Novel Mechanisms of Regenerative Wound Healing

项目摘要摘要 胎儿伤口愈合时有一种再生表型，与周围皮肤难以区分 恢复了皮肤的完整性。与这个基准相比，所有出生后的伤口愈合都受到了损害。我们可以使用 胎儿再生表型作为总结再生伤口愈合路线图的生物学基础 成人皮肤。这将对正常伤口修复以及受损伤口产生重大影响。 治愈状态，如糖尿病。胎儿伤口的特点是炎症反应减弱， 一种特有的成纤维细胞介导的细胞外基质，由高相对分子质量的透明质酸组成。真皮 成纤维细胞是胎儿皮肤中透明质酸的主要来源；相反，在成人伤口中，成纤维细胞是主要来源 疤痕形成的介体。我们假设胎儿成纤维细胞中有细胞过程调节 再生表型，也存在于成体伤口成纤维细胞中，但缺乏 适当的刺激。我们的数据表明，白介素10(IL-10)可能是重新激活一种 成人伤口的再生表型。除了IL-10的S接受免疫调节作用外，我们的 初步数据表明，IL-10在胎儿再生表型中有一个新的机制，那就是调节 细胞外基质，特别是透明质酸的合成。阐明IL-10的作用机制 控制胎儿的再生愈合，并确定这些相同机制的激活是否在 成体创面中的成纤维细胞可以再生修复，我们提出了以下三个目标： 目的1：鉴定和鉴定IL-10对胎儿成纤维细胞形成透明质酸的影响，并阐明 一条潜在的信号通路。在测试之后，这条调节细胞外基质的途径是否对胎儿是必要的 伤口愈合表型，我们可以确定IL-10诱导的透明质酸合成是否会影响再生 成人伤口的伤口愈合。目的2：用一系列新型转基因小鼠检测IL-10对S的影响 通过STAT3依赖的信号在真皮成纤维细胞中介导，并确定成纤维细胞是否是关键效应器 细胞对IL-10‘S的再生反应。目的3：检测IL-10诱导的透明质酸细胞外基质是否对 作为再生的一部分，增强成纤维细胞的细胞功能并减轻伤口炎症 回应。最后，使用以成纤维细胞功能障碍和伤口改变为特征的小鼠模型 对于炎症，我们将确定IL-10是否能够纠正这些集体缺陷并促进伤口修复。 由于未知的原因，我们所有人都拥有的在子宫内再生愈合的非凡能力在 妊娠晚期，缺省为疤痕表型。完成我们的目标将产生基本的见解 以及对IL-10生物学和成人伤口中胎儿再生愈合的新知识。这 将提供重大的可能性，以改善对患者的护理，应对虚弱的方面 由于治疗方法的发展而损害的伤口愈合质量和疤痕形成，可能有广泛的 对再生组织修复的影响。

Project Summary Abstract Fetal wounds heal with a regenerative phenotype that is indistinguishable from surrounding skin with restored skin integrity. Compared to this benchmark, all postnatal wound healing is impaired. We can use the biologic basis of the fetal regenerative phenotype as a roadmap to recapitulate regenerative wound healing in adult skin. This would have significant impact for normal wound repair, as well as in impaired wound healing states, such as diabetes. Fetal wounds are characterized by an attenuated inflammatory response and a characteristic fibroblast-mediated ECM, that is composed of high molecular weight hyaluronan. The dermal fibroblast is a primary source of hyaluronan in fetal skin; conversely, in adult wounds, the fibroblast is the main mediator of scar formation. We hypothesize that there are cellular processes in fetal fibroblasts that regulate the regenerative phenotype, which are also present in fibroblasts resident in adult wounds but lack an appropriate stimulus. Our data suggests that interleukin-10 (IL-10) may be the initial stimulus that reactivates a regenerative phenotype in adult wounds. In addition to IL-10's accepted immuno-regulatory role, our preliminary data indicate a new mechanism for IL-10 in the fetal regenerative phenotype and that is regulation of the extracellular matrix, specifically hyaluronan synthesis. To elucidate the mechanisms by which IL-10 governs fetal regenerative healing and to determine whether activation of these same mechanisms in fibroblasts resident in adult wounds can recapitulate regenerative repair, we propose the following three aims: Aim 1: identify and characterize the effects of IL-10 on the fetal fibroblast formation of hyaluronan and elucidate a potential signaling pathway. After testing if this pathway that regulates the ECM is essential to the fetal wound healing phenotype, we can determine if IL-10 induction of hyaluronan synthesis can affect regenerative wound healing in adult wounds. Aim 2: use a series of novel transgenic mice to test if IL-10's effects are mediated via STAT3 dependent signaling in dermal fibroblasts and determine if the fibroblast is the key effector cell of IL-10's regenerative response. Aim 3: test if the IL-10 induced hyaluronan ECM is essential to enhancing cellular functions of the fibroblast and attenuating wound inflammation as part of the regenerative response. Lastly, using mouse models that are characterized by dysfunctional fibroblasts and altered wound inflammation, we will determine if IL-10 can correct these collective deficiencies and augment wound repair. For unknown reasons, the remarkable ability that we all possess to heal regeneratively in utero is lost in late gestation and instead defaults to a scarring phenotype. Completing our aims will yield fundamental insights and new knowledge into IL-10 biology and the recapitulation of fetal regenerative healing in adult wounds. This will offer significant possibilities to improve the care of patients who cope with the debilitating aspects of impaired wound healing quality and scar formation by the development of therapeutics that may have broad implications for regenerative tissue repair.