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

该项目的目标是测试一个关于母亲慢性压力对其后代干细胞影响的新假设。考虑到压力的长期影响可以远远超过大多数分化细胞的寿命，这些细胞的补充不是来自已经分化的细胞，而是来自干细胞/祖细胞，我们提出母体慢性压力影响的生物嵌入可能一直延伸到她后代的干细胞生物学特征。我们将进行一项研究，N=180名在妊娠后期招募的母子二人组，并随访至分娩。我们使用一种包含妊娠应激传递途径的主要生物标志物的母体适应负荷的复合生物学测量来操作母体慢性应激。出生后，我们将从脐带血中分离培养新生儿造血干细胞和祖细胞（hsc）。造血干细胞产生的免疫细胞在免疫系统和年龄相关疾病的背景下具有特殊的相关性。我们将描述在维持DNA完整性中起核心作用的细胞过程，即端粒酶功能能力和DNA修复能力。由于应激反应性是慢性应激效应的关键调节因子，我们还建议通过体外生物应激刺激（皮质醇或IL-6预孵卵）来表征hsc中的这种表型。为了确定新生儿HSC端粒生物学变异与免疫功能的相关性，我们将描述新生儿（脐带血）免疫细胞对抗原攻击的免疫/炎症反应。目的1将验证母体慢性应激暴露与胎儿（新生儿）造血干细胞端粒酶功能能力和DNA修复能力降低相关的假设。Aim 2A将检验母体慢性应激暴露与胎儿HSC细胞功能的应激反应表型（对皮质醇或IL-6挑战的反应）相关的假设。Aim 2B将在Aim 2A中验证抗氧化剂（白藜芦醇）预处理会减弱预期效应的假设。目的3将测试胎儿HSC端粒酶功能能力与DNA修复能力和新生儿免疫功能之间的关联强度。我们的研究将定义人类新生干细胞的新措施，以描述细胞健康、衰老和年龄相关疾病风险的最早脆弱性。我们的研究结果将扩大对新的细胞靶点和应激生物嵌入的分子机制的理解，进而可能为风险识别、预防、早期诊断和个性化干预提供信息。

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.