Engineering cell-instructive injectable hydrogels with pro-survival signals to promote oligodendrocyte progenitor cell transplantation for demyelinating diseases

Introduction:: In Multiple Sclerosis (MS), the inflammatory environment of chronically demyelinated lesions prevents efficient myelin repair. Transplantation of highly myelinogenic fetal or iPSC-derived human oligodendrocyte progenitor cells (hOPCs) has been proposed as an attractive approach to achieve therapeutic remyelination. However, the poor viability of locally injected cells and lack of control of OPC fate are major barriers to the successful translation of this approach to clinical treatment. 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 a widely accepted mouse model of hypomyelination.

Materials and Methods:: We developed a novel STH via host-guest complexation between adamantane-terminated multi-arm polyethylene glycol, monosubstituted β-cyclodextrin-maleimide, thiol-functionalized hyaluronic acid, and thiolated heparin. We also employed Michael’s addition to conjugate pro-survival and cell fate-determining cues into the hydrogel. hOPCs were transplanted bilaterally into the corpus callosum of immunodeficient NSG mice to assess short-term (6 weeks) survival and oligodendrocyte fate. A congenital hypomyelination model of neonatal shiverer/rag2 mice was also utilized to evaluate remyelination from transplanted hOPCs.

Results, Conclusions, and Discussions:: Fig A presents a schematic illustration of the development of STHs via the incorporation of dynamic host-guest bonds to dissipate the injection force and immobilization of a recombinant bidomain adhesion peptide (H2R5) and PDGF-AA via their heparin-binding domains to enhance cell survival. The STHs demonstrated excellent self-healing behavior as shown by a sharp decrease in viscosity at the high (10 s^-1) shear rate and immediate recovery at a low (0.1 s^-1) shear rate (Fig B). The oscillatory frequency sweep revealed the dependence of the storage modulus on frequency, indicating the reversibility and dynamics of the host-guest bonds (Fig C). hOPCs showed a dose-dependent increase in proliferation in response to PDGF-AA and H2R5 (Fig D-F). Interaction of the hOPCs with the H2R5 peptide did not compromise their in-vitro differentiation potential as shown by O4 expression, except for very high doses (Fig G-J). Following implantation by injection, a large percentage of fetal PDGFαR⁺ hOPCs undergo acute apoptosis (25% death), which was significantly reduced (13%) with STH (Fig K-M). STH functionalized with biological cues significantly promoted hOPC survival after 6 weeks, production of myelinating oligodendrocytes, and enhanced myelination of the hypomyelinating mouse brain after 12 weeks post-implantation (Fig N-Q).

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