Multiscale Modeling of Wound Healing

项目总结 慢性创面是对公共健康的主要威胁，并与主要的 人类的疾病。尽管皮肤创伤的适当愈合需要集体和 多种细胞类型的协调行为，关键一步是真皮的招募和功能 成纤维细胞，它被引导通过一种化学诱导剂的梯度侵入伤口，血小板衍生 生长因子(PDGF)。一些生物制品，最著名的重组PDGF-BB，目前正在 被批准用于治疗伤口；然而，目前的治疗方法在加速伤口方面缺乏疗效 治愈，因此他们在临床上没有获得牵引力。这些令人失望的结果 强调伤口愈合的动力学在组织规模和需求方面的了解程度有多低 将分子、细胞和组织水平的过程知识联系起来，以提供信息和预测结果 旨在提高伤口修复速度和保真度的治疗策略。我们一直在 考虑分子(信号极化)的成纤维细胞趋化模型的建立 转导)、超分子(肌动球蛋白结构的组装)、细胞(偏向细胞运动)、 和组织水平(伤口侵袭)动力学，跨越不同的时间(秒到周)和空间 (海里到厘米)刻度。许多挑战依然存在。首先是缺乏一种模型连接，在机械上 膜突起/收缩机制的途径、信号转导和细胞骨架动力学 细胞的前沿；我们称之为分子运动问题(目标1)。它的动机是我们最近 发现PDGF的趋化和迁移受细胞外基质(ECM)梯度的影响 密度(趋触性)由不同的信号通路控制，这些信号通路影响F-肌动蛋白的动力学和 机械以不同的方式。这一根本区别与第二个关键需求有关，我们 把线索的多样性称为问题(目标2)。PDGF只是成纤维细胞迁移的一个空间线索，而且 因此，最重要的是考虑趋化、趋化和趋化(梯度)的融合 在机械僵硬中)同时存在于伤口中的线索。初步的建模工作表明， 我们建议探索的另一种形式的空间偏见：细胞形状或形态趋向性的影响。 第三个需要是整合关于伤口的空间和生物异质性的信息。 快速移动的巨噬细胞分泌PDGF，因此是趋化物质和细胞外基质的焦点来源 密度和刚度预计也会在空间和时间上有所不同。我们指的是…的关系 异质环境中巨噬细胞的位置和细胞外基质的动态组织 问题(目标3)。

PROJECT SUMMARY Chronic wounds are a major threat to public health and present as a comorbid complication with major diseases in humans. Although the proper healing of cutaneous wounds requires collective and coordinated behaviors of multiple cell types, a critical step is the recruitment and function of dermal fibroblasts, which are directed to invade the wound by gradients of a chemoattractant, platelet-derived growth factor (PDGF). A handful of biologicals, most notably recombinant PDGF-BB, are currently approved for treatment of wounds; however, the current treatments lack efficacy in accelerating wound healing, and consequently they have not gained traction in the clinic. These disappointing results underscore how poorly the dynamics of wound healing are understood at the tissue scale and the need to connect knowledge of molecular, cellular, and tissue-level processes to inform and predict outcomes of therapeutic strategies aimed at improving the rate and fidelity of wound repair. We have been developing models of fibroblast chemotaxis with consideration of molecular (polarization of signal transduction), supramolecular (assembly of actomyosin structures), cellular (biased cell movement), and tissue-level (wound invasion) dynamics, which span disparate time (seconds to weeks) and spatial (nm to cm) scales. Many challenges remain. First is the lack of a model connecting, in a mechanistic way, signaling and cytoskeletal dynamics to the mechanics of membrane protrusion/retraction at the cell's leading edge; we call this the molecules to motility problem (Aim 1). It is motivated by our recent discoveries that PDGF chemotaxis and migration biased by gradients of extracellular matrix (ECM) density (haptotaxis) are governed by distinct signaling pathways that affect F-actin dynamics and mechanics in different ways. This fundamental difference is tied to the second critical need, which we call the diversity of cues problem (Aim 2). PDGF is only one spatial cue for fibroblast migration, and hence it is paramount to consider the confluence of chemotactic, haptotactic, and durotactic (gradients in mechanical stiffness) cues that coexist in wounds. Preliminary modeling work has implicated an additional form of spatial bias that we propose to explore: the influence of cell shape, or morphotaxis. The third need is to integrate information about the spatial and biological heterogeneity of the wound. Fast-moving macrophages secrete PDGF and are thus focal sources of chemoattractant, and ECM density and stiffness are also expected to vary in space and time. We refer to the relation of macrophage positions and the dynamic organization of ECM in vivo as the heterogeneous milieu problem (Aim 3).