Mesenchymal stem cell-derived microRNAs: Key immunomodulators to prevent ocular tissue degeneration

Table 1 Effects of mesenchymal stem cell-derived microRNAs in corneal diseases

Type of MSC	MiRNA	Target	Expression pattern	Function	Ref.
Human umbilical cord-MSC	MiR-21	PTEN	Upregulated	Enhanced corneal epithelial cell proliferation, migration, and wound healing, both in vitro and in vivo	Liu et al[53]
Human limbal MSC	MiR-155, miR-29	TGF-β1/β3	Upregulated	Negatively regulated corneal fibrosis by inhibiting collagen matrix synthesis instead of inhibiting myofibroblast formation	Altug et al[58]
Mouse bone marrow-MSC	MiR-29b-3p	PI3K	Upregulated	Improved the therapeutic effect via activated autophagy and inhibited corneal inflammation and fibrosis	Liu et al[59]
Rabbit adipose derived MSC	MiR-19	HIPK2	Upregulated	Suppressed fetal bovine serum induced differentiation of rabbit corneal keratocytes into myofibroblasts by inhibiting HIPK2 expression	Shen et al[57]
Rabbit adipose-derived MSC	MiR-24-3p	-	Upregulated	Enhanced healing of corneal epithelial defect, cell migration, and maturation while inhibiting fibrosis and reducing the levels of inflammatory cytokines (CD163, and MMP9) in both in vitro and in vivo	Sun et al[56]
Human adipose-derived MSC	Let-7a-5p, miR-23a-3p, miR-29b-3p, miR-302-3p, and miR-1246	-	Upregulated	Improved the wound healing and migration of corneal epithelial cells by inducing a shift in the cell cycle, and inhibiting senescence and autophagy pathways	Ryu et al[55]

HIPK2: Homeodomain-interacting protein kinase 2; miRNA: MicroRNA; MMP9: Matrix metalloproteinase-9; MSC: Mesenchymal stem cell; PI3K: Phosphatidylinositol 3-kinase; PTEN: Phosphatase and tensin homolog; TGF-1: Transforming growth factor beta 1.

Table 2 Effects of mesenchymal stem cell-derived microRNAs in dry eye disease

Type of MSC	MiRNA	Target	Expression pattern	Function	Ref.
Human umbilical cord-MSC	MiR-204	IL-6R	Upregulated	Downregulated IL-6/IL-6R/STAT3 signaling responsible for macrophage phenotypes and alleviated dry eye (prospective clinical trial)	Zhou et al[63]
Human umbilical cord-MSC	MiR-100-5p	mTOR	Upregulated	Attenuated by skewed macrophages into a M2 phenotype and increased Treg proportion	Li et al[66]
Human umbilical cord-MSC	MiR-125b, let-7b, miR-6873	IRAK1	Upregulated	Inhibited ocular surface inflammation by multitargeting the IRAK1/TAB2/NF-κB signaling pathway	Wang et al[65]
Rat bone marrow-MSC	MiR-21-5p	TLR4	Upregulated	Decreased production of inflammatory and promoted synthesis of immunosuppressive cytokines and enhanced Tregs-driven suppression of inflammatory Th17 cells	Zhao et al[67]
Mouse adipose-derived MSC	MiR-223-3p	Fbxw7	Upregulated	Alleviated ocular surface damage and decreased pro-inflammatory cytokines or chemokines by targeting Fbxw7	Wang et al[68]

Fbxw7: F-box and WD repeat domain containing 7; IL: Interleukin; IL-6R: Interleukin 6 receptor; IRAK1: Interleukin 1 receptor-associated kinase 1; miRNA: MicroRNA; MSC: Mesenchymal stem cell; mTOR: Mechanistic target of rapamycin; NF-κB: Nuclear factor kappa B; STAT3: Signal transducer and activator of transcription 3; TAB2: TGF-beta activated kinase 1; Th17: T helper type 17; TLR4: Toll-like receptor 4; Treg: Regulatory T cell.

Table 3 Effects of mesenchymal stem cell-derived microRNAs in diabetic retinopathy

Type of MSC	MiRNA	Target	Expression pattern	Function	Ref.
ADMSC	MiR-192	ITGA1	Upregulated	Negatively regulated ITGA1 and ameliorated diabetic retinal damage	Gu et al[75]
Rabbit ADMSCs	MiR-222	STAT5	Upregulated	Induced repair of diabetic retinal degeneration	Safwat et al[74]
Human BMSC	MiR-486-3p	TLR4	Upregulated	Inhibited oxidative stress, inflammation and apoptosis, and promoted proliferation of high glucose-treated Muller cells by downregulating TLR4; through TLR4/NF-κB axis repression	Li et al[81]
Human umbilical cord-MSC	MiR-18b	MAP3K1	Upregulated	Reduced vascular leakage and inflammation by targeting MAP3K1, thereby inhibited NF-κB p65 phosphorylation	Xu et al[78]
Human umbilical cord-MSC	MiR-17-3p	STAT1	Upregulated	Decreased contents of inflammatory factors and VEGF, alleviated oxidative injury, and inhibited retinal cell apoptosis through inhibiting STAT1	Li et al[77]
Human umbilical cord-MSC	MiR-30c-5p	PLCG1	Upregulated	Inhibited oxidative stress and inflammation in high glucose-treated retinal endothelial cells via the PLCG1/PKC/NF-κB axis	He et al[79]
Human umbilical cord-MSC	MiR-5068, miR-10228	HIF-1α	Upregulated	Exhibited enhanced retinal therapeutic efficiency by regulating HIF-1α/EZH2/PGC-1α pathway	Sun et al[80]

ADMSC: Adipose tissue-derived mesenchymal stem cell; EZH2: Enhancer of zeste homolog 2; HIF: Hypoxia-inducible factor; ITGA1: Integrin alpha 1; MAP3K1: Mitogen-activated protein kinase kinase kinase 1; miRNA: MicroRNA; MSC: Mesenchymal stem cell; NF-κB: Nuclear factor kappa B; PGC-1α: Proliferator-activated receptor gamma coactivator 1 alpha PKC: Protein kinase C; PLCG1: Phospholipase C gamma 1; STAT5: Signal transducer and activator of transcription 5; TLR4: Toll-like receptor 4; VEGF: Vascular endothelial growth factor.

Table 4 Effect of mesenchymal stem cell-derived microRNAs in age-related macular degeneration and glaucoma

Type of MSC	MiRNA	Target	Expression pattern	Function	Ref.
Mouse bone marrow-MSC	MiR-21a-5p	PDCD4	Upregulated	Promoted RGC survival	Su et al[100]
Rat bone marrow-MSCs	MiR-21	PDCD4	Upregulated	Maintained photoreceptor survival by targeting PDCD4 to inhibit apoptosis	Deng et al[87]
TNF-α-stimulated gingival MSC	MiR-21-5p	PDCD4	Upregulated	Increased retinal cell viability and neuroinflammation in vitro, prevented the apoptosis and inflammation of retina	Yu et al[101]
Human bone marrow-MSC	MiR-144-5p, miR-126-5p, and miR-100-5p	-	Upregulated	Increased neuroprotection and functional preservation of RGC	Mead et al[98]
Human bone marrow-MSC	MiR-17–5p, miR-30c-2 and miR-92a; miR-92a, miR-292 and miR-182	PTEN	Upregulated	Protected RGCs and their axons from degeneration and dysfunction through PTEN knockdown	Mead and Tomarev[99]
Human umbilical cord-MSC	MiR-27-b	HOXC6	Upregulated	Inhibited TGF-β-induced epithelial-mesenchymal transition by targeting HOXC6 and attenuated subretinal fibrosis	Li et al[89]
Human umbilical cord-MSC	MiR-146a	Nr43a	Upregulated	Significantly decreased the expression of LPS-induced pro inflammatory cytokines	Zhang et al[88]
Human umbilical cord-MSC	MiR-22-3p	MAPK312	Upregulated	Ameliorated NMDA-induced RGC injury through the inhibition of MAPK signaling pathway-mediated apoptosis	Yu et al[102]

HOXC6: Homeobox C6; LPS: Lipopolysaccharide; MAPK: Mitogen-activated protein kinase; miRNA: MicroRNA; MSC: Mesenchymal stem cell; NMDA: N-methyl-D-aspartic acid; PDCD4: Programmed cell death 4; PTEN: Phosphatase and tensin homolog; RGC: Retinal ganglion cell; TGF: Transforming growth factor; TNF: Tumor necrosis factor.