Microphysiological stroke model for systematic evaluation of neurorestorative potential of stem cell therapy

Stem cell therapy is emerging as a promising treatment option to restore a neurological function after ischemic stroke. Despite the growing number of candidate stem cell types, each with unique characteristics, there is a lack of experimental platform to systematically evaluate their neurorestorative potential. When stem cells are transplanted into ischemic brain, the therapeutic efficacy primarily depends on the response of the neurovascular unit (NVU) to these extraneous cells. In this work, we developed an ischemic stroke microphysiological system (MPS) with a functional NVU on a microfluidic chip. Our new chip design facilitated the incorporated cells to form a functional blood-brain barrier (BBB) and restore their in vivo-like behaviors in both healthy and ischemic conditions. We utilized this MPS to track the transplanted stem cells and characterize their neurorestorative behaviors reflected in gene expression levels. Each type of stem cells showed unique neurorestorative effects, primarily through supporting the endogenous recovery, rather than through direct cell replacement. And the recovery of synaptic activities, critical for neurological function, was more tightly correlated with the recovery of the structural and functional integrity in NVU, rather than with the regeneration of neurons itself.