Lifelong impact of PAE on stem cell dynamics and cellular aging

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Project Summary: Prenatal alcohol exposure (PAE) is common and can result in brain-based disabilities and growth deficits. The impact of PAE is not just in early development, but also can lead to secondary health problems throughout the lifespan. These secondary problems can include higher rate and earlier onset of aging-related diseases, including cardiovascular disease, autoimmune disorders such as arthritis, and decreased bone density. The early onset of these aging-related diseases indicates that a consequence of PAE is premature aging of tissues and organs. There is an unmet need to better understand this PAE-induced premature aging and determine the underlying mechanisms that could be leveraged to delay or prevent these secondary health conditions. We know that PAE is a potent teratogen that reprograms stem cells. Our hypothesis is that this stem cell reprogramming has lifelong consequences, including the premature aging of stem cells as a mechanism that drives systemic aging. This hypothesis is supported by published literature that shows PAE can disrupt stem cell self-renewal, due, in part, to premature or aberrant differentiation, and that these disrupted stem cell behaviors persist into adulthood. Based on these data, we plan to address two questions: firstly, “does PAE in human populations diminish stem cell function across the lifespan?”; secondly, “does PAE induce or exacerbate human stem cell aging?”. To address the above two questions, we plan to create human induced pluripotent stem cells (hiPSCs), as early passages of these cells retain epigenetic markers of aging. These cells will be derived from regionally and ethnically diverse neonatal, child/adolescent, and adult cohorts of individuals with PAE/fetal alcohol spectrum disorders (FASDs) and from matched controls. In Aim 1 we plan to use a panel of cellular and molecular assays to assess PAE/FASD-induced changes in stem cell growth, self-renewal, and trilineage (ectoderm, mesoderm, endoderm) differentiation. In Aim 2 we plan to assess alterations to stem cell aging, including exhaustion, senescence, and release of pro-inflammatory molecules as part of the senescence- associated secretory phenotype. Our overarching goal, to ultimately identify underlying mechanisms mediate the emergence of secondary health conditions for individuals with FASDs, is consistent with the mission of the NIAAA (RFA-AA-21-014). PAE is known to inhibit stem cell function. However, tissue stem cells may also be a novel target for the prevention and treatment of PAE-induced premature aging. At the conclusion of these studies, we will have: firstly, created a unique community resource, a panel of patient-derived hiPSC cells, that can be used to assess the systemic impact of PAE across the lifespan; secondly, expanded our knowledge of the impact of PAE on stem cell behavior; and thirdly, identified important cellular mechanisms of premature aging.