708. Treatment of Inherited Eye Defects By Systemic Hematopoietic Stem Cell Transplantation

Corneal disease is a significant cause of blindness worldwide, largely due to the low availability of donor corneas and the risks associated with transplantation, such as immune rejection, cataract, and glaucoma. Stem cell transplantation represents an attractive alternative for corneal repair because of their capacity to differentiate into corneal cells. Limbal epithelial stem (LEST) cells, which reside within the corneo-limbus, have been used for more than a decade to repair corneal epithelium, and mesenchymal stem cells (MSCs) have been shown to migrate and promote corneal healing and even differentiate into epithelial/keratocyte-like cells. However, risks of immune rejection with LEST cells, and heterogeneity in repair mechanisms with MSCs have led to discrepancies in treatment outcomes. Alternatively, very little is known about the potential for hematopoietic stem cells (HSCs) in eye repair. HSCs have attractive features; they are multipotent cells capable of self-renewal and easily mobilized from bone marrow into the circulatory system. Here we report that engraftment of HSPCs can treat corneal defects in a mouse model of a degenerative hereditary metabolic disorder, cystinosis. Cystinosis is caused by a deficiency in the lysosomal cystine transporter, cystinosin, resulting in cystine crystal accumulation in tissues. In eyes, a primary affected organ, crystals accumulate within the cornea causing photophobia and eventually blindness, if untreated. Using the mouse model of cystinosis, Ctns-/- mice, which develops similar eye anomalies than patients, we showed that systemic HSC transplantation led to the long-term preservation of the eyes. Effective therapy, however, was dependent on achieving relatively high level of donor-derived blood cell engraftment (more than 50%). Abundant GFP-expressing bone marrow-derived cells were detected within the cornea but also in the sclera, ciliary body, retina, choroid, and lens. In addition, HSCs engraftment led to substantial decrease in corneal cystine crystals, restoration of normal corneal thickness and intraocular pressure, and improved vision after one-year post-transplantation. Finally, we showed that HSCs mainly differentiated into MHC class II+ macrophages, which transferred cystinosin-bearing lysosomes via tunneling nanotubes to disease cells. This work is the first demonstration that HSCs can rescue corneal defects, which brings forth a new potential therapeutic strategy for treating ocular pathologies.