Tissue mechanics in regenerative wound healing of the skin

摘要 我们的长期目标是通过完全功能恢复来治愈皮肤伤口 (再生伤口愈合)而不是疤痕形成(修复性伤口愈合)。我们渴望学习 在新的创伤修复过程中，哪些因素控制着再生 建立了“创伤诱导毛发新生”(WIHN)的范式。在这个模型中，新的头发 当在小鼠身上造成一个大的(&gt；1 cm)皮肤创伤时，毛囊从伤口中心出来 (例如，C57BL/6)。然而，我们在多刺小鼠(Acomys)身上的新发现表明，WIHN开始 从伤口的边缘向中心形成。我们的初步数据进一步显示， 机械刚度在伤口区域的明显空间分布，以及这种扰动 创面床中机械转导的改变改变了WIHN的结局。这些新发现 促使我们假设组织力学调节组织再生和WIHN。 WIHN很容易访问，是评估这一假设的一个很好的模型。而上皮性 胎盘的形成可以由胚胎期间存在的不同化学形态原启动 C57BL/6和C57BL/6在WIHN中的发育(融合以诱导β-连环蛋白信号) 多刺的老鼠，伤口的机械环境可以调节，平行或 独立地，成功地形成胎盘的门槛。这一行为改变了 上皮细胞活化，基底膜重塑，真皮凝聚。在目标1A中，我们 将比较导致WIHN的不同细胞和分子事件，对比多刺和 C57BL/6小鼠。在生物信息学分析的支持下，Twist1被建议为MASTER 刺鼠体内胎盘形成的调节剂。因此，Twist1的作用及其 WIHN的下游MSX2将在Aim1B进行检查。在目标2a中，我们将映射到 原子力显微镜观察创面不同部位的细胞形态 分析和FRET生物传感器，以间接“可视化”体内细胞力的结果 伤口处。组织力学在WIHN中的作用将通过微扰研究进一步检验。 Aim 2B将研究和定义在导电中起作用的分子电路 胎盘再生的机械环境。总体而言，该提案旨在探索小说 再生创面愈合过程中的表皮-真皮网络 构成元素宏大主题的表观遗传、分子和机械输入 对于未来再生医学的发展来说是必要的。 好了！

Summary Our long term objective is to heal skin wounds with full functional restoration (regenerative wound healing) instead of scarring (reparative wound healing). We aspire to learn what factors control regeneration as supposed to repair during wound healing under the newly established paradigm of “Wound-Induced Hair Neogenesis” (WIHN). In this model, new hair follicles emerge from the wound center when a large (>1cm) skin wound is made on the mice (e.g., C57BL/6). Our new finding in Spiny mice (Acomys) shows, however, that WIHN starts to form from the periphery of wounds toward the center. Our preliminary data further shows a distinct spatial distribution of mechanical stiffness across the wound field, and that perturbation of mechanotransduction in the wound bed alters the outcome of WIHN. These new findings prompted us to hypothesize that tissue mechanics modulate tissue regeneration and WIHN. WIHN is easily accessible and is a good model to evaluate this hypothesis. While epithelial placode formation can be initiated by different chemical morphogens present during embryonic development (which converge to induce beta-catenin signaling), in WIHN of both C57BL/6 and spiny mouse, the mechanical environment of the wound can modulate, in parallel or independently, the threshold of successful placode formation. This acts to alter the status of epithelia activation, basement membrane remodeling, and dermal condensation. In Aim 1A, we will compare the different cellular and molecular events leading to WIHN, contrasting spiny and C57BL/6 mice. Supported by the bioinformatic analyses, Twist1 is proposed as a master regulator for placode formation in the spiny mouse. Therefore, the role of Twist1 and its downstream Msx2 in WIHN will be examined in Aim1B. In Aim 2A, we will map the stiffness in different parts of the wound field employing atomic force microscopy accompanied by cell shape analyses and FRET-biosensors to indirectly “visualize” the consequence of cell forces within the wound site. The role of tissue mechanics in WIHN will be further tested by perturbation studies. Aim 2B will investigate and define the molecular circuits which are functioning in the conductive mechanical environment for placode regeneration. Overall, the proposal aims to explore novel epidermal-dermal networks during regenerative wound healing from the perspective of epigenetic, molecular, and mechanical inputs that construct the grand theme of elements necessary for future progression of regenerative medicine. !