TABLE 1.

Comparison of studies demonstrating mesenchymal stem cell (MSC) efficacy in various ocular surface disease models, using different delivery mechanisms

MSC source	Delivery mechanism	Procedure	Cell passage	Animal model	Study length	Key findings	Ref.
Human AD‐MSCs	Topical	2.5E+05 cells seeded on amniotic membrane; eyelids sutured	3/4	Rabbit partial and total LSCD	11 weeks	MSCs migrated to inflamed tissues, reduced inflammation, inhibited neovascularization, and corneal opacification, and expressed CK3 in the corneal epithelium, demonstrating partial restoration of epithelial phenotypes	75
Human AD‐MSCs	Topical	1.25E+05/mm2 cells seeded on a scleral contact lens	3	Rabbit severe acute alkaline burn	4 weeks	MSCs prevented corneal melting and symblepharon, reduced the inflammatory and fibroblastic response, and significantly reduced epithelial defects	76
Human BM‐MSCs	Topical	1E+05 cells/cm2 seeded on amniotic membrane and cultured to 90% confluence. Eyelids sutured for 10 day	1	Rat corneal chemical burn	4 weeks	MSCs enhanced repairmen of injured ocular surface and epithelial integrity. They inhibited inflammation and inflammation‐induced neovascularization, decreasing levels of IL‐2 and CD45, therefore improving transparency	77
Mouse BM‐MSCs	Topical	4E+04 cells on polyamide 6/12 nanofiber scaffold. Eyelids sutured closed. Also seeded with LESCs	Unknown	Mouse corneal mechanical injury	2 weeks	MSCs significantly reduced immune response, through suppression of IFN‐y, iNOS, and IL‐2 gene expression in local corneal cells	78
Rabbit BM‐MSCs	Topical	Unknown cell dose seeded in a fibrin gel, sutured to corneal surface. Eyelids sutured for 7 days	Unknown	Rabbit corneal alkali burn	4 weeks	MSCs did not improve corneal epithelium integrity, neovascularization, or corneal opacity. They expressed CK3, demonstrating differentiation into corneal‐like cells	79
Rabbit BM‐MSCs and AD‐MSCs	Topical	3E+05 cells seeded on PLA nanofiber scaffold, sutured to the conjunctiva. Eyelids closed	3	Rabbit corneal alkali burn	15 days	MSCs caused suppression of MMP9 and iNOS, reduced levels of αSMA, TGF‐B, and VEGF, leading to reduced corneal opacification, neovascularization, and corneal thickness	50
Rat MSC line. Source unknown	Topical	2E+06 cells in media applied for 2 hours a day for three consecutive days. Eyelids sutured	Unknown	Rat corneal chemical burn	3 weeks	MSC anti‐inflammatory potency through IL‐6 suppressing maturation of DCs, and anti‐angiogenic through upregulation of TSP‐1	37
Human and mouse C‐MSCs	Topical	5E+03 cells in a fibrinogen (Ethicon) gel, eyelids sutured	3	Mouse pathologic corneal vascularization	3 days	Inhibition of corneal neovascularization, likely through secreted sFLT‐1 and PEDF	80
Human immature DPSCs	Topical	Cell sheet held in place with sutured amniotic membrane	6 to 7	Rabbit mild and severe chemical induced LSCD	3 months	MSCs lead to reconstruction of the corneal epithelia in the mild model, but not severe. Cells in both models adopted an epithelial‐like phenotype	64
Rabbit limbal‐MSC	Topical	0.5E+05 cells/cm2 on human AM. Also seeded with LESCs. AM sutured into place	3/4	Rabbit epithelial debridement and limbal keratectomy	12 weeks	MSCs promoted epithelialization, however neovascularization was seen when L‐MSC were applied without LESC. Cell did not migrate into the healing epithelium	81
Human BM‐MSCs	Intravenous injection	1E+06 cells in balanced salt solution	2	Mouse suture induced corneal neovascularization	1 week	MSCs reduced neovascularization, through a TSG‐6 dependent mechanism. They reduced inflammation through reduction of IL‐1B, IL‐6, and TNF‐a and suppression of infiltrating immune cells	40
Mouse BM‐MSCs	Intravenous injection	5E+05 cells in saline. Eyelids sutured closed for 3 days	2	Mouse corneal transplant model	2 months	MSCs inhibited corneal leukocyte infiltration, maturation of APCs and generation of Th1 cells to promote graft survival. Data show HGF as key paracrine factor	38
Mouse BM‐MSCs	Intravenous injection	5E+05 cells in saline	2	Mouse corneal mechanical injury	3 days	MSCs lead to increased levels of HGF at the ocular surface, which helped to restore corneal transparency and suppress TGF‐B‐induced α‐SMA expression	39
Mouse BM‐MSCs	Intravenous injection	1E+06 cells	5 to 6	Mouse corneal transplant model	2 weeks	MSCs homed directly to the inflamed ocular surface, inhibited APC maturation, suppress allosensitization, and promote allograft survival	31
Rat BM‐MSCs	Intravenous injection	1E+06 cells in PBS	2	Rat high‐risk corneal transplant model	37 days	MSCs increased rejection‐free survival, reducing inflammation through increasing regulatory T cells and release of immunomodulatory mediators including PGE2	82
Rabbit AD‐MSCs	Intravenous injection	2E+06 cells in HBSS. 4 injections; D‐7, D0, D3, and D14‐15	3 to 4	Rabbit high‐risk corneal allograft rejection model	19 days	MSCs did not home to cornea or engraft. MSCs increased edema and neovascularization and had no effect on infiltration of immune cells	53
Human BM‐MSCs	Subconjunctival injection	2E+05 cells in PBS	3	Mouse GVHD	18 days	MSCs did not engraft but prevented T lymphocyte infiltration and reduced inflammatory gene markers TNF, PAX6, and Sprr1b and reduced keratinization of the cornea	83
Mouse BM‐MSCs	Subconjunctival injection	5E+04 cells in PBS	3 to 5	Diabetic mouse model of corneal epithelial injury	3 days	Homing of MSCs to wound edge of cornea, with TSG‐6 secretion responsible for enhanced wound healing, increased epithelial stem cell proliferation, and reduction of inflammatory infiltrates and inflammatory markers; MPO, TNF‐α, and IL‐1β	84
Rat BM‐MSCs	Subconjunctival injection	2E+06 cells in PBS. Used polysaccharide hydrogel as bandage	3	Rat corneal alkali burn	4 weeks	MSCs promoted epithelial recovery, corneal clarity, reduced neovascularization, and reduced MIP‐1a and MCP‐1. All results were enhanced with hydrogel	85
Human and mouse BM‐MSCs	Periorbital injection	1E+03 or 1E+05 cells in balanced salt solution	2	Mouse inflammation‐induced dry eye	1 week	MSCs did not engraft, but increased tear production, reduced CD4+ IFN‐γ secreting cell infiltration and restored goblet cells in the conjunctiva	51
Human UC‐MSCs	Multiple	2E+06 cells in PBS	5	Rabbit corneal alkali burn	4 weeks	MSCs lead to reduced neovascularization, corneal opacification, and VEGF and α‐SMA in the cornea. They also resulted in increased re‐epithelialization and proliferation of keratocytes	86
Mouse BM‐MSCs	Multiple	5E+05 cells in PBS	3	Mouse corneal mechanical injury	4 days	MSCs administered through intravenous and subconjunctival injection significantly reduced inflammation, corneal opacity, fibrosis, and restored epithelial integrity and tissue architecture. No significant difference observed for topical and intraperitoneal administration	87
Human UC‐MSC	Multiple	2E+04 cells in alpha‐MEM (intrastromal injection) 2E+04 cells in a fibrin gel carrier	Unknown (after P4)	Mouse keratectomy wound	2 weeks	MSCs increased corneal transparency and increase collagen fiber organization	88