Recently, the research team led by Prof. Yan Liu from the School of Pharmacy at Nanjing Medical University published a research article in Cell Stem Cell (SCI Impact Factor = 20.4), entitled “Generation of human nucleus basalis organoids with functional nbM–cortical cholinergic projections in transplanted assembloids.” The study presents an efficient strategy for generating a novel, nucleus-specific brain organoid and demonstrates its application in transplantation.This work was also featured in an invited Cell Stem Cell Preview, which highlighted the successful reconstruction of the human nbM–cortical cholinergic projection circuit and emphasized that the dual-transplantation strategy provides a powerful human-specific platform for investigating brain-circuit development and disease mechanisms.
The nucleus basalis of Meynert (nbM) is a key cholinergic hub in the basal forebrain, and damage to its projections to the cortex is closely associated with major neurological disorders such as Alzheimer’s disease (AD) and Down syndrome (DS). In this study, the researchers generated region-specific human nbM organoids (hnbMOs) by optimizing Sonic Hedgehog (SHH) induction conditions to promote nbM identity and maturation. They systematically validated the organoids’ electrophysiological properties and cholinergic neurotransmitter function.
They then rebuilt long-range cholinergic pathways by co-culturing these organoids with human fetal brain tissue and by transplanting them into immunodeficient mice. The team further engineered nbM–cortical assembloids by fusing hnbMOs with human cortical organoids, establishing a human-specific cholinergic projection system both in vitro and in vivo. Using viral tracing and functional assays, they demonstrated that cholinergic neurons extend axonal projections into cortical organoids and form active synaptic connections. Importantly, this work also revealed projection deficits in Down syndrome–derived assembloids, underscoring the value of this platform for studying nbM-related neural circuits and the mechanisms underlying neurological disorders.
This study was jointly led by Prof. Yan Liu from the School of Pharmacy, Nanjing Medical University (NMU), Prof. Xing Guo from the School of Basic Medical Sciences at NMU, Prof. Qing Cheng from Nanjing Women and Children's Healthcare Hospital, and Prof. Yi Dong from East China Normal University. Dr. Da Wang (postdoctoral fellow, School of Pharmacy, NMU), Xingyue Zhang (PhD candidate, National Key Laboratory of Reproductive Medicine and Offspring Health), Dr. Xiaoyan Tang (School of Pharmacy, NMU; currently a postdoctoral fellow at the University of California, San Francisco), Yixia Gan (PhD candidate, East China Normal University), and Dr. Hanwen Yu (Associate Professor, School of Pharmacy, NMU) contributed equally to this work as co–first authors.
Full-text link: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(25)00372-8
(Drafted and translated byProf. Liu Yan’s research team; Reviewed by Han Feng & Liu Mingjie; Translation Revised by Wu Wenbo)
