Effects of Circulating Factors and Progenitors on Wound Healing during Pregnancy

摘要： 伤口愈合是一个复杂的生物学过程，需要生长因子和祖细胞协同作用 恢复受损组织的完整性非特异性修复也会导致组织纤维化或瘢痕形成 作为响应于组织损伤的异常伤口愈合，不仅使组织易于继发性损伤， 也是西方世界死亡人数的45-50%。年龄增长是一个主要的风险因素， 由于组织纤维化导致的伤口愈合。在细胞和分子水平上的许多研究已经检查了与年龄相关的 伤口愈合的差异，并已确定祖细胞的年龄相关性下降。据报 暴露于年轻小鼠血清中存在的因子可以恢复老年祖细胞的再生能力， 细胞此外，胎儿真皮已被证明在损伤后再生而无疤痕，而成人皮肤伤口 愈合通常导致疤痕组织。怀孕代表了一种独特的生物学模式， 年轻和年老生物体之间的循环系统。我们的初步数据显示， 妊娠小鼠损伤后愈合。更重要的是，我们已经观察到改善的肌源性分化 老化的肌肉祖细胞（MPCs）的能力，用孕鼠血清刺激后，表明 循环因素可能会影响怀孕期间母亲体内干细胞的效力。我们假设 怀孕期间的循环因素对母体伤口愈合有有益的影响，例如减少 以获得最佳的组织再生。因此，我们建议，在目标1中，确定是否怀孕 加速伤口愈合（骨骼肌和皮肤），怀孕期间的循环因素负责 这种有益的效果。我们将利用先前描述的皮肤创伤和肌肉损伤小鼠模型， 调整它们以研究愈合过程，包括纤维化和促进循环因素， 怀孕此外，我们还将在手术后对孕妇和非孕妇进行皮肤活检， 分析组织愈合与活检部位瘢痕形成的关系。已有报道，胎儿微嵌合体 细胞（FMCs）可以发现在循环和器官的哺乳动物在怀孕期间，由于双向 母细胞和胎儿细胞的传代。母体循环中胎儿细胞的存在可能起到有益的作用 修复受损的母体组织很少有人确定循环中胎儿激素的确切作用， 祖细胞以及它们在妊娠期间如何与母体祖细胞相互作用 治愈在目标2中，我们提出确定妊娠小鼠中循环的胎儿和母体祖细胞， 对怀孕期间的伤口愈合有有益的影响。绿色荧光蛋白（GFP）- 表达GFP的雄性小鼠将与不含GFP的雌性小鼠杂交，GFP将用于追踪FMCs。的 Y染色体将用作追踪FMCs的附加方法。这项研究的结果将确定 再生因子和新的祖细胞在怀孕期间的血液循环中， 开发新的和临床相关的疗法，以改善伤口愈合和减少纤维化。

Abstract: Wound healing is a complex biological process requiring growth factors and progenitor cells that act in concert to restore the integrity of the injured tissue. Fibrosis or scarring of tissue results from nonspecific repair as well as aberrant wound healing in response to tissue injury and not only predisposes tissue to a secondary injury but also contributes to 45–50% of deaths in the Western world. Increased age is a major risk factor for impaired wound healing due to tissue fibrosis. Many studies at the cellular and molecular level have examined age-related differences in wound healing and have identified an age-related decline in progenitor cells. It has been reported that exposure to factors present in the serum of young mice restores the regenerative capacity of aged progenitor cells. Also, fetal dermis has been shown to regenerate after injury without scarring, while adult skin wound healing usually results in scar tissue. Pregnancy represents a unique biological model of a naturally-shared circulatory system between young and old organisms. Our preliminary data have demonstrated improved muscle healing after injury in pregnant mice. More importantly, we have observed an improved myogenic differentiation capacity of aged muscle progenitor cells (MPCs) after stimulation with serum from pregnant mice, suggesting that circulating factors may influence the potency of stem cells in the mother during pregnancy. We hypothesize that circulating factors during pregnancy have beneficial effects on maternal wound healing, such as reduction in fibrosis for optimal tissue regeneration. Therefore, we propose, in Aim1, to determine whether pregnancy accelerates wound healing (skeletal muscle and skin) and which circulating factors in pregnancy are responsible for this beneficial effect. We will utilize previously described skin wound and muscle injury mouse models and adapt them to investigate the healing process, including fibrosis and contributing circulating factors, during pregnancy. In addition, we will obtain skin biopsies from pregnant and non-pregnant women after surgery to analyze tissue healing with respect to scarring at the biopsy site. It has been reported that fetal microchimeric cells (FMCs) can be found in the circulation and organs of mammals during pregnancy as a result of bidirectional passage of maternal and fetal cells. The presence of fetal cells in maternal circulation may play a beneficial role in repairing damaged maternal tissues. Little has been done to determine the exact roles of circulating fetal progenitor cells and how they interact with maternal progenitor cells during pregnancy with respect to wound healing. In Aim 2, we propose to determine which circulating fetal and maternal progenitor cells in pregnant mice are responsible for the beneficial effects on wound healing during pregnancy. Green fluorescent protein (GFP)- expressing male mice will be crossed with female mice without GFP, and GFP will be used to track FMCs. The Y chromosome will be used as an additional method to track the FMCs. Results from this study will identify rejuvenating factors and novel progenitor cells within blood circulation during pregnancy with potential for development of novel and clinically relevant therapies to improve wound healing and reduce fibrosis.