Potential therapeutic applications of mesenchymal stem cells for the treatment of eye diseases

Table 1 Summary of the main results obtained in mesenchymal stem cell-based experiments for diabetic retinopathy

MSC source	Treatment	Results	Ref.
Human/mouse ASCs	In vitro pericyte-like differentiation of ASCs by addition of TGF-β1	Increased expression of typical pericyte markers (α-smooth muscle actin and Nerve/glial-antigen 2)	Mendel et al[19], 2013
	Intravitreal injection of native or pericyte-like differentiated MSCs in a murine model of diabetic retinopathy	Prevention of retinal capillary dropout and improved revascularization of the central retina
Human ASCs	In vitro pericyte-like differentiation of ASCs by using a culture medium designed for pericytes	Increased expression of typical pericyte markers (α-smooth muscle actin and Nerve/glial-antigen 2)	Mannino et al[20], 2020
	Co-cultures of pericyte-like ASCs and human retinal endothelial cells	Enhanced endothelial expression of junction proteins (VE-cadherin, zone occludens 1 and occludin). Increased trans endothelial electrical resistance in a blood-retina barrier model
Human ASCs	High glucose cultures of retinal endothelial cells treated with conditioned medium from ASCs cultured in high glucose conditions	Suppression of pro-inflammatory and proangiogenic genes. Restoration of retinal endothelial cell parameters to normal glucose conditions	Hajmousa et al[23], 2018
Human ASCs	ASC effects on endothelial cells of the human umbilical cord veins	Vascular network stabilization by ASC expression of NOTCH2. NOTCH2 downregulation impaired ASC migratory ability	Terlizzi et al[24], 2018
Mouse ASCs	Intravitreal ASC injection in streptozotocin-induced diabetic mouse model	Retinal ganglion cell loss was prevented. Reduced oxidative damage and increased intraocular levels of neurotrophic and anti-angiogenic factors	Ezquer et al[26], 2016
Human ASCs	Intravitreal ASC injection in streptozotocin-induced diabetic mouse model	Significant decrease of vascular leakage and apoptotic cells around the retinal vessels. Down-regulation of inflammatory gene expression in diabetic retina. Significantly improved “b’’ wave amplitude in the electroretinogram	Rajashekhar et al[27], 2014
Mouse ASCs	Intravitreal injections in Akimba mice of ASCs from diabetic or healthy mice, and respective conditioned media.	ASCs from healthy mice better improved retinal protection, likely because of higher levels of insulin-like growth factor binding protein-3 and stromal cell-derived factor-1	Cronk et al[28], 2015
Human ASCs	Intravitreal injection of cytokine-stimulated ASCs or their conditioned medium in a mouse model	ASC injection ameliorated electroretinogram parameters and reduced vascular leakage. Conditioned medium injections also improved visual acuity	Elshaer et al[17], 2018
EngineeredMouse BMSCs	High glucose treated Müller cells exposed to extracellular vesicles obtained from BMSCs overexpressing miRNA-486-3p	Improvement of Müller cell proliferation and inhibition of Toll-like receptor 4-mediated oxidative stress, inflammation and apoptosis	Li et al[30], 2020
EngineeredRat BMSCs	Intravitreal injections of BMSCs overexpressing C-X-C chemokine receptor type 4 in a streptozotocin-induced diabetic rat model	Reduced retinal damage and pro-inflammatory cytokine levels. Increased expression of rhodopsin and neuron specific enolase protein. Improved migratory ability	Wang et al[31], 2018
EngineeredRat BMSCs	Co-cultures of blue light injured retinal pigment epithelium cells with BMSCs overexpressing ciliary neurotrophic factor	Improved antioxidant ability and autophagic flux of retinal cells, whereas VEGF secretion and apoptosis were decreased	Lin et al[32], 2018
Engineered Human placenta MSCs	Co-cultures of oxidative stress-injured retinal pigment epithelium cells with BMSCs overexpressing pigment epithelium-derived factor	Improved mitochondrial functions and reduced apoptosis of retinal cells	Kim et al[33], 2021
	Intravitreal injection of engineered BMSCs in a rat model of retinal degeneration	Decreased levels of pro-inflammatory cytokines and vascular endothelial growth factor. Restoration of retina structure and function
Autologous BMSCs	Pilot clinical trial carried out by intravitreal injection of autologous BMSCs in patients with diabetic retinopathy	Fasting blood glucose and hypersensitive C-reactive protein were reduced. Eyes of patients with non-proliferative diabetic retinopathy showed a macular thickness reduction and a significant improvement of best corrected visual acuity	Gu et al[34], 2018

ASCs: Adipose tissue stem cells; MSCs: Mesenchymal stem cells; TGF: Transforming growth factor; BMSCs: Bone marrow stem cells.

Table 2 Summary of the main results obtained in mesenchymal stem cell-based experiments for glaucoma

MSC source	Treatment	Results	Ref.
Rat BMSCs	In vitro co-cultures of BMSCs with pigmented cells from ciliary margin	Enhanced expression of cone-rod homeobox, at both mRNA and protein level	Li et al[43], 2017
Mouse BMSCs	BMSC injection into the ocular anterior chamber of a laser-induced rat model	Decreased intraocular pressure likely due to MSC paracrine activity	Manuguerra-Gagné et al[44], 2013
Rat BMSCs	BMSC injection into the ocular anterior chamber of a rat model obtained by cauterization of episcleral veins	Reduced intraocular pressure, associated to MSC engrafting to the ciliary processes and to the trabecular meshwork	Roubeix et al[45], 2015
	BMSC-conditioned medium treatment of TGF-β2-induced fibrotic human trabecular meshwork cell cultures	Improved survival of trabecular meshwork cells, by activation of anti-apoptotic signaling pathway Akt
Rat BMSCs	Intravitreal or intravenous administration of labeled BMSCs in a laser-induced ocular hypertension rat model	Local but not systemic BMSC administration improved retinal ganglion cell survival. Transplanted BMSCs were preferentially located in a perivascular position	Johnson et al[47], 2010
Rat/humanBMSCs	Co-cultures of retinal explants with rat and human BMSCs, or rat and human fibroblasts	BMSCs but not fibroblasts improved retinal ganglion cell survival. An increased density of cells expressing islet-1 and NeuN was found in retinal ganglion cell layer	Johnson et al[48], 2014
	Exposure of retinal explant cultures to conditioned media from BMSCs or fibroblast	Moderate improvements were observed only for BMSC conditioned medium treatment
Human BMSCs	Intravitreal injections of extracellular vesicles obtained from BMSCs of fibroblasts in two rat models of glaucoma	BMSC extracellular vesicles more efficiently reduced retinal ganglion cell apoptosis	Mead et al[38], 2018
Engineered mouse BMSCs	Indirect co-cultures of BMSCs with retinal ganglion cells in a transwell system	BMSCs enhanced anti-apoptotic effects on retinal ganglion cells by upregulation of stanniocalcin-1. Improved effects were obtained by miRNA-21-overexpressing BMSCs	Su et al[49], 2017
Autologous BMSCs	Clinical trial carried out by intravitreal injection of autologous BMSCs in patients with advanced stage of glaucoma	No significant improvements were reported	Vilela et al[50], 2021

MSCs: Mesenchymal stem cells; TGF: Transforming growth factor; BMSCs: Bone marrow stem cells; miRNA: MicroRNA.

Table 3 Summary of the main results obtained in mesenchymal stem cell-based experiments for retinitis pigmentosa

MSC source	Treatment	Results	Ref.
ConjunctivaMSCs	Retinal-like MSC differentiation in 3D scaffold fibrin gel, by an induction medium containing taurine	Increased expression of typical retinal markers (nestin, rhodopsin, and RPE65)	Soleimannejad et al[68], 2017
Rat BMSCs	Intravitreal BMSC injections in a rat model of retina degeneration	Increased expression of typical photoreceptor marker (rhodopsin) and retinal pigment epithelium (pancytokeratin)	Huo et al[65], 2010
Mouse BMSCs	BMSC injections in the subretinal space of rhodopsin knockout mice	MSC engrafting in retinal pigment epithelium and neuroretina, acquiring neuronal and glial morphology, and prolonging photoreceptor survival	Arnhold et al[69], 2007
Rat BMSCs	Intravenous BMSC administration in a rat model of retinitis pigmentosa, before photoreceptor loss	Rod and cone cell preservation. Improved visual functions	Wang et al[70], 2010
Mouse ASCs/human UCMSCs	Intravitreal MSC or their exosomes in a laser-induced mouse model of retinal injury	Both MSCs and their exosomes reduced retinal damage, apoptosis and inflammatory responses	Yu et al[71], 2016
Human BMSCs	Physically separated co-cultures of BMSCs with porcine neuroretina	BMSC secretomes induced increased levels of anti-inflammatory cytokines, antioxidant and anti-apoptotic proteins, and anti-neurodegeneration proteins, Photoreceptors and the retinal general organization were better preserved	Usategui-Martìn et al[72], 2020
Engineered human UCMSCs	Photoreceptor-like differentiation of UCMSCs overexpressing erythropoietin, by an induction medium containing taurine	Transduced UCMSCs better overexpressed cone-rod homeobox and rhodopsin	Ding et al[73], 2019
Engineered human BMSCs	Photoreceptor-like differentiation of BMSCs overexpressing miRNA-183/96/182 cluster	Transduced BMSCs overexpressed recoverin, a neuronal calcium-binding protein primarily detected in photoreceptors.	Mahmoudian-Sani et al[74], 2019
Engineered conjunctiva MSCs	Photoreceptor-like differentiation of MSCs overexpressing miRNA-9	In a time dependent manner, MSCs overexpressed photoreceptor markers recoverin, rhodopsin, PKC, and peripherin	Rahmani et al[75], 2020
Engineered mouse BMSCs	Intravitreal injections of BMSCs genetically modified to overexpress neurotrophin-4, in a mouse model of retinopathy	Neurotrophin-4-overexpressing BMSCs induced a significant retinal protection, as indicated by bioelectrical recordings and optical coherence tomography.	Machalińska et al[76], 2013
Autologous MSCs	In a phase I clinical trial, the safety, feasibility, and efficacy of autologous BMSC was tested after their intravitreal injection in patients with advanced retinitis pigmentosa	In spite of several mild and transient adverse effects, a significant improvement of best corrected visual acuity was observed. Only one severe, though manageable adverse effect was observed after three years	Tuekprakhon et al[77], 2021
Human UCMSCs	In a phase 3 clinical study, UCMSC administration was carried out by surgical procedures in the suprachoroidal area of 82 patients with retinitis pigmentosa	Over 6-month follow-up period, no serious adverse events were reported. Significant improvements were detected for best corrected visual acuity, visual field and multifocal electroretinography recordings. Beneficial effects might be due to MSC secretion of growth factors.	Kahraman et al[78], 2020
Human UCMSCs	In a phase I/II clinical trial, the protocol safety and efficacy was tested by intravenous administration of UCMSCs in 32 patients with advanced retinitis pigmentosa	The intravenous infusion of UCMSCs was safe, since no serious local or systemic adverse effects occurred over a period of 12 mo. Most patients improved their best corrected visual acuity, especially in the first 3 months. It was concluded that this strategy may improve the quality of life of patients with retinitis pigmentosa.	Zhao et al[79], 2020

ASCs: Adipose tissue stem cells; MSCs: Mesenchymal stem cells; TGF: Transforming growth factor; BMSCs: Bone marrow stem cells; UCMSCs: Umbilical cord mesenchymal stem cells.