Transplantation of bioengineered Reelin‐loaded PLGA/PEG micelles can accelerate neural tissue regeneration in photothrombotic stroke model of mouse

Ischemic stroke is characterized by extensive neuronal loss, glial scar formation, neural tissue degeneration that leading to profound changes in the extracellular matrix, neuronal circuitry, and long‐lasting functional disabilities. Although transplanted neural stem cells (NSCs) can recover some of the functional deficit after stroke, retrieval is not complete and repair of lost tissue is negligible. Therefore, the current challenge is to use the combination of NSCs with suitably enriched biomaterials to retain these cells within the infarct cavity and accelerate the formation of a de novo tissue. This study aimed to test the regenerative potential of polylactic‐co‐glycolic acid‐polyethylene glycol (PLGA‐PEG) micelle biomaterial enriched with Reelin and embryonic NSCs on photothrombotic stroke model of mice to gain appropriate methods in tissue engineering. For this purpose, two sets of experiments, either in vitro or in vivo models, were performed. In vitro analyses exhibited PLGA‐PEG plus Reelin‐induced proliferation rate (Ki‐67(+) NSCs) and neurite outgrowth (axonization and dendritization) compared to PLGA‐PEG + NSCs and Reelin + NSCs groups (p < 0.05). Besides, neural differentiation (Map‐2(+) cells) was high in NSCs cultured in the presence of Reelin‐loaded PLGA‐PEG micelles (p < 0.05). Double immunofluorescence staining showed that Reelin‐loaded PLGA‐PEG micelles increased the number of migrating neural progenitor cells (DCX(+) cells) and mature neurons (NeuN(+) cells) around the lesion site compared to the groups received PLGA‐PEG and Reelin alone after 1 month (p < 0.05). Immunohistochemistry results showed that the PLGA/PEG plus Reelin significantly decreased the astrocytic gliosis and increased local angiogenesis (vWF‐positive cells) relative to the other groups. These changes led to the reduction of cavity size in the Reelin‐loaded PLGA‐PEG+NSCs group. Neurobehavioral tests indicated Reelin‐loaded PLGA‐PEG+NSCs promoted neurological outcome and functional recovery (p < 0.05). These results indicated that Reelin‐loaded PLGA‐PEG is capable of promoting NSCs dynamic growth, neuronal differentiation, and local angiogenesis following ischemic injury via providing a desirable microenvironment. These features can lead to neural tissue regeneration and functional recovery.