Maternal chronic stress and fetal programming of hematopoietic stem/ progenitor cells

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The goal of the project is to test a novel hypothesis about the impact of maternal chronic stress on her offspring’s stem cells. Based on the consideration that the long-term effects of stress can extend well beyond the lifespan of most differentiated cells, whose replenishment does not occur from already-differentiated cells, but only from stem/progenitor cells, we propose that biological embedding of the effects of maternal chronic stress may extend all the way down to characteristics of her offspring’s stem cell biology. We will conduct a study in N=180 mother-child dyads recruited during late gestation and followed through birth. We operationalize maternal chronic stress using a composite biological measure of maternal allostatic load that incorporates the principal biomarkers of the gestational stress transmission pathway. At birth, we will isolate and culture newborn hematopoietic stem and progenitor cells (HSCs) from umbilical cord blood. HSCs give rise to immune cells that are of particular relevance in the context of immune system- and age-related disorders. We will characterize cellular processes that play a central role in maintenance of DNA integrity, i.e., telomerase functional capacity and DNA repair capacity. Because stress responsivity is a key modulator of chronic stress effects, we additionally propose to characterize this phenotype in HSCs via an in vitro biological stress challenge (pre-incubation with cortisol or IL-6). To establish the relevance of variation in newborn HSC telomere biology for immune function, we will characterize the immune/inflammatory response of neonatal (cord) blood immune cells to antigen challenge. Aim 1 will test the hypothesis that maternal chronic stress exposure is prospectively associated with reduced telomerase functional capacity and DNA repair capacity of fetal (newborn) HSCs. Aim 2A will test the hypothesis that maternal chronic stress exposure is associated with the stress responsivity phenotype (response to cortisol or IL-6 challenge) of fetal HSC cellular function. Aim 2B will test the hypothesis that antioxidant (resveratrol) pre-treatment attenuates the expected effects in Aim 2A. Aim 3 will test the strength of the associations between fetal HSC telomerase functional capacity and DNA repair capacity and newborn immune function. Our study will define novel measures in human newborn stem cells that profile the earliest vulnerabilities for cellular health, aging and risk of age-related disorders. Our findings will broaden understanding of novel cellular targets and molecular mechanisms underlying biological embedding of stress, that, in turn, may inform risk identification, prevention, early diagnosis, and personalized intervention.