Robust cell integration from co-transplantation of biodegradable MMP2-PLGA microspheres with retinal progenitor cells

The failure of the adult mammalian retina to regenerate can be partly attributed to the barrier formed by inhibitory extracellular matrix (ECM) and cell adhesion molecules, such as CD44 and neurocan, after degeneration. These molecules act to separate a sub-retinal graft from integrating into the host retina. It has been shown that matrix metalloproteinase 2 (MMP2) can promote host-donor integration by degrading these molecules. In order to enhance cellular integration and promote retinal repopulation, we co-transplanted biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres that have the ability to deliver active MMP2 with retinal progenitor cells (RPCs) to the sub-retinal space of adult retinal degenerative Rho-/- mice. Following delivery, significant degradation of CD44 and neurocan at the outer surface of the degenerative retina without disruption of the host retinal architecture was observed. Coincident with this, we observed a significant increase in the number of cells migrating beyond the barrier into the degenerative retina. No changes in the differentiation characteristics of RPCs were observed. Cells in the outer nuclear layer (ONL) could express the mature photoreceptor markers recoverin, make contacts with residual protein kinase C (PKC)-positive cells and express the ribbon synapse protein bassoon. Thus, co-transplantation of MMP2-PLGA microspheres with RPCs provides controlled release of active MMP2 to the site of retinal degeneration, stimulating inhibitory barrier removal and enhancing cell integration. This suggests a practical and effective strategy for retinal repair.