PDF(Pubmed)
Abstract：
Tissue formation and healing both require cell proliferation and migration, but also extracellular matrix production and tensioning. In addition to restricting proliferation of damaged cells, increasing evidence suggests that cellular senescence also has distinct modulatory effects during wound healing and fibrosis. Yet, a direct role of senescent cells during tissue formation beyond paracrine signaling remains unknown. We here report how individual modules of the senescence program differentially influence cell mechanics and ECM expression with relevance for tissue formation. We compared DNA damage-mediated and DNA damage-independent senescence which was achieved through over-expression of either p16Ink4a or p21Cip1 cyclin-dependent kinase inhibitors in primary human skin fibroblasts. Cellular senescence modulated focal adhesion size and composition. All senescent cells exhibited increased single cell forces which led to an increase in tissue stiffness and contraction in an in vitro 3D tissue formation model selectively for p16 and p21-overexpressing cells. The mechanical component was complemented by an altered expression profile of ECM-related genes including collagens, lysyl oxidases, and MMPs. We found that particularly the lack of collagen and lysyl oxidase expression in the case of DNA damage-mediated senescence foiled their intrinsic mechanical potential. These observations highlight the active mechanical role of cellular senescence during tissue formation as well as the need to synthesize a functional ECM network capable of transferring and storing cellular forces.
摘要：
组织形成和愈合都需要细胞增殖和迁移，而且细胞外基质的产生和张紧。除了限制受损细胞的增殖，越来越多的证据表明，细胞衰老在伤口愈合和纤维化过程中也具有明显的调节作用。然而，除旁分泌信号外,衰老细胞在组织形成过程中的直接作用尚不清楚.我们在这里报告衰老程序的各个模块如何差异地影响细胞力学和ECM表达与组织形成相关。我们比较了DNA损伤介导的衰老和DNA损伤非依赖性衰老，这是通过在原代人皮肤成纤维细胞中过表达p16Ink4a或p21Cip1细胞周期蛋白依赖性激酶抑制剂而实现的。细胞衰老调节粘着斑大小和组成。所有衰老细胞表现出增加的单细胞力,这导致在体外3D组织形成模型中选择性地对于p16和p21过表达细胞增加的组织硬度和收缩。机械成分由ECM相关基因（包括胶原蛋白）的表达谱改变补充。赖氨酰氧化酶，和MMPs。我们发现，在DNA损伤介导的衰老的情况下，特别是胶原蛋白和赖氨酰氧化酶表达的缺乏削弱了其固有的机械潜力。这些观察结果突出了组织形成过程中细胞衰老的主动机械作用以及合成能够转移和储存细胞力的功能性ECM网络的需要。
