(247f) Engineering Cell-Instructive Injectable Hydrogels with Pro-Survival Signals to Promote Oligodendrocyte Progenitor Cell Transplantation for Demyelinating Diseases

In Multiple Sclerosis (MS), the inhibitory tissue environment in chronically demyelinated lesions acts to prevent efficient myelin repair and remyelination. Stem/progenitor cell transplantation of highly myelinogenic fetal and iPSC-derived human oligodendrocyte progenitor cells (hOPCs) has been proposed as an attractive means to achieve therapeutic remyelination. While significant advances have been made in the preparation of hOPCs capable of mediating widespread myelination, poor survival of donor cells and maintenance of OPC fate are major barriers to the successful translation of this approach to clinical treatment. Excessive cell death leads to the release of intracellular alloantigens, which likely exacerbate local inflammation and may predispose the graft to eventual rejection.

Here, we engineered innovative cell-instructive shear-thinning hydrogels (STHs) with tunable viscoelasticity and bioactivity for minimally invasive delivery of human oligodendrocyte progenitor cells (hOPCs) to the brain of a shiverer/rag2 mouse, a model of congenital hypomyelinating disease. Michael-addition and host-guest complexation were employed to endow hydrogels with shear-thinning properties and the ability to immobilize pro-survival signals, including a recombinantly designed bidomain peptide and platelet-derived growth factor. The stiffness of STHs was adjusted by altering the weight percentage of the hydrogel components to correspond with the mechanical stiffness of the brain. Dynamic rheology measurements demonstrated the shear-thinning behavior and immediate recovery of hydrogels after damage.

Notably, STHs reduced the death rate of hOPCs significantly, promoted the production of myelinating oligodendrocytes, and enhanced myelination of the mouse brain twelve weeks post-implantation. Our results demonstrate the potential of STHs loaded with biological cues to improve cell therapies for the treatment of devastating myelopathies.