hPSC-derived sacral neural crest cells restore erectile function in pelvic ganglia injury

Pelvic surgeries frequently injure the major pelvic ganglia (MPG), resulting in refractory erectile dysfunction (ED) with limited therapeutic options. Regenerative medicine offers promising avenues for nerve injury-induced ED. Sacral neural crest (NC) cells, the embryonic progenitors of MPG neurons and glia, represent an ideal cell source for targeted neural repair. Here, we establish a robust protocol to differentiate human pluripotent stem cells (hPSCs) into sacral NC cells. Upon transplantation into rats with MPG injury, these cells engraft at the lesion site, differentiate into functional autonomic neurons and glia, and secrete neurotrophic factors. Sacral NC cell therapy reconstructs MPG architecture, promotes axonal regeneration and remyelination, and restores nitrergic innervation. Furthermore, transplantation significantly improves erectile function, evidenced by an increased intracavernous pressure/mean arterial pressure (ICP/MAP) ratio, accompanied by reduced apoptosis and fibrosis and restored smooth muscle and endothelial integrity in the penis. These findings demonstrate that hPSC-derived sacral NC cells offer a novel therapeutic strategy for neurogenic ED by restoring pelvic autonomic nerve structure and function through both neurogenic differentiation and sustained neurotrophic support. Overall design: The neurogenic erectile dysfunction model was established by bilaterally clamping the major pelvic ganglia (MPG) in rats (injury group). In the Sham group, rats underwent the same surgical procedure without MPG injury. In the sacral NC group, rats received sacral neural crest cell transplantation following MPG injury. Four weeks later, penile tissue from each group was evaluated.