Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: Current status and outlook

Abstract

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.

Alcohol-responsive genes identified in human iPSC-derived neural cultures

“…Differentiation of neural cell cultures from induced pluripotent stem cells (iPSCs) 18 may provide an in vitro model to examine the effects of alcohol on human neural cells derived from characterized donors, potentially facilitating the identification of novel pathways associated with the effects of alcohol exposure on the brain. Recent work has highlighted the potential of iPSC technologies to study the complex actions of alcohol (for review, see 19,20 ). To our knowledge, no report to date has coupled human iPSC neural differentiation with RNA sequencing to explore transcriptome-wide effects of alcohol exposure in vitro.…”

Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

“…Because of the high prevalence of opioid addiction and a high prevalence of the A118G minor allele in human populations (Bergen et al, 1997;Gelernter et al, 1999;Tan et al, 2003;Mague and Blendy, 2010), it is important to gain a more mechanistic and functional understanding of MORs with different SNPs (Lötsch and Geisslinger, 2005) by using mouse (Mague et al, 2009;Bilbao et al, 2015) as well as using human neuronal models (Scarnati et al, 2019). In the rodent model, high heterogeneity of VTA neurocircuitry (Watabe-Uchida et al, 2012;Matsui et al, 2014;Beier et al, 2015) and possible gender-dependent implications (Kanaji et al, 2014;Browne et al, 2017) should be considered.…”

“…In the rodent model, high heterogeneity of VTA neurocircuitry (Watabe-Uchida et al, 2012;Matsui et al, 2014;Beier et al, 2015) and possible gender-dependent implications (Kanaji et al, 2014;Browne et al, 2017) should be considered. Moreover, given the discrepancy of findings related to A118G SNPs, it is also likely that species-specific-dependent mechanisms are involved; recent developments in human stem cell and human neural stem cell technology (Prytkova et al, 2018;Scarnati et al, 2019) may help facilitate the study of SNPs in a human neuronal context.…”

Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells

“…In addition, alcohol exposure induces gene expression changes in hESC-derived cortical neurons, including a significant up-regulation of N -methyl- d -aspartate (NMDA) receptor subunit gene expression [82]. Alcohol-mediated changes in NMDA receptor function was also assessed in iPS-derived neural cells [83], indicating that iPSCs may offer a novel approach for better understanding the molecular mechanisms of alcohol use disorders [73, 84]. Exposure of iPSc to alcohol (100 mM) was also demonstrated to induce apoptosis and impair hepatic differentiation [85].…”