Emerging Human Pluripotent Stem Cell-Based Human–Animal Brain Chimeras for Advancing Disease Modeling and Cell Therapy for Neurological Disorders

 Yanru Ji1  · Jenna Lillie McLean1  · Ranjie Xu1
1 Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA

Human pluripotent stem cell (hPSC) models provide unprecedented opportunities to study human neurological disorders by recapitulating human-specific disease mechanisms. In particular, hPSC-based human–animal brain chimeras enable the study of human cell pathophysiology in vivo. In chimeric brains, human neural and immune cells can maintain human-specific features, undergo maturation, and functionally integrate into host brains, allowing scientists to study how human cells impact neural circuits and animal behaviors. The emerging human–animal brain chimeras hold promise for modeling human brain cells and their interactions in health and disease, elucidating the disease mechanism from molecular and cellular to circuit and behavioral levels, and testing the efficacy of cell therapy interventions. Here, we discuss recent advances in the generation and applications of using human–animal chimeric brain models for the study of neurological disorders, including disease modeling and cell therapy.

Human pluripotent stem cell; Human–animal chimera; Neurological disorder; Disease modeling; Cell therapy; Human neurons and glia; Microglia · Organoid