Glial restricted precursor delivery of dendrimer N-acetylcysteine promotes migration and differentiation following transplant in mouse white matter injury model.

Abstract

Oligodendrocyte replacement using glial restricted precursors (GRPs) is a promising avenue for the treatment of acquired or genetic white matter disorders; however, limited long-term survival of these cells post-transplant may impede maximal recovery. Nanotherapeutic approaches can facilitate stem cell delivery while simultaneously delivering factors aimed at enhancing and nourishing stem cells en route to, and at, the target site. Hydroxyl polyamidoamine (PAMAM) dendrimer nanoparticles have been used in a variety of models to deliver therapeutics in a targeted manner to injury sites at low doses. Here, survival and migration of GRPs was assessed in a mouse model of neonatal white matter injury with different methods of dendrimer nanoparticle support. Our findings demonstrate the ability of GRPs to take up nanoparticle-drug conjugates and for these conjugates to act beyond the injury site in vivo. Compared to GRPs alone, mice receiving dendrimer-drug in parallel to GRPs, or via GRPs as the delivery vector, showed improved migration and differentiation of cells 8 weeks post-transplant. These studies demonstrate that drug-conjugated nanoparticles can enhance transplanted progenitor cell survival and migration, and suggest that combination therapies may allow engraftment without overt immunosuppression.