Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Small. 2017 Apr;13(15). doi: 10.1002/smll.201603737. Epub 2017 Feb 17.
Organ-on-a-chip platforms seek to recapitulate the complex microenvironment of human organs using miniaturized microfluidic devices. Besides modeling healthy organs, these devices have been used to model diseases, yielding new insights into pathophysiology. Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease showing accelerated vascular aging, leading to the death of patients due to cardiovascular diseases. HGPS targets primarily vascular cells, which reside in mechanically active tissues. Here, a progeria-on-a-chip model is developed and the effects of biomechanical strain are examined in the context of vascular aging and disease. Physiological strain induces a contractile phenotype in primary smooth muscle cells (SMCs), while a pathological strain induces a hypertensive phenotype similar to that of angiotensin II treatment. Interestingly, SMCs derived from human induced pluripotent stem cells of HGPS donors (HGPS iPS-SMCs), but not from healthy donors, show an exacerbated inflammatory response to strain. In particular, increased levels of inflammation markers as well as DNA damage are observed. Pharmacological intervention reverses the strain-induced damage by shifting gene expression profile away from inflammation. The progeria-on-a-chip is a relevant platform to study biomechanics in vascular biology, particularly in the setting of vascular disease and aging, while simultaneously facilitating the discovery of new drugs and/or therapeutic targets.
器官芯片平台旨在使用微型化微流控设备来模拟人体器官的复杂微环境。除了模拟健康器官外，这些设备还被用于模拟疾病，为病理生理学提供了新的见解。亨廷顿病性进行性肌阵挛震颤综合征（HGPS）是一种早衰疾病，表现为血管老化加速，导致心血管疾病患者死亡。HGPS 主要针对血管细胞，这些细胞存在于机械活跃的组织中。在这里，开发了一种早衰症芯片模型，并在血管老化和疾病的背景下研究了生物力学应变的影响。生理应变会诱导原代平滑肌细胞（SMCs）产生收缩表型，而病理应变则会诱导类似于血管紧张素 II 治疗的高血压表型。有趣的是，源自 HGPS 供体的人诱导多能干细胞（HGPS iPS-SMCs）的 SMCs，但不是源自健康供体的 SMCs，对应变表现出更严重的炎症反应。具体而言，观察到炎症标志物水平以及 DNA 损伤增加。通过将基因表达谱从炎症转向，药物干预可逆转应变引起的损伤。早衰症芯片是研究血管生物学中生物力学的相关平台，特别是在血管疾病和衰老的背景下，同时也有助于发现新的药物和/或治疗靶点。
