A 3D tissue model-on-a-chip for studying the effects of human senescent fibroblasts on blood vessels
A 3D tissue model-on-a-chip for studying the effects of human senescent fibroblasts on blood vessels
复制标题
用于研究人类衰老成纤维细胞对血管影响的 3D 组织芯片模型
DOI：
10.1039/d0bm01297a
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发表时间：
2021
影响因子：
6.6
通讯作者：
Matsunaga Yukiko T.
中科院分区：
文献类型：
--
作者：
Pauty Joris;Nakano Shizuka;Usuba Ryo;Nakajima Tadaaki;Johmura Yoshikazu;Omori Satotaka;Sakamoto Naoya;Kikuchi Akihiko;Nakanishi Makoto;Matsunaga Yukiko T.
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。在体外培养的成纤维细胞中发现了细胞衰老。对于成年人来说，它是对抗癌症的主要防御机制，也是导致寿命限制和与衰老相关的疾病的主要原因。为了评估人类血管在衰老环境中的变化，我们开发了一种基本组织芯片模型，其中包括嵌入胶原凝胶中的血管体外三维模型，以及年轻或衰老的皮肤成纤维细胞。我们发现衰老的成纤维细胞通过施加过度的牵引应力机械地改变周围的细胞外基质。然后我们发现衰老的成纤维细胞通过其衰老相关的分泌表型（SASP）诱导微血管的萌芽血管生成。最后，我们收集的证据表明微环境的机械变化在维持 SASP 诱导的血管生成中发挥着作用。该模型被证明可用于监测衰老成纤维细胞诱导的血管形态变化，同时控制衰老细胞的比例，并使 SASP 抑制剂（一类用于衰老和癌症研究的药物）的研究成为可能。
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.