Novel Mechanisms of Regenerative Wound Healing

项目摘要 胎儿伤口愈合的再生表型与周围皮肤无法区分， 恢复皮肤完整性。与此基准相比，所有产后伤口愈合都受到损害。我们可以使用 胎儿再生表型的生物学基础作为概括再生伤口愈合的路线图， 成人皮肤这将对正常的伤口修复以及受损的伤口具有显著的影响。 治疗状态，如糖尿病。胎儿伤口的特征是炎症反应减弱， 一种特征性成纤维细胞介导的ECM，由高分子量透明质酸组成。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。 瘢痕形成的介质。我们假设胎儿成纤维细胞中有细胞过程， 再生表型也存在于成人伤口中的成纤维细胞中，但缺乏 适当的刺激。我们的数据表明，白细胞介素-10（IL-10）可能是重新激活细胞凋亡的初始刺激。 再生表型。除了IL-10公认的免疫调节作用外，我们的 初步数据表明，IL-10在胎儿再生表型中存在一种新的机制， 尤其是透明质酸的合成为了阐明IL-10 控制胎儿再生愈合，并确定是否激活这些相同的机制， 成人伤口中的成纤维细胞可以重现再生修复，我们提出以下三个目标： 目的1：鉴定和表征IL-10对胎儿成纤维细胞形成透明质酸的作用， 潜在的信号通路。在测试这种调节ECM的途径是否对胎儿至关重要后， 伤口愈合表型，我们可以确定IL-10诱导透明质酸合成是否可以影响再生 成人伤口的愈合目的2：使用一系列新的转基因小鼠来测试IL-10的作用是否是 通过真皮成纤维细胞中的STAT 3依赖性信号传导介导，并确定成纤维细胞是否是关键效应子 IL-10的再生反应。目的3：测试IL-10诱导的透明质酸ECM是否是 增强成纤维细胞的细胞功能和减轻伤口炎症作为再生的一部分， 反应最后，使用以功能障碍的成纤维细胞和改变的伤口为特征的小鼠模型， 在炎症中，我们将确定IL-10是否可以纠正这些集体缺陷并增强伤口修复。 由于未知的原因，我们都拥有的在子宫内再生愈合的非凡能力在子宫内丢失了。 妊娠晚期，而是默认为瘢痕表型。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重演的新知识。这 将提供重要的可能性，以改善照顾病人谁科普衰弱方面的 由于治疗方法的发展而损害了伤口愈合质量和疤痕形成， 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.