Tissue mechanics in regenerative wound healing of the skin

总结 我们的长期目标是治愈皮肤伤口，并恢复完整的功能 （再生性伤口愈合）而不是瘢痕形成（修复性伤口愈合）。我们渴望学习 什么因素控制再生，因为应该在伤口愈合过程中修复， 建立了“创伤诱导毛发新生”（WIHN）的范例。在这个模型中， 当在小鼠上造成大的（>1cm）皮肤伤口时，毛囊从伤口中心出现 (e.g., C57BL/6）。然而，我们在刺鼠（Acomys）中的新发现表明，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， 在整个伤口领域的机械刚度的独特的空间分布， 在创伤床中的机械传导改变了WIHN的结果。这些新发现 提示我们假设组织力学调节组织再生和WIHN。 WIHN很容易获得，并且是评估这一假设的良好模型。虽然上皮 基板的形成可由胚胎发育期间存在的不同化学形态发生素启动 在C57 BL/6和C57 BL/6的WIHN中， 在多刺小鼠中，伤口的机械环境可以平行或平行地调节， 独立地，成功基板形成的阈值。这一行为改变了 上皮活化、基底膜重塑和真皮冷凝。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 c57 bl/6小鼠在生物信息学分析的支持下，Twist 1被认为是一个主因子 多刺小鼠基板形成的调节因子。因此，Twist 1的作用及其 将在Aim 1B中检查WIHN中的下游Msx 2。在目标2A中，我们将刚度映射到 采用原子力显微镜观察伤口不同部位的细胞形态 分析和FRET-生物传感器，以间接“可视化”细胞内的细胞力的结果， 伤口部位组织力学在WIHN中的作用将通过微扰研究进一步测试。 目标2B将研究和定义在导电介质中起作用的分子电路。 基板再生的机械环境。总体而言，该提案旨在探索新的 表皮-真皮网络在再生伤口愈合过程中的作用 表观遗传、分子和机械输入，构成了元素的宏大主题 这是再生医学未来发展的必要条件。 !

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. !