2023/11/16 by Yunlong Tao, Xueyan Li, Qiping Dong +12 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #CRISPR and Genetic Engineering #Neuroscience and Neural Engineering #Pluripotent Stem Cells Research
paper · pdf · doi:10.1038/s41587-023-01977-4
openalex publication_date 2023/11/16 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04
Abstract Central norepinephrine (NE) neurons, located mainly in the locus coeruleus (LC), are implicated in diverse psychiatric and neurodegenerative diseases and are an emerging target for drug discovery. To facilitate their study, we developed a method to generate 40–60% human LC-NE neurons from human pluripotent stem cells. The approach depends on our identification of ACTIVIN A in regulating LC-NE transcription factors in dorsal rhombomere 1 (r1) progenitors. In vitro generated human LC-NE neurons display extensive axonal arborization; release and uptake NE; and exhibit pacemaker activity, calcium oscillation and chemoreceptor activity in response to CO 2 . Single-nucleus RNA sequencing (snRNA-seq) analysis at multiple timepoints confirmed NE cell identity and revealed the differentiation trajectory from hindbrain progenitors to NE neurons via an ASCL1 -expressing precursor stage. LC-NE neurons engineered with an NE sensor reliably reported extracellular levels of NE. The availability of functional human LC-NE neurons enables investigation of their roles in psychiatric and neurodegenerative diseases and provides a tool for therapeutics development.