Induced pluripotent stem cells as a platform to understand patient‐specific responses to opioids and anaesthetics

Obal, Detlef; Wu, Joseph C.

doi:10.1111/bph.15228

Cited by 6 publications

(6 citation statements)

References 141 publications

(176 reference statements)

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“…One downside of modeling diseases using iPSC models is that the dedifferentiation process to induce the stem cells effectively erases many of the disease, aging, and environmental epigenetic signatures from the source patient, a phenomenon known as epigenetic rejuvenation ( 6 , 58 , 59 ). However, this epigenetic reprograming can be useful in designing experiments to answer questions related to an individual perturbagen, such as consequences of drug exposure in substance use disorders or drug overdose ( 31 ). It is important to note that OUD and CUD are an incredibly complex diseases characterized by behavioral drug seeking, tolerance, withdrawal, and psychosocial distress ( 60 ), and many aspects of the diseases are impossible to model in a dish with current technologies.…”

Section: Discussionmentioning

confidence: 99%

“…iPSC-derived cellular brain models can therefore provide an important system for controlled pharmacological manipulation to elucidate drug-induced gene regulation mechanisms. Utilization of iPSCs derived from subjects with OUD as well as iPSC models of opioid exposure is currently limited ( 31 ). iPSC-derived dopaminergic neurons demonstrate differences in expression of dopaminergic system genes in subjects carrying a variable number tandem repeat polymorphism in DAT, and treatment with valproic acid altered dopaminergic gene expression specifically in cell lines from opioid addiction subjects ( 32 ).…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2023

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IntroductionHuman-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.MethodsWe 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.ResultsWithin 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.DiscussionIn 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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“…Overall, we demonstrated that this method can be applied directly to the measurement of calcium signaling in individual CMs and results in increased data collection efficiency from 20 to 80% by binding a biotinylated CM to a streptavidin surface. The overarching significance of these methods extends beyond studying primary CMs to the increasingly used induced pluripotent derived CMs in mechanistic and therapeutic studies. − …”

Section: Discussionmentioning

confidence: 99%

Increased Retention of Cardiac Cells to a Glass Substrate through Streptavidin–Biotin Affinity

et al. 2021

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In vitro analysis of primary isolated adult cardiomyocyte physiological processes often involves optical imaging of dye-loaded cells on a glass substrate. However, when exposed to rapid solution changes, primary cardiomyocytes often move to compromise quantitative measures. Improved immobilization of cells to glass would permit higher throughput assays. Here, we engineer the peripheral membrane of cardiomyocytes with biotin to anchor cardiomyocytes to borosilicate glass coverslips functionalized with streptavidin. We use a rat cardiac myoblast cell line to determine general relationships between processing conditions, ligand density on the cell and the glass substrate, cellular function, and cell retention under shear flow. Use of the streptavidin−biotin system allows for more than 80% retention of cardiac myoblasts under conventional rinsing procedures, while unmodified cells are largely rinsed away. The adhesion system enables the in-field retention of cardiac cells during rapid fluid changes using traditional pipetting or a modern microfluidic system at a flow rate of 160 mL/min. Under fluid flow, the surfaceengineered primary adult cardiomyocytes are retained in the field of view of the microscope, while unmodified cells are rinsed away. Importantly, the engineered cardiomyocytes are functional following adhesion to the glass substrate, where contractions are readily observed. When applying this adhesion system to cardiomyocyte functional analysis, we measure calcium release transients by caffeine induction at an 80% success rate compared to 20% without surface engineering.

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“…It appears that hiPSCs were widely used in various aspects of SUD research, including disease mechanism/ modeling, drug efficacy/safety/toxicity, drug response, and drug discovery. In these studies, hiPSCs were differentiated into a variety of cell types, for example, neurons (e.g., GABAergic, dopaminergic, and brain organoid), cardiomyocytes, and endothelial cells, and used in exploring different classes of substances [79][80][81][82][83][84][85][86]. In addition, the use of hiPSC model allowed researchers to examine the developmental mechanisms underlying prenatal exposure [87,88].…”

Section: Plos Onementioning

confidence: 99%

On the utilization of the induced pluripotent stem cell (iPSC) model to study substance use disorders: A scoping review protocol

Niemis,

Peterson,

Javier

et al. 2023

PLoS ONE

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Introduction Induced pluripotent stem cells (iPSCs) are cells derived from somatic cells via reprogramming techniques. The iPSC approach has been increasingly used in neuropsychiatric research in the last decade. Though substance use disorders (SUDs) are a commonly occurring psychiatric disorder, the application of iPSC model in addiction research has been limited. No comprehensive review has been reported. We conducted a scoping review to collate existing evidence on the iPSC technologies applied to SUD research. We aim to identify current knowledge gaps and limitations in order to advance the use of iPSCs in the SUD field. Methods and analysis We employed a scoping review using the methodological framework first created by Arksey and O’Malley and further updated by Levac et al. and the Joanna Briggs Institute (JBI). We adopted the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Protocols (PRISMA-P) to report items for the protocol. We searched evidence from four electronic databases: PubMed®, Embase®, Web of Science™, and Scopus®. Primary research, systematic reviews, and meta-analyses were included and limited to studies published in English, at the time from 2007 to March 2022. This is an “ongoing” scoping review. Searched studies will be independently screened, selected, and extracted by two reviewers. Disagreement will be solved by the third reviewer and discussion. Extracted data will be analyzed in descriptive and quantitative approaches, then summarized and presented in appropriate formats. Results will be reported following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guideline and disseminated through a peer-reviewed publication and conference presentations. Conclusion To our best knowledge, this is the first comprehensive scoping review of iPSC methods specifically applied to a broad range of addictive drugs/substances that lead to SUDs or misuse behavior. Registration This protocol is registered on Zenodo repository (https://zenodo.org/) with doi:10.5281/zenodo.7915252.

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Induced pluripotent stem cells as a platform to understand patient‐specific responses to opioids and anaesthetics

Cited by 6 publications

References 141 publications

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

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

Increased Retention of Cardiac Cells to a Glass Substrate through Streptavidin–Biotin Affinity

On the utilization of the induced pluripotent stem cell (iPSC) model to study substance use disorders: A scoping review protocol

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