Interspecies chimerism with human embryonic stem cells generates functional human dopamine neurons at low efficiency

Hu Wang; Xiling Yin; Jinchong Xu; Li Chen; Senthilkumar S Karuppagounder; Enquan Xu; Xiaobo Mao; Valina L Dawson; Ted M Dawson

doi:10.1016/j.stemcr.2023.11.009

Interspecies chimerism with human embryonic stem cells generates functional human dopamine neurons at low efficiency

Stem Cell Reports. 2024 Jan 9;19(1):54-67. doi: 10.1016/j.stemcr.2023.11.009. Epub 2023 Dec 21.

Authors

Hu Wang¹, Xiling Yin¹, Jinchong Xu¹, Li Chen¹, Senthilkumar S Karuppagounder¹, Enquan Xu¹, Xiaobo Mao¹, Valina L Dawson², Ted M Dawson³

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: vdawson1@jhmi.edu.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: tdawson@jhmi.edu.

Abstract

Interspecies chimeras offer great potential for regenerative medicine and the creation of human disease models. Whether human pluripotent stem cell-derived neurons in an interspecies chimera can differentiate into functional neurons and integrate into host neural circuity is not known. Here, we show, using Engrailed 1 (En1) as a development niche, that human naive-like embryonic stem cells (ESCs) can incorporate into embryonic and adult mouse brains. Human-derived neurons including tyrosine hydroxylase (TH)⁺ neurons integrate into the mouse brain at low efficiency. These TH⁺ neurons have electrophysiologic properties consistent with their human origin. In addition, these human-derived neurons in the mouse brain accumulate pathologic phosphorylated α-synuclein in response to α-synuclein preformed fibrils. Optimization of human/mouse chimeras could be used to study human neuronal differentiation and human brain disorders.

MeSH terms

Adult
Animals
Cell Differentiation / physiology
Chimerism
Dopaminergic Neurons
Human Embryonic Stem Cells*
Humans
Mice
Pluripotent Stem Cells*
alpha-Synuclein

Substances

alpha-Synuclein