Organoid-to-organoid transplantation and pro-neurogenic treatment promote graft integration and neuronal repair in a human ischemic model

SUMMARY Neuronal loss resulting from brain injury and neurodegenerative diseases currently lacks effective regenerative therapies. While neurogenic compounds and cell transplantation hold promise, clinical translation is hindered by poor graft integration and limited cell survival. Here, we developed a novel organoid-to-organoid transplantation model using human pluripotent stem cell-derived cortical organoids (hCOs) to evaluate a dual cell transplantation and pro-neurogenic strategy for brain repair. We demonstrate that pro-neurogenic treatment with ER272 stimulates early-stage hCO growth and enhances neurogenesis through a PKC- and Notch-dependent pathway. Mechanistically, ER272 upregulates genes associated with extracellular matrix, cell adhesion and growth factor signaling. Notably, combining early-stage hCO transplantation with ER272 treatment significantly enhanced graft integration and improved neuronal repair in an ischemic-like model of late-stage host hCOs. This novel human organoid-to-organoid platform offers a robust translational tool to test regenerative therapies and highlight the potential of combining cell transplantation with pro-neurogenic stimulation for the treatment of neurological conditions associated with neuronal loss.