Axonal Extensions along Corticospinal Tracts from Transplanted Human Cerebral Organoids

Summary The reconstruction of lost neural circuits by cell replacement is a possible treatment for neurological deficits after cerebral cortex injury. Cerebral organoids can be a novel source for cell transplantation, but because the cellular composition of the organoids changes along the time course of the development, it remains unclear which developmental stage of the organoids is most suitable for reconstructing the corticospinal tract. Here, we transplanted human embryonic stem cell-derived cerebral organoids at 6 or 10 weeks after differentiation (6w- or 10w-organoids) into mouse cerebral cortices. 6w-organoids extended more axons along the corticospinal tract but caused graft overgrowth with a higher percentage of proliferative cells. Axonal extensions from 10w-organoids were smaller in number but were enhanced when the organoids were grafted 1 week after brain injury. Finally, 10w-organoids extended axons in cynomolgus monkey brains. These results contribute to the development of a cell-replacement therapy for brain injury and stroke.
Graphical Abstract
Highlights • Human cerebral organoids extended axons along the corticospinal tract in mice • Early-stage organoids extended more axons but caused graft overgrowth • Axonal extensions from the organoids were enhanced in injured brains • Human cerebral organoids extended axons in the brains of nonhuman primates
Kitahara et al. show that cerebral organoids at early stage (SCPN-generating stage) extend more axons along the host corticospinal tract compared with those at late stage (CPN-generating stage) but cause graft overgrowth. Axonal extensions from the organoids are enhanced in an injured brain. Optimization of donor cells and host environment will enable successful transplantation to reconstruct the corticospinal tract.