Advancements in ocular surface reconstruction by mesenchymal stem cells and immunomodulatory mechanism

Current clinical treatment for limbal stem cell deficiency (LSCD) relies mainly on allogeneic transplantation, but the lack of donors and postoperative rejection has resulted in many patients facing treatment difficulties. Mesenchymal stem cells (MSCs), a class of adult stem cells with self-renewal and multidirectional differentiation potential, are widely distributed in various tissues, including dental pulp, adipose tissue, umbilical cord, bone marrow, and hair follicles. Due to their autologous availability, the ability to differentiate into corneal epithelial-like cells, and unique properties of mediating matrix reconstruction and immune regulation via exosomes, this approach presents significant potential in treating corneal diseases. These characteristics establish MSCs as a crucial approach to tackling the combined issues of donor scarcity and immune rejection in patients with bilateral LSCD, providing an innovative alternative for the functional and structural restoration of the ocular surface. This review systematically examines the roles of recent advancements in research on MSCs derived from umbilical cord, dental pulp, adipose tissue, bone marrow, hair follicles, and induced pluripotent stem cells (iPSCs) for corneal reconstruction. It analyzes and compares the strengths and weaknesses of different MSCs in treating corneal injuries. Various research groups have systematically addressed challenges such as the scarcity of cell sources, insufficient mechanical support, and the risk of immune rejection through three dimensions: cell function reconstruction, biomaterials combination, and technological pathway upgrades. However, the long-term survival and functioning of transplanted cells in the host’s immune system remain significant obstacles in the application of stem cells. Therefore, the immunomodulatory properties of MSCs are crucial to promote their in vivo differentiation and participation in ocular surface repair. This article focuses on elucidating how MSCs regulate the expansion of Tregs through CD80 target binding and non-target-mediated cell contact, as well as the secretion of soluble factors such as TSG-6, HGF, IL-10, and TGF-β, and the delivery of regulatory molecules like miR-22 and miR-150-5p via extracellular vehicles (EVs). These mechanisms aim to restore the balance between Th17 and Tregs, providing an in-depth analysis of the immune mechanisms involved in MSC-mediated ocular surface reconstruction. This review discusses the challenges encountered in the clinical translation of MSC-based therapies for corneal diseases. These challenges include functional exhaustion resulting from chronic inflammatory microenvironments, variability in efficacy due to source heterogeneity, inadequate differentiation efficiency, and the potential for postoperative scarring. Current research is focusing on innovative solutions based on engineering technologies to mitigate these bottlenecks. The research includes the development of engineered EV delivery systems featuring targeted modifications, the loading of functional molecules, and the adjustment of surface charge to enhance binding to corneal cells and improve enrichment in inflammatory regions; the preparation of microneedle arrays for precise and sustained exosome delivery; and the directed differentiation of corneal stromal cells in combination with gelatin-based hydrogel scaffolds to construct biomimetic corneal stroma and reduce fibrosis. Recent research findings suggest potential future directions for the development of MSCs. Based on this, the article proposes a new treatment plan for LSCD utilizing 3D technology and engineering combined with MSCs, aiming to overcome the current limitations of MSC therapy. This work aims to disseminate recent research on ocular surface reconstruction utilizing MSCs and MSC-EVs, facilitating comprehension for non-professionals and encouraging discussion with leading researchers. Through ongoing innovation and collaboration between academia and industry, we expect the development of more efficient and clinically appropriate MSC-based treatment strategies.