BIOLOGICAL EMBEDDING OF CONTEXTUAL FACTORS IN HUMAN STEM CELLS: IMPLICATIONS FOR POPULATION HEALTH DIFFERENCES - Modified Abstract Section ABSTRACT Contextual factors related to social and economic conditions are the most salient determinant of population health differences. Although substantial progress had been made in understanding how contextual factors becomes biologically embedded, crucial knowledge gaps remain. Biological embedding has been described primarily at the lev-el of differentiated cell types and tissues. Based on the consideration that a) the long-term effects of contextual factors extend well beyond the lifespan of differentiated cells, whose replenishment occurs only from stem/progenitor cells, and b) can be perpetuated across generations, we advance the novel hypothesis that the origins of health differences may extend all the way down to the level of stem cells, and specifically to the effects of maternal exposure to contextual factors on offspring stem cells during prenatal life. Our proposed study will focus on differences between Hispanic, non-Hispanic Black, and non-Hispanic White mothers and their newborns in obesity and metabolic phenotypes; on mesenchymal pro-genitor/stromal cells (MSCs) and MSC-derived adipocytes as the stem and differentiated cells of interest; on mitochondrial function, adipogenic propensity/activity and insulin sensitivity as the key intracellular processes of importance; on newborn ad-ipose tissue mass and glucose-insulin regulation as the outcomes of significance; and on maternal-fetal gestational biology as the proximate transmission pathway. We will conduct this study in a cohort of N=240 child-mother dyads; isolate and culture fetal MSCs from newborn cord tissue; perform high-resolution cellular experiments; and characterize neona-tal phenotypes in vitro in MSC-derived adipoctyes, and in vivo using whole body densitometry. Aim 1 will test the hy-pothesis that maternal exposure to unfavorable contextual factors is associated with newborn mesenchymal stem cell characteristics, i.e., reduced mitochondrial efficiency, increased adipogenic propensity, and reduced insulin sensitivity. Aim 2 will test the hypothesis that variation in maternal and fetal gestational biology (composite measures of endo-crine, immune/inflammatory, and metabolic ligands) mediates the effects of contextual factors on newborn mesen-chymal stem cells. Aim 3 will establish the clinical significance of variation in MSC characteristics for neonatal obesi-ty-related phenotypes at the a) cellular level (MSC-derived adipocyte size and fat content; mitochondrial function; ad-ipogenic activity), and b) whole-body level (percent fat mass and systemic insulin sensitivity). Aim 4 (exploratory) will elucidate potentially modifiable maternal psychosocial and behavioral factors that relate to the specific components of contextual factors that are associated with newborn MSC biology. Aim 5 will establish a shared repository (bi-obank) of MSC, cord blood, cord and placental tissue samples for future studies of molecular mechanisms (gene ex-pression profiles, epigenetic characteristics) and in vitro cell differentiation analyses. Significance and impact: 1) Our study will define novel measures (with norms) in human newborn stem cells that profile the earliest vulnerabili-ties for health and population health differences; 2) broaden understanding of novel cellular targets and molecular mechanisms underlying biological embedding of contextual factors to inform risk identification, prevention, early di-agnosis, and personalized intervention; and 3) provide a unique and valuable shared resource (human newborn stem cell culture biobank).
