Bioinspired Engineering of Living Materials to Reconstruct Stromal-Parenchymal Interactions for Post-Stroke Neural Regeneration.

Abstract

Stroke remains a leading cause of neurological disability worldwide. A major obstacle to brain tissue regeneration after stroke is the persistent local inflammation and the absence of extracellular matrix (ECM) support within the infarct cavity, which severely impedes the brain's endogenous repair. Inspired by the natural interactions between stromal and parenchymal cells, we developed an engineered living material to recreate a regenerative niche within the stroke cavity. This system integrates a programmable supramolecular DNA hydrogel with interleukin-10-secreting engineered-mesenchymal stem cells (eMSCs) and neural stem cells (NSCs). The hydrogel mimics the structural and mechanical properties of the native ECM, enhancing the retention and viability of transplanted cells. Meanwhile, eMSCs modulate the inflammatory environment, suppress glial scar formation, and promote vascular regeneration, thereby facilitating the neuronal differentiation of NSCs. In a rat model of ischemic stroke, these engineered living materials significantly promote neuronal regeneration, synaptic remodeling, and neovascularization, leading to improved motor and cognitive function. These findings highlight a modular strategy for repairing damaged neural tissues by re-establishing stromal-parenchymal interactions, offering a promising therapeutic avenue for post-stroke brain regeneration.