Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: Current status and outlook.
- Authors
- Scarnati, Matthew S; Halikere, Apoorva; Pang, Zhiping P
- Year
- 2019
- Journal
- Alcohol (Fayetteville, N.Y.)
- PMID
- 30087005
- DOI
- 10.1016/j.alcohol.2018.03.008
- PMCID
- PMC6167197
Alcohol use disorders (AUDs), which include alcohol abuse and dependence, are among the most common types of neuropsychiatric disorders in the United States (U.S.). Approximately 14% of the U.S. population is affected in a single year, thus placing a tremendous burden on individuals from all socioeconomic backgrounds. Animal models have been pivotal in revealing the basic mechanisms of how alcohol impacts neuronal function, yet there are currently limited effective therapies developed based on these studies. This is mainly due to a limited understanding of the exact cellular and molecular mechanisms underlying AUDs in humans, which leads to a lack of targeted therapeutics. Furthermore, compounding factors including genetic background, gene copy number variants, single nucleotide polymorphisms (SNP) as well as environmental and social factors that affect and promote the development of AUDs are complex and heterogeneous. Recent developments in stem cell biology, especially the human induced pluripotent stem (iPS) cell development and differentiation technologies, has provided us a unique opportunity to model neuropsychiatric disorders like AUDs in a manner that is highly complementary to animal studies, but that maintains fidelity with complex human genetic contexts. Patient-specific neuronal cells derived from iPS cells can then be used for drug discovery and precision medicine, e.g. for pathway-directed development in alcoholism. Here, we review recent work employing iPS cell technology to model and elucidate the genetic, molecular and cellular mechanisms of AUDs in a human neuronal background and provide our perspective on future development in this direction.
Applications for iPS Cells in Modeling Alcohol Use Disorders (AUDs): From Disease Modeling to Precision MedicineSomatic tissue (mainly fibroblasts) can be obtained from patients that have been clinically diagnosed to have an AUD. Fibroblasts are then reprogrammed to an embryonic state through coexpression of the OSKM factors (Oct4, Sox2, Klf4 and c-Myc) to produce induced pluripotent stem (iPS) cells. iPS cells can then be differentiated into neurons. Conversely, it is possible to convert fibroblasts, via forced expression of specific transcription factors (Brn2, Ascl1 and Mytl1), into functional induced neuronal (iN) cells (Pang et al., 2011). iPS-derived patient specific neurons can be used for modeling AUDs to understand underlying mechanisms driving pathology. In addition, assays can be employed to assess the cytotoxicity of small molecules being tested for potential drug development. iPS cells generated from a patient carrying a known genetic variant linked to AUDs can be edited using genetic engineering prior to terminal neuronal differentiation. The “fixed” human neurons can then be used in applications for precision medicine such as transplantation/regenerative medicine. It is also possible to model the effects of ethanol on various stages of iPS cell development, self-propagation and differentiation (see pink boxes). The diagram above illustrates how iPS cells provide an upgraded model system for AUD disease modeling, high-throughput drug screening and cytotoxicity assays.
| # | Section | Preview |
|---|---|---|
| 20 | Current Work Attempting to Use iPS Cell Technology to Model AUDs | to accumulating DNA damage when exposed to alcohol, due to acetaldehyde accumulation? Interestingly,… |
| 21 | Current Work Attempting to Use iPS Cell Technology to Model AUDs | In addition, given the fact that ALDH isoforms are key enzymes of alcohol metabolism (Edenberg,… |
| 22 | Current Work Attempting to Use iPS Cell Technology to Model AUDs | astrocytes (Shaltouki et al., 2013; TCW et al., 2017). Given the reliable platforms for generating… |
| 23 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on NMDA receptor function in human neurons | Studies performed assaying NMDA receptor function and measuring specific receptor subtype mRNA… |
| 24 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on NMDA receptor function in human neurons | cell-derived human neurons. These data, taken together, suggest that tolerance to attenuation of the… |
| 25 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on GABAA receptor function in human neurons | Accumulating evidence suggests that GABA is a major player in dictating many of the behavioral… |
| 26 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on GABAA receptor function in human neurons | using human iPS cell-derived neuronal cells contradict findings obtained from animal models… |
| 27 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on GABAA receptor function in human neurons | Grayson, & Morrow, 1995), specifically an increase in GABAA α4 (GABRA4) subunit and a decrease in… |
| 28 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on GABAA receptor function in human neurons | Modeling the effect of alcohol exposure in vitro on human subject-derived neuronal cells is… |
| 29 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on GABAA receptor function in human neurons | be due to differences in cell-type and/or brain regions. Whole-cell patch clamp recordings were used… |
| 30 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on innate neuroinflammation in human neurons | Interference of cellular metabolism and differentiation as a result of epigenetic disruption is a… |
| 31 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on innate neuroinflammation in human neurons | The proliferation capacity of patient-derived iPS cells and NPCs were unaffected by either acute (24… |
| 32 | Current Work Attempting to Use iPS Cell Technology to Model AUDs — Alcohol’s impact on innate neuroinflammation in human neurons | the context of fetal alcohol exposure. It has been shown that in utero alcohol exposure disrupts the… |
| 33 | Advantages and Disadvantages for iPS Cells in Modeling Human Neuropsychiatric and Neurological Disorders | Enormous effort has been devoted to generation of defined subtypes of neural cells from iPS cells… |
| 34 | Advantages and Disadvantages for iPS Cells in Modeling Human Neuropsychiatric and Neurological Disorders | 2017, 2012; Oni et al., 2016) because it will allow studies to mitigate an individual’s genetic… |
| 35 | Advantages and Disadvantages for iPS Cells in Modeling Human Neuropsychiatric and Neurological Disorders | Importantly, cross species analyses could be conducted using human iPS cell model as well as animal… |
| 36 | Advantages and Disadvantages for iPS Cells in Modeling Human Neuropsychiatric and Neurological Disorders | Use of human neuronal cells derived from iPS cells to examine gene expression profiles may only… |
| 37 | Advantages and Disadvantages for iPS Cells in Modeling Human Neuropsychiatric and Neurological Disorders | accurately model the environment that human neurons reside in? 2) iPS cell technology is expensive… |
| 38 | Advantages and Disadvantages for iPS Cells in Modeling Human Neuropsychiatric and Neurological Disorders | Reprogramming relies on the expression of certain TFs in order for the original somatic tissue to… |
| 39 | Concluding Remarks and Future Perspectives | The glaring potential of reprogramming technology resides in the future application for precision… |
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model. | Boreland AJ et al. | — | 2026 | → |
| Polygenic risk for alcohol use disorder affects cellular responses to ethanol exposure in a human microglial cell model. | Li X et al. | — | 2024 | → |
| 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics. | Gameiro-Ros I et al. | — | 2023 | → |
| Modeling SARS-CoV-2 infection in individuals with opioid use disorder with brain organoids. | Willner MJ et al. | — | 2021 | → |
| Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons. | Halikere A et al. | — | 2020 | → |
| Differential sensitivity of human neurons carrying μ opioid receptor (MOR) N40D variants in response to ethanol. | Scarnati MS et al. | — | 2020 | → |
| Alcohol-responsive genes identified in human iPSC-derived neural cultures. | Jensen KP et al. | — | 2019 | → |
| Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells. | Di Rocco G et al. | — | 2019 | → |
| Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry. | Popova D et al. | — | 2019 | → |