Postmortem-derived iPSC models in substance use disorders research.
Postmortem-derived iPSC models in substance use disorders research.
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物质使用障碍研究中的死后 iPSC 模型。
DOI：
10.1038/s41386-023-01703-3
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Walss-Bass,Consuelo
中科院分区：
文献类型：
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作者：
Mendez,EmilyFrances;Walss-Bass,Consuelo
Patient-derived induced pluripotent stem cell (iPSC) models have accelerated discovery in the biomedical sciences, with high potential to model human physiology and disease. The use of these models in substance use disorders (SUD) has been limited. Studies using iPSC-derived dopaminergic neurons have explored the effects of genetic polymorphisms in opioid-dependent patients [1, 2], and iPSC-derived models of non-neuronal drug exposure, including endothelial cells and cardiomyocytes, have been established. While these studies shed light on effects of drugs in SUD, how well the models recapitulate the actual druginduced brain alterations, genomic landscape and cell function remains to be determined.We established an iPSC-neuron model derived from postmortem fibroblasts of subjects with SUD from which brain tissue is also available [3], to explore neurotoxic consequences of cocaine and opioid exposure in isogenic ex-vivo and in-vitro brain models. The differentiated neurons showed potential for modeling of opioidergic and endorphinergic signaling. Gene expression profiles in morphine-or cocaine-treated cells paralleled those observed in brain of the respective opioid and cocaine overdose subjects they were derived from, including alterations in cell communication and signaling transduction. Postmortem-derived iPSC models such as this one show great promise to be directly comparable to inaccessible isogenic human tissues, such as brain, that can be collected at time of autopsy and used to validate and augment SUD research. Figure 1 denotes the potential for iPSC-derived models in SUD research. More complex in vitro systems are currently being engineered to model tissue-and systems-level responses to drugs. Recent studies using organoid models of opioid use disorder show differential transcriptomic signatures between oxycodone and
