A Human Stem Cell-Derived Neuronal Model of Morphine Exposure Reflects Brain Dysregulation in Opioid Use Disorder: Transcriptomic and Epigenetic Characterization of Postmortem-Derived iPSC Neurons

Authors

Emily F Mendez
Sandra L Grimm
Laura Stertz
Damian Gorski
Sai V Movva
Katherine Najera
Karla Moriel
Thomas D Meyer
Gabriel R Fries
Cristian Coarfa
Consuelo Walss-Bass

Publication Date

1-1-2023

Journal

Frontiers in Psychiatry

Abstract

INTRODUCTION: Human-derived induced pluripotent stem cell (iPSC) models of brain promise to advance our understanding of neurotoxic consequences of drug use. However, how well these models recapitulate the actual genomic landscape and cell function, as well as the drug-induced alterations, remains to be established. New

METHODS: We engineered a novel induced pluripotent stem cell-derived model of neural progenitor cells and neurons from cultured postmortem human skin fibroblasts, and directly compared these to isogenic brain tissue from the donor source. We assessed the maturity of the cell models across differentiation from stem cells to neurons using RNA cell type and maturity deconvolution analyses as well as DNA methylation epigenetic clocks trained on adult and fetal human tissue. As proof-of-concept of this model's utility for substance use disorder studies, we compared morphine- and cocaine-treated neurons to gene expression signatures in postmortem Opioid Use Disorder (OUD) and Cocaine Use Disorder (CUD) brains, respectively.

RESULTS: Within each human subject (N = 2, 2 clones each), brain frontal cortex epigenetic age parallels that of skin fibroblasts and closely approximates the donor's chronological age; stem cell induction from fibroblast cells effectively sets the epigenetic clock to an embryonic age; and differentiation of stem cells to neural progenitor cells and then to neurons progressively matures the cells

DISCUSSION: In summary, we introduce an iPSC model generated from human postmortem fibroblasts that can be directly compared to corresponding isogenic brain tissue and can be used to model perturbagen exposure such as that seen in opioid use disorder. Future studies with this and other postmortem-derived brain cellular models, including cerebral organoids, can be an invaluable tool for understanding mechanisms of drug-induced brain alterations.

Keywords

epigenetic aging, RNAseq, induced pluripotent stem cells, postmortem brain, cocaine use disorder, opioid use disorder, dermal fibroblast cells, neurons

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Supplementary Materials

PMID: 36873219