IMPROVING FUNCTIONAL INTEGRATION OF HIPSC-DERIVED NEURAL PROGENITORS TRANSPLANTED INTO THE ISCHEMIC BRAIN

Ischemic stroke is a leading cause of death and long-term disability worldwide, and no effective therapies currently exist to restore lost brain function. Stem cell–based transplantation of neural progenitors represents a promising strategy for post-stroke recovery; however, its clinical translation requires a deeper mechanistic understanding of how grafted cells integrate into the injured brain.
In this project, we investigate neuronal replacement and functional integration of human induced pluripotent stem cell (hiPSC)–derived neural progenitors in ischemic stroke–damaged tissue. Using an experimental model of focal ischemic stroke, we perform intracerebral transplantation of hiPSC-derived neuronal progenitors and systematically assess their maturation, connectivity, and contribution to host circuit function. To determine whether transplantation reshapes brain-wide connectivity, we combine monosynaptic rabies virus tracing, functional magnetic resonance imaging, calcium imaging, and comprehensive histological characterization of both grafted cells and host microenvironment.
Our previous work demonstrates that transplanted human neural progenitors survive, differentiate into mature neurons, and establish functional synaptic connections with defined host brain regions, leading to improved behavioral recovery. Despite these encouraging outcomes, the cellular and molecular mechanisms governing graft integration—and the extent to which functional recovery can be further enhanced—remain incompletely understood, particularly with respect to the inflammatory response elicited by transplantation.
By elucidating the mechanisms that regulate functional integration of transplanted neural progenitors after stroke, this study aims to identify key factors limiting or promoting regenerative success. These insights will be essential for optimizing stem cell–based therapies and advancing their clinical application in stroke recovery.