COACERVATES DELIVER PROLIFERATION CUES TO ASTROCYTES FOR IMPROVED WOUND HEALING AFTER INJURY

After SCI, host astrocyte reprogramming involves de-differentiation and proliferation to wall off injured tissue and constrain immune responses; this response is spatially confined and transient to the injury site margins, contributing to poor overall repair. However, in neonate mammals, proliferative and migratory responses of immature astrocytes following injury enables comprehensive wound repair, preserving neural function and preventing formation of non-neural lesion cores. Here, we explore co-delivery of pro-proliferative growth factors and small molecule inhibitors of anti-mitotic cues to stimulate an enhanced endogenous astrocyte wound response for improved neural repair. We have shown in astrocyte cultures that high serum environments attenuate the proliferation-stimulating effects of pro-proliferative factors, but inclusion of inhibitors of quiescence-inducing factors rescues proliferation (a). Because it is difficult to deliver high concentrations of both proteins and small molecules to injury environments in vivo, we have developed trehalose coacervates to deliver cargo to regulate astrocyte wound responses after SCI. Trehalose coacervates form as a viscous, polymer-dense phase that can be loaded with therapeutics at high concentrations and facilitate controlled release over weeks. They are injectable to mouse CNS tissue and disperse locally within neural tissue beds, accomplishing focal retention of cargo while avoiding bulk tissue disruption (b-c). Using trehalose coacervates, we aim to co-deliver pro-proliferative EGF+FGF with small molecule-based TGF superfamily quiescence inhibitors and will evaluate effects via immunohistochemistry, cell specific transcriptomics, and behavioral testing. We will outline our findings on individual and synergistic contributions of pro-proliferative and anti-mitotic growth factor signaling molecules on astrocyte wound repair after SCI.