Human iPSC Models

Induced pluripotent stem cells (iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka, M.D., Ph.D., who showed that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells. Given the significant differences between mice and humans, methods that recapitulate paradigms of human brain development in vitro have enormous potential.

Researchers have recently established an iPSC-based cerebral organoid culture system that models the major processes and structural features of human brain development. These "mini-brains" provide a physiologically relevant in vitro 3D brain model to study neurological development and disease processes unique to the human nervous system. They have important applications in studying human brain development and neurological disorders.

The apolipoprotein E4 (APOE4) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) as compared with the common APOE3 allele. Dr. Bu's lab has successfully established the cerebral organoid 3D-culture system. Multiple iPSC lines from healthy individuals and people with sporadic AD who have APOE3/3 or APOE4/4 genotypes were generated. The lab has found that 3D brain organoids from AD patient-derived iPSCs could recapitulate AD-like pathologies. The cerebral organoids from patients with AD grew differently compared with those from individuals that do not have AD. The establishment of this valuable model will not only provide the opportunity to study the effects of apoE isoforms and disease-related pathways in a physiologically relevant environment but also facilitate the development of novel therapeutics for treating AD.

Key Publications

Zhao J, Lu W, Ren Y, Fu Y, Martens YA, Shue F, Davis MD, Wang X, Chen K, Li F, Liu CC, Graff-Radford NR, Wszolek ZK, Younkin SG, Brafman DA, Ertekin-Taner N, Asmann YW, Dickson DW, Xu Z, Pan M, Han X, Kanekiyo T, Bu G. Apolipoprotein E regulates lipid metabolism and alpha-synuclein pathology in human iPSC-derived cerebral organoids. Acta Neuropathologica. 2021; doi:10.1007/s00401-021-02361-9

Zhao J, Fu Y, Yamazaki Y, Ren Y, Davis MD, Liu CC, Lu W, Wang X, Chen K, Cherukuri Y, Jia L, Martens YA, Job L, Shue F, Nguyen TT, Younkin SG, Graff-Radford NR, Wszolek ZK, Brafman DA, Asmann YW, Ertekin-Taner N, Kanekiyo T, Bu G. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids. Nature Communications. 2020; doi:10.1038/s41467-020-19264-0