: a survey of the American Glaucoma Society. J Glaucoma. 2017;26(8):687-93.
76. Binibrahim IH, Bergström AK. The role of trabeculectomy in enhancing glaucoma patient’s quality of life. Clin Ophthalmol. 2017;11:141-6.
77. Rotchford AP, King AJ. Moving the goal posts: Definitions of success after glaucoma surgery and their effect on reported outcome. Am J Ophthalmol. 2009;148(3):356-61.
78. Al Habash A, Aljasim LA, Owaidhah O, Edward DP. A review of the efficacy of mitomycin C in glaucoma filtration surgery. Clin Ophthalmol. 2015;9:1945-51.
79. Kansal V, Armstrong JJ, Hutnik CM. Trends in glaucoma filtration procedures: A retrospective administrative health records analysis over a 13-year period in Canada. Clin Ophthalmol. 2020;14:501-8.
80. Wang J, Barton K. Aqueous shunt implantation in glaucoma. Taiwan J Ophthalmol. 2017;7(3):130-7.
81. Melamed S, Fiore PM. Molteno implant surgery in refractory glaucoma. Surv Ophthalmol. 1990;34(6):441-8.
82. The changing paradigm of outflow resistance generation: towards synergistic models of the JCT and inner wall endothelium. Exp Eye Res. 2009;88(4):656-70.
83. Fellman RL, Mattox C, Singh K, Flowers B, Francis BA, Robin AL, et al. American Glaucoma Society position paper: Microinvasive glaucoma surgery. Ophthalmology. 2020;127(2):278-86.
84. Pereira IC, van de Wijdeven R, Wyss HM, Beckers HJ, den Toonder JM. Conventional glaucoma implants and the new MIGS devices: A comprehensive review of current options and future directions. Eye Vis (Lond). 2021;8(1):17.
85. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-86.
86. DCCT/EDIC Research Group, Aiello LP, Sun W, Das A, Gangaputra S, Kiss S, et al. Intensive diabetes therapy and ocular surgery in type 1 diabetes. N Engl J Med. 2015;372(18):1722-33.
87. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-12.
88. Bressler SB, Odia I, Maguire MG, Dhoot DS, Glassman AR, Jampol LM, et al. Factors associated with visual acuity and central subfield thickness changes when treating diabetic macular edema with anti-vascular endothelial growth factor therapy. JAMA Ophthalmol. 2019;137(4):382-9.
89. Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib for diabetic macular edema. Ophthalmology. 2005;112(10):1747-57.
90. Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, et al. Intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study): 12-month data. Ophthalmology. 2010;117(6):1078-86.
91. Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, bevacizumab or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-9.
92. Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol. 2001;132(3):425-7.
93. Campochiaro PA, Brown DM, Pearson A, Ciulla T, Boyer D, Holz FG, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):626-35.
94. Kaur S, Yangzes S, Singh S, Sachdev N. Efficacy and safety of topical difluprednate in persistent diabetic macular edema. Int Ophthalmol. 2016;36(3):335-40.
95. ED Donnenfeld. Difluprednate ophthalmic emulsion is effective in reducing refractory diabetic macular edema. Retina. 2010;30(6):963-9.
96. Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: Two-year results of a randomized clinical trial. Ophthalmology. 2007;114(4):716-23.
97. Khan Z, Kuriakose RK, Khan M, Chin EK, Almeida DRP. Efficacy of the intravitreal sustained-release dexamethasone implant for diabetic macular edema refractory to anti-VEGF therapy. Ophthalmic Surg Lasers Imaging Retina. 2017;48(2):160-6.
98. Pessoa B, Coelho J, Correia N, Ferreira N, Beirão M, Meireles A. Fluocinolone acetonide intravitreal implant in vitrectomized versus nonvitrectomized eyes for chronic diabetic macular edema. Ophthalmic Res. 2018;59(2):68-75.
99. Maturi RK, Glassman AR, Liu D, Beck RW, Bhavsar AR, Bressler NM, et al. Effect of adding dexamethasone to continued ranibizumab treatment in persistent diabetic macular edema. JAMA Ophthalmol. 2018;136(1):29-38.
100. Krick TW, Bressler NM. Recent clinically relevant highlights from the Diabetic Retinopathy Clinical Research Network. Curr Opin Ophthalmol. 2018;29(3):199-205.
101. Kodjikian L, Bellocq D, Mathis T. Pharmacological management of diabetic macular edema in real-life observational studies. Clin Ophthalmol. 2018;12:1257-64.
102. Callanan DG, Loewenstein A, Patel SS, Massin P, Corcóstegui B, Li XY, et al. A multicenter randomized study comparing dexamethasone intravitreal implant with ranibizumab in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2017;255(3):463-73.
103. Cicinelli MV, Cavalleri M, Querques L, Rabiolo A, Bandello F, Querques G. Early response to ranibizumab predictive of functional outcome after dexamethasone for unresponsive diabetic macular oedema. Br J Ophthalmol. 2017;101(12):1689-93.
104. Storey PP, Obeid A, Pancholy M, Goodman J, Borkar D, Su D, et al. Ocular hypertension after intravitreal injection of 2-mg triamcinolone. Retina. 2020;40(1):75-9.
105. Friedman SM, Almukhtar TH, Baker CW, Glassman AR, Elman MJ, Bressler NM, et al. Topical nepafenac in eyes with noncentral diabetic macular edema. Ophthalmology. 2015;122(5):1038-45.
106. Kim SJ, Schoenberger SD, Thorne JE, Ehlers JP, Yeh S, Bakri SJ. Topical nonsteroidal anti-inflammatory drugs and cataract surgery: A report by the American Academy of Ophthalmology. Ophthalmology. 2015;122(11):2159-68.
107. Pinna A, Blasetti F, Ricci GD, Boscia F. Bromfenac eyedrops in the treatment of diabetic macular edema: A pilot study. Clin Ophthalmol. 2017;11:1733-9.
108. AM Elbendary. Intravitreal diclofenac versus intravitreal triamcinolone acetonide in diabetic macular edema. Retina. 2012;32(4):702-8.
109. A Seth. Intravitreal diclofenac for treatment of macular edema of various etiologies: A pilot study. Retina. 2009;29(8):1084-91.
110. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361(1):40-51.
111. Chase HP, Garg SK, Harris S, Hoops S, Jackson WE, Holmes DL. Angiotensin-converting enzyme inhibitor treatment for young normotensive diabetic subjects: a two-year trial. Ann Ophthalmol. 1993;25(8):284-9.
112. Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes (EUCLID study). Lancet. 1998;351(9095):28-31.
113. SA Virk. Interventions for diabetic retinopathy in type 1 diabetes: Systematic review and meta-analysis. JAMA. 2015;314(4):349-60.
114. Deissler HL, Lang GE. The protein kinase C inhibitor ruboxistaurin. Dev Ophthalmol. 2016;55:295-301.
115. Cho WB, Oh SB, Moon JW, Kim HC. Panretinal photocoagulation combined with intravitreal bevacizumab in high-risk proliferative diabetic retinopathy. Retina. 2009;29(4):516-22.
116. Sun JK, Glassman AR, Beaulieu WT, Stockdale CR, Bressler NM, Flaxel C, et al. Rationale and application of the Protocol S anti-vascular endothelial growth factor algorithm for proliferative diabetic retinopathy. Ophthalmology. 2019;126(1):87-95.
117. Mehta H, Gillies MC, Fraser‐Bell S. Combination of vascular endothelial growth factor inhibitors and laser therapy for diabetic macular oedema: A review. 2022.
118. Bressler SB, Glassman AR, Almukhtar T, Bressler NM, Ferris FL, Googe JM, et al. Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. Am J Ophthalmol. 2016;164:57-68.
119. Jackson TL, Johnston RL, Donachie PHJ, Williamson TH, Sparrow JM, Steel DHW. The Royal College of Ophthalmologists’ National Ophthalmology Database study of vitreoretinal surgery: report 6, diabetic vitrectomy. JAMA Ophthalmol. 2016;134(1):79-85.
120. Mikhail M, Ali-Ridha A, Chorfi S, Kapusta MA. Long-term outcomes of sutureless 25-G+ pars-plana vitrectomy for the management of diabetic tractional retinal detachment. 2024.
121. Nakajima T, Roggia MF, Noda Y, Ueta T. Effect of internal limiting membrane peeling during vitrectomy for diabetic macular edema: Systematic review and meta-analysis. Retina. 2015;35(9):1719-25.
122. Hartley KL, Smiddy WE, Harry W Flynn Jr, Murray TG.Pars plana vitrectomy with internal limiting membrane peeling for diabetic macular edema. 2020.
123. Arevalo JF, Lasave AF, Wu L, Maia M, Diaz-Llopis M, Alezzandrini AA, et al. Intravitreal bevacizumab for proliferative diabetic retinopathy: results from the Pan-American Collaborative Retina Study Group at 24 months of follow-up. Retina. 2017;37(2):334-43.
124. Jackson TL, Nicod E, Angelis A, Grimaccia F, Pringle E, Kanavos P. Pars plana vitrectomy for diabetic macular edema: a systematic review, meta-analysis and synthesis of safety literature. Retina. 2017;37(5):886-95.
125. Bressler SB, Melia M, Glassman AR, Almukhtar T, Jampol LM, Shami M, et al. Ranibizumab plus prompt or deferred laser for diabetic macular edema in eyes with vitrectomy prior to anti-vascular endothelial growth factor therapy. Retina. 2015;35(12):2516-28.
126. Yamada Y, Suzuma K, Ryu M, Tsuiki E, Fujikawa A, Kitaoka T. Systemic factors influence the prognosis of diabetic macular edema after pars plana vitrectomy with internal limiting membrane peeling. Curr Eye Res. 2013;38(12):1261-5.
127. Tuekprakhon A, Sangkitporn S, Trinavarat A, Pawestri AR, Vamvanij V, Ruangchainikom M, et al. Intravitreal autologous mesenchymal stem cell transplantation: a non-randomized phase I clinical trial in patients with retinitis pigmentosa. Stem Cell Res Ther. 2021;12(1):52.
128. Özmert E, Arslan U. Management of retinitis pigmentosa by Wharton’s jelly-derived mesenchymal stem cells: Prospective analysis of 1-year results. Stem Cell Res Ther. 2020;11(1):353.
129. Özmert E, Arslan U. Management of retinitis pigmentosa by Wharton’s jelly-derived mesenchymal stem cells: Preliminary clinical results. Stem Cell Res Ther. 2020;11(1):25.
130. Wiącek MP, Gosławski W, Grabowicz A, Sobuś A, Kawa MP, Baumert B, et al. Long-term effects of adjuvant intravitreal treatment with autologous bone marrow-derived lineage-negative cells in retinitis pigmentosa. Stem Cells Int. 2021;2021:6631921.
131. Kahraman NS, Oner A. Umbilical cord derived mesenchymal stem cell implantation in retinitis pigmentosa: a 6-month follow-up results of a phase 3 trial. Int J Ophthalmol. 2020;13(9):1423-9.
132. Özkan B, Yılmaz Tuğan B, Hemşinlioğlu C, Sır Karakuş G, Şahin Ö, Ovalı E. Suprachoroidal spheroidal mesenchymal stem cell implantation in retinitis pigmentosa: clinical results of 6 months follow-up. Stem Cell Res Ther. 2023;14(1):252.
133. Oner A, Gonen ZB, Sinim N, Cetin M, Ozkul Y. Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: a phase I clinical safety study. Stem Cell Res Ther. 2016;7(1):178.
134. Limoli PG, Limoli CSS, Morales MU, Vingolo EM. Mesenchymal stem cell surgery, rescue and regeneration in retinitis pigmentosa: clinical and rehabilitative prognostic aspects. Restor Neurol Neurosci. 2020;38(3):223-37.
135. Siqueira RC, Messias A, Voltarelli JC, Scott IU, Jorge R. Intravitreal injection of autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy: A phase I trial. Retina. 2011;31(6):1207-14.
136. Suen HC, Qian Y, Liao J, Luk CS, Lee WT, Ng JKW, et al. Transplantation of retinal ganglion cells derived from male germline stem cell as a potential treatment to glaucoma. Stem Cells Dev. 2019;28(20):1365-75.
137. Seong HR, Noh CH, Park S, Cho S, Hong SJ, Lee AY, et al. Intraocular pressure-lowering and retina-protective effects of exosome-rich conditioned media from human amniotic membrane stem cells in a rat model of glaucoma. Int J Mol Sci. 2023;24(9):8073.
138. Ji S, Xiao J, Liu J, Tang S. Human umbilical cord mesenchymal stem cells attenuate ocular hypertension-induced retinal neuroinflammation via Toll-like receptor 4 pathway. Stem Cells Int. 2019;2019:9274585.
139. Mead B, Tomarev S. BMSC-derived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms. Stem Cells Transl Med. 2017;6(4):1273.
140. Kumar A, Siqi X, Zhou M, Chen W, Yang E, Price A, et al. Stem cell-free therapy for glaucoma to preserve vision. bioRxiv. 2021.
141. Vilela CAP, Messias A, Calado RT, Siqueira RC, Silva MJL, Covas DT, et al. Retinal function after intravitreal injection of autologous bone marrow-derived mesenchymal stromal cells in advanced glaucoma. Doc Ophthalmol. 2021;143(1):33-8.
142. Mead B, Ahmed Z, Tomarev S. Mesenchymal stem cell-derived small extracellular vesicles promote neuroprotection in a genetic DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci. 2018;59(13):5473-80.
143. Limoli PG, Limoli C, Vingolo EM, Franzone F, Nebbioso M. Mesenchymal stem and non-stem cell surgery, rescue and regeneration in glaucomatous optic neuropathy. Stem Cell Res Ther. 2021;12(1):275.
144. Wang Y, Lv J, Huang C, Li X, Chen Y, Wu W, et al. Human umbilical cord mesenchymal stem cells survive and migrate within the vitreous cavity and ameliorate retinal damage in a novel rat model of chronic glaucoma. Stem Cells Int. 2021;2021:8852517.
145. Reddy SK, Ballal AR, Shailaja S, Seetharam RN, Raghu CH, Sankhe R, et al. Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy. Theranostics. 2023;13(7):2241-55.
146. Fu Y, Gu ZH, Wen XY, Yang N. Effects of intravitreal injection of hypoxia-induced umbilical cord mesenchymal stem cell exosomes on diabetic retinopathy. Research Square. 2022.
147. Rajashekhar G, Ramadan A, Abburi C, Callaghan B, Traktuev DO, Evans-Molina C, et al. Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy. PLoS One. 2014;9(1):e84671.
148. Lupo G, Agafonova A, Cosentino A, Giurdanella G, Mannino G, Lo Furno D, et al. Protective effects of human pericyte-like adipose-derived mesenchymal stem cells on human retinal endothelial cells in an in-vitro model of diabetic retinopathy. Int J Mol Sci. 2023;24(2):913.
149. Kremer H, Gebauer J, Elvers-Hornung S, Uhlig S, Hammes HP, Beltramo E, et al. Pro-angiogenic activity discriminates human adipose-derived stromal cells from retinal pericytes: Considerations for cell-based therapy of diabetic retinopathy. Front Cell Dev Biol. 2020;8:387.
150. Gu X, Yu X, Zhao C, Duan P, Zhao T, Liu Y, et al. Efficacy and safety of autologous bone marrow mesenchymal stem cell transplantation in patients with diabetic retinopathy. Cell Physiol Biochem. 2018;49(1):40-52.
151. Kim H, Goh YS, Park SE, Hwang J, Kang N, Jung JS, et al. Preventive effects of exosome-rich conditioned medium from amniotic membrane-derived mesenchymal stem cells for diabetic retinopathy in rats. Transl Vis Sci Technol. 2023;12(8):18.
152. Zhao K, Liu J, Dong G, Xia H, Wang P, Xiao X, et al. Preliminary research on the effects and mechanisms of umbilical cord-derived mesenchymal stem cells in streptozotocin-induced diabetic retinopathy. Int J Mol Med. 2020;46(2):849-58.
153. Sun F, Sun Y, Zhu J, Wang X, Ji C, Zhang J, et al. Mesenchymal stem cells-derived small extracellular vesicles alleviate diabetic retinopathy by delivering NEDD4. Stem Cell Res Ther. 2022;13:293.
154. Xu Z, Tian N, Li S, Li K, Guo H, Zhang H, et al. Extracellular vesicles secreted from mesenchymal stem cells exert anti-apoptotic and anti-inflammatory effects via transmitting microRNA-18b in rats with diabetic retinopathy. Int Immunopharmacol. 2021;101:108234.
155. Fiori A, Hammes HP, Bieback K. Adipose-derived mesenchymal stromal cells reverse high glucose-induced reduction of angiogenesis in human retinal microvascular endothelial cells. Cytotherapy. 2020;22(5):261-75.