The cornea is a transparent and vitally multifaceted component of the eye, playing a pivotal role in vision and ocular health. It has primary refractive and protective functions. Typical corneal dysfunctions include opacities and deformities that result from injuries, infections, or other medical conditions. These can significantly impair vision. The conventional challenges in managing corneal ailments include the limited regenerative capacity (except corneal epithelium), immune response after donor tissue transplantation, a risk of long-term graft rejection, and the global shortage of transplantable donor materials. This review delves into the intricate composition of the cornea, the landscape of corneal regeneration, and the multifaceted repercussions of scar-related pathologies. It will elucidate the etiology and types of dysfunctions, assess current treatments and their limitations, and explore the potential of regenerative therapy that has emerged in both in vivo and clinical trials. This review will shed light on existing gaps in corneal disorder management and discuss the feasibility and challenges of advancing regenerative therapies for corneal stromal scarring.

Corneal fibrosis, clinically referred to as corneal scarring, disrupts the normal architecture and transparency of the cornea and remains a major cause of visual impairment worldwide. Although corneal transplantation can restore vision, its effectiveness is constrained by limited accessibility, donor tissue shortages, and the risk of allograft rejection. Treatments with human corneal stromal stem cells (hCSSCs) have demonstrated scarless healing in preclinical models of acute corneal injury. Here, we report that hCSSCs also modulated pre-existing corneal opacities. We established a reproducible in vivo model of chronic corneal opacity. Given that scar severity varies among corneas even after identical injuries, we developed a non-invasive, image-based method to quantify opacity volume longitudinally in individual corneas. Using this approach, we evaluated the scar-reducing potential of three hCSSC batches previously shown to inhibit acute scarring. Following cell treatment, the pre-existing opacity volumes gradually decreased. In vitro, hCSSCs exposed to pro-inflammatory stimulus exhibited increased metalloproteinase (MMP) activity relative to tissue inhibitor of metalloproteinase (TIMP), as indicated by an elevated MMP2/TIMP2 ratio. This shift may promote matrix remodeling and scar resolution. Overall, our findings provide proof-of-concept for hCSSC-based therapy as a strategy to reduce established corneal scarring and restore corneal transparency.