Matricellular Signaling in Senescence and Wound Healing

描述(由申请人提供)：哺乳动物的伤口愈合是一个复杂的、多步骤的过程，必须严格监管。虽然细胞外基质的合成是伤口愈合的关键步骤，但过度的基质沉积会导致纤维化瘢痕的形成，导致受影响器官或组织的结构和功能受损。纤维性伤口愈合的一些有害后果包括肝硬变、肺纤维化和充血性心力衰竭。另一方面，基质沉积不足可能在伤口愈合障碍中发挥作用，导致慢性无法愈合的伤口，这是糖尿病患者特别容易发生的一种并发症。我们最近的研究表明，在正常的皮肤创伤愈合过程中，肉芽组织中的肌成纤维细胞被CCN1驱动进入衰老，CCN1是一种在伤口修复部位动态表达的基质细胞蛋白。CCN1通过整合素介导的新途径诱导细胞衰老，并激活衰老细胞特有的抗纤维化遗传程序的表达。表达衰老缺陷CCN1的突变敲击小鼠不会积累衰老细胞，并在伤口中遭受加剧的纤维化。这些结果支持一种假设，即依赖于CCN1的细胞衰老是一种控制纤维化形成的程序性伤口愈合反应。然而，在病理条件下，这种纤维化控制机制可能会失控，导致过度衰老的细胞积累，并导致无法愈合的伤口的慢性化。我们将从三个方面探讨CCN1诱导的细胞衰老在皮肤创伤愈合中的作用：目的1剖析CCN1诱导衰老的分子机制；目的2评价细胞衰老在伤口愈合过程中控制纤维化的作用；以及目的3阐明衰老细胞在慢性不可愈合创面中的作用。总之，这些研究将促进我们对细胞衰老如何参与纤维化控制和伤口愈合慢性化的了解。

DESCRIPTION (provided by applicant): Mammalian wound healing is a complex, multi-step process that must be tightly regulated. Whereas synthesis of extracellular matrix is an essential step in wound healing, excessive matrix deposition can lead to the formation of fibrotic scars, resulting in compromised structure and function of the affected organ or tissue. Some of the deleterious consequences of fibrotic wound healing include liver cirrhosis, pulmonary fibrosis, and congestive heart failure. On the other hand, deficient matrix deposition can play a role in impaired wound healing leading to chronic non-healing wounds, a complication for which patients with diabetes are at particular risk. Our recent studies have revealed that in the course of normal cutaneous wound healing, myofibroblasts in the granulation tissue are driven into senescence by CCN1, a matricellular protein that is dynamically expressed at sites of wound repair. CCN1 induces cellular senescence through a novel integrin-mediated pathway, and activates the expression of an anti-fibrotic genetic program characteristic of senescent cells. Mutant knockin mice that express a senescence-defective CCN1 do not accumulate senescent cells and suffer exacerbated fibrosis in wounds. These results support the hypothesis that CCN1-dependent cellular senescence is a programmed wound healing response that controls fibrogenesis. However, this mechanism of fibrosis control may become deregulated under pathological conditions, leading to excessive senescent cell accumulation and contributing to the chronicity of non-healing wounds. We will investigate the role of CCN1-induced cellular senescence in cutaneous wound healing in three specific aims: Aim 1 dissects the molecular mechanism of CCN1-induced senescence; Aim 2 evaluates the role of cellular senescence in controlling fibrosis during wound healing; and Aim 3 elucidates the effects of senescent cells on chronic non-healing wounds. Together, these studies will advance our knowledge of how cellular senescence participates in fibrosis control and chronicity in wound healing.