Molecular and Cellular Mechanisms of the Therapeutic Effect of Mesenchymal Stem Cells and Extracellular Vesicles in Corneal Regeneration

Abstract

The cornea is a vital component of the visual system, and its integrity is crucial for optimal vision. Damage to the cornea resulting from trauma, infection, or disease can lead to blindness. Corneal regeneration using mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) offers a promising alternative to corneal transplantation. MSCs are multipotent stromal cells that can differentiate into various cell types, including corneal cells. They can also secrete a variety of anti-inflammatory cytokines and several growth factors, promoting wound healing and tissue reconstruction. This review summarizes the current understanding of the molecular and cellular mechanisms by which MSCs and MSC-EVs contribute to corneal regeneration. It discusses the potential of MSCs and MSC-EV for treating various corneal diseases, including corneal epithelial defects, dry eye disease, and keratoconus. The review also highlights finalized human clinical trials investigating the safety and efficacy of MSC-based therapy in corneal regeneration. The therapeutic potential of MSCs and MSC-EVs for corneal regeneration is promising; however, further research is needed to optimize their clinical application.

Keywords: cell-based therapy; corneal epithelium; corneal regeneration; corneal stroma; dry eye disease; extracellular vesicles; immune and inflammatory modulation; keratoconus; limbal stem cell deficiency; mesenchymal stem cells.

Figure 1

Schematic cross-section of a human eye with an expanded view of the cornea.

Figure 2

Various corneal pathologies can lead to corneal edema and opacification (A,B), which is conventionally treated by surgical removal and donor corneal transplantation (penetrating (C) and lamellar keratoplasties (D)). (A) Bullous keratopathy and corneal scar years after penetrating injury and (C) 1 month after PK. (B) Bullous keratopathy years after cataract surgery and (D) 1 month after DMEK. (E) A schematic representation of different types of corneal transplantation techniques. The blue section represents the recipient cornea and the yellow section in the red square–dot line represents the transplanted donor corneal graft tissue. In PK, all corneal layers are transplanted, whereas in DALK, only the anterior corneal layers are transplanted. Posterior lamellar techniques involve selective removal of the patient’s Descemet membrane (DM) and endothelium, which is followed by either the transplantation of the donor corneal endothelium, the DM and a thin stromal layer in DSAEK or by the transplantation of only the donor DM and the endothelium in DMEK. Abbreviations: PK—penetrating keratoplasty; DALK—deep anterior lamellar keratoplasty; DSAEK—Descemet’s stripping automated endothelial keratoplasty; DMEK—Descemet’s membrane endothelial keratoplasty.

Figure 3

Schematic representation of different regenerative corneal therapies. Abbreviations: LESC—limbal epithelial stem cell; CSSC—corneal stromal stem cell; CEnC—corneal endothelial cell; MSC—mesenchymal stem cell; SC—stem cell; iPSC—induced pluripotent stem cell; AM—amniotic membrane; MSC-EV—extracellular vesicle derived from mesenchymal stem cell; MSC(M)—bone marrow-derived mesenchymal stem cell; MSC(UC)—umbilical cord-derived mesenchymal stem cell.

Figure 4

Schematic representation of mesenchymal stem cell-derived extracellular vesicles (such as exosomes, microvesicles and apoptotic bodies), their biogenesis and transfer from cell of origin to recipient cell. They are capable of transferring bioactive molecules to recipient cells through three different mechanisms: endocytosis, specific receptor–ligand interactions and direct fusion. Extracellular vesicles have various effects on corneal cells. Abbreviations: MSC—mesenchymal stem cell; ECM—extracellular matrix; SC—stem cell.