Ph. D Student Center for iPS Cell Research and Application (CiRA), Kyoto University Center for iPS Cell Research and Application (CIRA), Kyoto University, Kyoto, Japan
Abstract: Ischemic stroke is a disease characterized by cerebral blood vessel occlusion, resulting in neuronal death. The fact that many patients continue to suffer from long-term neurological deficits indicates that current therapies are insufficient. In this context, transplantation of human induced pluripotent stem cell (hiPSC)-derived cortical neurons has emerged as a promising approach for ischemic stroke. The corticospinal tract, extending from cerebral cortex to spinal cord, is a critical neural circuit damaged by stroke and crucial for sophisticated motor functions, including fine finger movements essential for daily activities. Previously, we demonstrated that hiPSC-derived cortical neuron transplantation in stroke model mice leads to axonal extension to the spinal cord and improved motor function. However, the mechanism underlying this recovery remained unclear. We hypothesized that functional recovery is mediated by the reconstruction of the corticospinal tract through cell transplantation, and tried to verify this hypothesis. Using rabies virus vectors (RABV), which propagate retrogradely across synapses between neurons, we investigated neural connections between graft and host. In experiments examining neural inputs to grafted cells, RABV selectively infected transplanted cells and spread to host neurons providing direct neural input. When investigating outputs, RABV infected host spinal neurons and propagated to transplanted cells, indicating functional integration. This RABV-based synaptic tracing revealed connections between transplanted and host neurons, providing evidence for structural reconstruction of the corticospinal tract within damaged neural circuits. These findings suggest that post-transplantation motor recovery occurs through direct neural circuit reconstruction rather than indirect mechanisms, representing a significant advancement in understanding cell-based therapy for ischemic stroke.
Funding Source: This research is supported by AMED under Grant Number JP23bm1223005h0001. This research is supported by Grant-in-Aid for JSPS Fellows Grant Number 24KJ1351.
