Dataset Information

Extracellular Vesicle Proteomics in Substance Use Disorder

ABSTRACT: This study investigates the proteomic composition of extracellular vesicles (EVs) derived from postmortem prefrontal cortex brain tissues of individuals with substance use disorder (SUD) and matched controls.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Extracellular Vesicle

DISEASE(S): Substance Abuse

SUBMITTER: Carlos Gartner

LAB HEAD: Calvin Vary

PROVIDER: PXD061471 | Pride | 2025-05-14

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	gg_Wasif_102023_6600_IDA01.wiff	Wiff
	gg_Wasif_102023_6600_IDA01.wiff.scan	Wiff
	gg_Wasif_102023_6600_IDA02.wiff	Wiff
	gg_Wasif_102023_6600_IDA02.wiff.scan	Wiff
	gg_Wasif_102023_6600_IDA03.wiff	Wiff

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Project description: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 in vitro models of drug exposure are needed to advance our understanding of how to protect or reverse molecular changes related to substance use disorders. 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 via DNA methylation and RNA gene expression readouts. In neurons derived from an individual who died of opioid overdose, morphine treatment induced alterations in gene expression similar to those previously observed in OUD ex-vivo brain tissue, including differential expression of the immediate early gene EGR1, which is known to be dysregulated by opioid use. 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.

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Extracellular Vesicle Proteomics in Substance Use Disorder

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