Programmable Hydrogels for Optimized Human Oligodendrocyte Transplantation in Demyelinating Disease

ABSTRACT Some of the most devastating neurodegenerative diseases such as multiple sclerosis, are characterized by chronic demyelination and a tissue environment that prevents efficient myelin repair and remyelination. While cell therapies have the potential to promote remyelination and restore lost neurological function, major barriers remain that hamper their successful translation to clinical treatment. Among these, survival of donor oligodendrocytes cell (OPC) preparations and maintenance of OPC fate are key obstacles. Notably, more than 95% of neural progenitor cells (NPCs) transplanted into models of spinal cord injury die following injection 1,2, while only 1-3% of NPCs survive when transplanted into ischemic tissue 3,4. The result of such excessive cell death is the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft for eventual rejection. Indeed, following initial trials of glial cell replacement therapy in human congenital hypomyelination, half of the subjects developed alloantibodies even in the context of prolonged immunosuppression 5. In this proposal, we seek to address these major challenges. In aim 1, we will design, synthesize and characterize a series of novel shear-thinning and bioactive hydrogels to promote survival and minimize cell death when human (h)OPCs are subjected to shear stress during injection. In aim 2 we will use the optimal shear-thinning hydrogel (STH) formulation to deliver cells into the corpus callosum of Shiverer/Rag2- /- mice, a model of congenital hypomyelinating disease that has been widely accepted as the gold standard for the assessment of myelinating cell preparations. In aim 3, we will employ a large animal model (rabbit) of demyelination that we recently developed in our laboratories and better mimics the state of demyelinating disease like multiple sclerosis. We will also design programmable (p)STH to retain hOPC at the site of injury and control cell fate to maximize the myelogenic potential of transplanted cells into the injured rabbit brain. Overall, this is a very innovative MPI proposal that combines state-of-the-art biomaterials, neuroscience and unique animal models driven by the complementary expertise of two PIs, a bioengineer and a neuroscientist. Successful attainment of our goals will likely lead to design of novel hydrogels and development of animal models that may improve the potential of cell therapies for the treatment of devastating myelopathies.