Fetal Microchimeric Responses to Ischemic Stroke

描述（由申请人提供）：临床和实验数据表明，中风是一种性二态性疾病。特别是女性，在整个生命周期中具有不同程度的缺血敏感性。在怀孕期间，妇女与胎儿交换细胞，在许多妇女中，少量的胎儿来源的细胞可能会持续一生。胎儿细胞可以在分娩后数年在母体大脑中发现，这些细胞表达干细胞和成熟神经元标记物。小鼠模型的开发可用于在分娩后很长时间内跟踪胎儿细胞，为研究人员开辟了一条新的研究途径。最近的实验工作表明，胎儿细胞运输到损伤和炎症区域，并分化成各种细胞类型，这表明这些细胞可能具有未被识别的修复和再生能力。然而，目前尚不清楚这种贩运是否代表适应性反应或进一步的化合物损伤。我们将研究胎儿细胞是否在中风后运输到大脑，并评估这些细胞在母体大脑中的长期命运和分化。然后，我们将操纵大脑中存在的胎儿细胞的数量（通过增加产次），并确定这些细胞是否是老年雌性小鼠中风后缺血敏感性或功能恢复的重要贡献者。最近的研究表明，胚胎细胞可以移植和分化为内皮细胞，平滑肌细胞，心肌细胞后，母鼠心肌梗死。我们最近已经证明，在实验性中风后，可以在母亲受伤的大脑中找到先前怀孕的胎儿细胞（可行性）。由于胎儿细胞被怀疑具有多谱系分化能力，因此认为它们的行为与干细胞或祖细胞相似。这项工作可能对人类神经退行性疾病（如缺血性中风）的细胞替代策略具有重要意义。我们假设胎儿祖细胞作为缺血性卒中炎症反应的一部分被积极招募到母体脑中并参与修复。

DESCRIPTION (provided by applicant): Clinical and experimental data have shown that stroke is a sexually dimorphic disease. Females, in particular, have a varying degree of ischemic sensitivity across the lifespan. During pregnancy a woman exchanges cells with her fetus and in many women small numbers of cells of fetal origin persist, presumably throughout life. Fetal cells can be found in the maternal brain years after delivery and these cells express both stem cell and mature neuronal markers. The development of murine models that can be used to track fetal cells long after delivery has opened up a new avenue of research for investigators. Recent experimental work showing that fetal cells traffic to areas of injury and inflammation and differentiate into a variety of cell types suggests that these cells may have unrecognized capacity for repair and regeneration. However, it is unknown if this trafficking represents an adaptive response or further compounds injury. We will investigate if fetal cells traffic to the brain after stroke and evaluate the long-term fate and differentiation of these cell in the maternal brain. We will then manipulate the amount of fetal cells present in the brain (by increasing parity), and determine if these cells are an important contributor to either ischemic sensitivity or functional recovery after stroke in aged female mice. Recent work has shown that fetal cells can engraft and differentiate into endothelial cells, smooth muscle cells, and cardiomyocytes after murine maternal myocardial infarction. We have recently demonstrated that after an experimental stroke, fetal cells from a prior pregnancy can be found in the injured brain of the mother (for feasibility). As fetal cells are suspected to have multilineage differentiation capabilities, they are thought to behave similarly to stem or progenitor cells. Thi work may have significant implications for cell replacement strategies in human neurodegenerative diseases such as ischemic stroke. We hypothesize that fetal progenitors are actively recruited to the maternal brain as part of the inflammatory response to ischemic stroke and participate in repair.