Neural xenografts contribute to long-term recovery in stroke via molecular graft-host crosstalk

Stroke remains a leading cause of disability due to the brain’s limited ability to regenerate damaged neural circuits. Here, we show that local transplantation of iPSC-derived neural progenitor cells (NPCs) improves brain repair and long-term functional recovery in stroke-injured mice. NPCs survive for over five weeks, differentiate primarily into mature neurons, and contribute to regeneration-associated tissue responses including angiogenesis, blood–brain barrier repair, reduced inflammation, and neurogenesis. NPC-treated mice show improved gait and fine-motor recovery, as quantified by deep learning-based analysis. Single-nucleus RNA sequencing reveals that grafts predominantly adopt GABAergic and glutamatergic phenotypes, with GABAergic cells engaging in graft-host crosstalk via neurexin, neuregulin, neural cell adhesion molecule, and SLIT signaling pathways. Our findings provide mechanistic insight into how neural xenografts interact with host stroke tissue to drive structural and functional repair. These results support the therapeutic potential of NPC transplantation for promoting long-term recovery after stroke.