Wharton's jelly-derived mesenchymal stem cells in keratoconus

This review examines the potential of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) as regenerative therapies for corneal ectasia, with an emphasis on keratoconus. Current standards, including corneal cross-linking, intrastromal corneal ring segments, and keratoplasty, stabilize or reshape the cornea but do not restore native extracellular matrix (ECM) architecture or correct underlying cellular dysfunction. WJ-MSCs offer a scalable, ethically accessible cell source with high proliferative capacity, low immunogenicity, and robust paracrine activity. Preclinical studies suggest that WJ-MSCs may acquire corneal epithelial- and keratocyte-like characteristics under in vitro induction conditions and may promote epithelial healing, reduce inflammation and haze, and improve stromal organization and biomechanics, collectively supporting their potential role in corneal regeneration. Early clinical experiences with MSC-based therapies in ocular surface disease indicate favorable safety and preliminary evidence of efficacy, while a phase 1b clinical trial of locally delivered allogeneic bone marrow-derived MSCs supports the feasibility and short-term safety of ocular MSC administration, providing indirect translational support for future WJ-MSC studies. Mechanistically, WJ-MSCs act via coordinated paracrine signaling and extracellular vesicles, immunomodulation (TGF-β, IL-10, IDO, HLA-G), anti-fibrotic effects, ECM remodeling, and potential neurotrophic support. Cell-free derivatives (secretome/EVs) may replicate therapeutic benefits with simplified manufacturing and repeat dosing. Key challenges include optimizing dose, route, and timing; enhancing intrastromal persistence and potency (e.g., via biomaterials and preconditioning); and standardizing Good Manufacturing Practice (GMP) production. Rigorous, multicenter randomized trials with harmonized imaging, biomechanical, and patient-reported outcomes are needed to confirm durability and clinical benefit, including in combination strategies with cross-linking. The regulatory pathway also requires early engagement with relevant regulatory agencies, science-based chemistry, manufacturing, and controls (CMC), standardized product characterization, validated potency assays, ethical umbilical-cord sourcing, and appropriate preclinical toxicology before clinical implementation. With disciplined clinical development, WJ-MSC-based therapies, including cells or cell-free products, could evolve into disease-modifying options that complement existing care and, in selected cases, reduce reliance on keratoplasty.