Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells.

Autor: Tao Y; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA. taoyunlong@nju.edu.cn.; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. taoyunlong@nju.edu.cn., Li X; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Dong Q; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Kong L; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Petersen AJ; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Yan Y; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Xu K; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Zima S; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Li Y; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Schmidt DK; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Ayala M; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Mathivanan S; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA., Sousa AMM; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.; Department of Neuroscience, Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA., Chang Q; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.; Department of Neuroscience, Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA., Zhang SC; Waisman Center, University of Wisconsin-Madison, Madison, WI, USA. suchun.zhang@wisc.edu.; Department of Neuroscience, Department of Neurology, University of Wisconsin-Madison, Madison, WI, USA. suchun.zhang@wisc.edu.; Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore, Singapore. suchun.zhang@wisc.edu.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2024 Sep; Vol. 42 (9), pp. 1404-1416. Date of Electronic Publication: 2023 Nov 16.
DOI: 10.1038/s41587-023-01977-4
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: