Pauty Joris, Nakano Shizuka, Usuba Ryo, Nakajima Tadaaki, Johmura Yoshikazu, Omori Satotaka, Sakamoto Naoya, Kikuchi Akihiko, Nakanishi Makoto, Matsunaga Yukiko T
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
Biomater Sci. 2021 Jan 5;9(1):199-211. doi: 10.1039/d0bm01297a.
All human tissues experience aging that eventually causes organ dysfunction and disease. Cellular senescence was discovered in fibroblasts cultured in vitro. In adults, it is a primary defense mechanism against cancer, but also a major contributor to lifespan limits and disorders associated with aging. To assess how human blood vessels change in an aged environment, we developed an elementary tissue model-on-a-chip that comprises an in vitro three-dimensional model of a blood vessel embedded in a collagen gel with young or senescent skin fibroblasts. We found that senescent fibroblasts mechanically altered the surrounding extracellular matrix by exerting excessive traction stress. We then found that senescent fibroblasts induced sprouting angiogenesis of a microvessel via their senescence-associated secretory phenotype (SASP). Finally, we gathered evidence that the mechanical changes of the microenvironment play a role in sustaining SASP-induced angiogenesis. The model proved useful in monitoring morphological changes in blood vessels induced by senescent fibroblasts while controlling the proportion of senescent cells, and enabled the study of SASP inhibitors, a class of drugs useful in aging and cancer research.
所有人体组织都会经历衰老，最终导致器官功能障碍和疾病。细胞衰老最初是在体外培养的成纤维细胞中发现的。在成年人中，它是抵御癌症的主要防御机制，但也是寿命受限以及与衰老相关疾病的主要促成因素。为了评估人体血管在衰老环境中的变化，我们开发了一种基本的芯片组织模型，该模型包含一个体外三维血管模型，该血管模型嵌入含有年轻或衰老皮肤成纤维细胞的胶原蛋白凝胶中。我们发现衰老的成纤维细胞通过施加过度的牵张力在机械上改变了周围的细胞外基质。然后我们发现衰老的成纤维细胞通过其衰老相关分泌表型（SASP）诱导微血管的发芽血管生成。最后，我们收集了证据表明微环境的机械变化在维持SASP诱导的血管生成中起作用。该模型被证明在监测衰老成纤维细胞诱导的血管形态变化同时控制衰老细胞比例方面很有用，并且能够研究SASP抑制剂，这是一类在衰老和癌症研究中有用的药物。
