Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function
Momotaro Kawai, Kent Imaizumi, Mitsuru Ishikawa, Shinsuke Shibata, Munehisa Shinozaki, Takahiro Shibata, Shogo Hashimoto, Takahiro Kitagawa, Kentaro Ago, Keita Kajikawa, Reo Shibata, Yasuhiro Kamata, Junichi Ushiba, K. Koga, Hidemasa Furue, Morio Matsumoto, Masaya Nakamura, Narihito Nagoshi, Hideyuki Okano
Abstract
In cell transplantation therapy for spinal cord injury (SCI), grafted human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) mainly differentiate into neurons, forming synapses in a process similar to neurodevelopment. In the developing nervous system, the activity of immature neurons has an important role in constructing and maintaining new synapses. Thus, we investigate how enhancing the activity of transplanted hiPSC-NS/PCs affects both the transplanted cells themselves and the host tissue. We find that chemogenetic stimulation of hiPSC-derived neural cells enhances cell activity and neuron-to-neuron interactions in vitro. In a rodent model of SCI, consecutive and selective chemogenetic stimulation of transplanted hiPSC-NS/PCs also enhances the expression of synapse-related genes and proteins in surrounding host tissues and prevents atrophy of the injured spinal cord, thereby improving locomotor function. These findings provide a strategy for enhancing activity within the graft to improve the efficacy of cell transplantation therapy for SCI.