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.