(637a) Engineering Supramolecular Shear-Thinning Hydrogels 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 OPCs (hOPCs) into demyelinating disease have 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. Indeed, our studies confirm that the majority of even optimized preparations of fetal PDGFαR⁺ hOPCs undergo acute apoptosis following implantation. Therefore, the objective of this study was to design cell-instructive injectable shear-thinning hydrogels (STH) with tunable stiffness to promote hOPCs viability, retention, and engraftment post-transplantation in hypo-myelinating mouse brain.

The hydrogels were developed by Michael-addition chemistry and host-guest complexation between four components system; adamantane-terminated multi-arm polyethylene glycol, monosubstituted β-cyclodextrin-maleimide, thiol-functionalized hyaluronic acid, and thiol-containing heparin. Pro-survival signals, including a recombinantly designed adhesion peptide and PDGF-AA, were also immobilized into the hydrogel via their heparin-binding domains to enhance cell survival. The mechanical stiffness was controlled by varying the wt% of hydrogel components in the feed. Dynamic rheology measurements demonstrated the shear-thinning behavior and immediate recovery of hydrogels after damage.

Next, we evaluated the ability of STH to improve outcomes in the shiverer mouse, a model of congenital hypomyelinating disease that has become the gold standard for the assessment of myelinating cell preparations. hOPCs were transplanted bilaterally into the corpus callosum of neonatal shiverer/rag2 mice, and myelination was assessed by the expression of myelin basic protein, which is absent in shiverer mice. Notably, STH reduced the death rate of hOPCs significantly, promoted differentiation to myelinating (O4⁺) oligodendrocytes, and enhanced myelin basic protein and myelination of mouse brain after twelve weeks in vivo. Our results show that the STH loaded with biological cues may improve the potential of cell therapies for the treatment of devastating myelopathies.