Stress and Human Stem/Progenitor Cells: Biobehavioral Mechanisms

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ABSTRACT Our goal is to test a novel hypothesis in humans about the impact of chronic stress and stress-related biobehavioral processes on stem/progenitor cell biology. Although substantial progress has been made in understanding how stress becomes biologically embedded to produce long-term effects, crucial knowledge gaps remain. The processes implicated in biological embed- ding have been described primarily at the level of differentiated cells types that form tissues and organ systems. 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 ‘parent’ cells, but occurs from stem/progenitor cells, we advance the hypothesis that biological embedding of the effects of chronic stress may extend all the way down to the level of stem cells, to define fundamental aspects of their biology that determine the earliest vulnerabilities for common stress- and age-related disorders. We underscore the importance of studying fetal (newborn) stem cells, focus specifically on hematopoietic (HSCs) and mesenchymal stem/progenitor cells (MSCs), and on the functional capacity of their telomere and mitochondrial systems as our primary outcomes. We operationalize chronic stress using a composite biological measure of maternal allostatic load that incorporates the principal biomarkers of the gestational stress transmission pathway. Because stress responsivity is a key modulator of chronic stress effects, we additionally propose to characterize this phenotype in HSCs and MSCs via an in vitro oxidative stress [H2O2] challenge. We will conduct the proposed study in N=300 mother-child dyads; isolate and culture newborn HSCs and MSCs from umbilical cord blood and cord tissue, respectively; and perform cellular telomerase activity and high-resolution respirometry experiments to characterize telomere and mitochondrial functional capacity. Aim 1 will test the hypothesis that chronic stress exposure (allostatic load) is prospectively associated with reduced functional capacity of newborn HSC and MSC telomere and mitochondrial systems. Aim 2A will test the hypothesis that chronic stress exposure primes the stress responsivity phenotype of newborn HSCs and MSCs, and Aim 2B will determine whether antioxidant (resveratrol) pretreatment attenuates this effect. Both aims will include tests for effect modification by sex and key covariates of telomere and mitochondrial function. Aim 3 will elucidate the maternal sociodemographic, psychosocial, behavioral and biophysical determinants of variation in components of allostatic load that impact newborn HSC/MSC biology using state-of-the-art machine learning and prediction approaches. Aim 4 will establish a shared Biobank repository of HSC, MSC, cord blood, cord and placental tissue samples for future studies of molecular mechanisms (gene expression, epigenetic profiles) and in vitro differen- tiation. Significance and Impact: Our project will 1) define novel measures (and their norms) in human newborn stem cells that profile the earliest vulnerabilities for cell health and risk of age-related disorders; 2) broaden under- standing of novel cellular targets and molecular mechanisms underlying biological embedding of stress, that, in turn, may inform the development of personalized interventions; and 3) provide shared resources (human newborn stem cell, placenta, cord, and cord blood biobank).