Elucidating the Endothelial-Smooth Muscle Cell Interactions in Marfan Syndrome Using iPSCs

项目摘要 马凡氏综合征（MFS）是一种遗传性结缔组织疾病，由结缔组织蛋白突变引起， 1（FBN 1）基因。这些突变导致血管平滑肌细胞（vSMC）凋亡增加， 基质金属蛋白酶（MMP）表达、过度弹性蛋白变性和胶原过度表达; 削弱血管结构，损害血流动力学调节，并最终导致严重的血管 并发症原代细胞、组织外植体和转基因小鼠模型遭受不相容性， 抑制对疾病发病机理或潜在治疗方法的新见解的发展; 建模平台生物材料的最新进展已经产生了模拟血管移植物的性质的血管移植物， 细胞外基质（ECM）在天然血管系统。人类诱导多能干细胞（hiPSC）是一种 理想的，患者特异性的可再生细胞来源，为研究遗传疾病如何影响细胞提供了途径 机械生物学，信号和功能，以更好的发展治疗。在这里，使用天然纤维素为基础的 我们的目的是：（1）充分表征来自马凡氏综合征患者的血管移植物和hiPSCs 和收缩性vSMC，（2）研究hiPSC-EC对 剪切力和hiPSC-vSMCs对周向应变的影响，（3）研究机械力（即剪切力） 力和周向应变）和旁分泌信号，特别是活性氧 物种（ROS），对vSMC表型和移植物降解率使用纤维蛋白为基础的血管移植。我们 多学科的方法支持这个项目将阐明MFS疾病进展的关键介质 早期发现和治疗目标。

Project Summary Marfan Syndrome (MFS) is a genetic disorder of the connective tissue caused by mutations in the fibrillin- 1(FBN1) gene. These mutations cause increased vascular smooth muscle cell (vSMC) apoptosis, increased matrix metalloproteinase (MMP) expression, excessive elastin degeneration and collagen overexpression; weakening the vascular architecture, impair hemodynamic regulation, and ultimately leading to severe vascular complications. Primary cells, tissue explants, and transgenic mouse models suffer from insufficiencies that inhibit development of novel insights into disease pathogenesis or potential therapeutics; warranting new modeling platforms. Recent advances in biomaterials have generated vascular grafts that mimic properties of the extracellular matrix (ECM) in the natural vasculature. Human induced pluripotent stem cells (hiPSC) are an ideal, patient specific renewable cell source that provides an avenue to study how genetic diseases effect cell mechanobiology, signaling and function to better development therapeutics. Here, using a natural fibrin-based vascular graft and hiPSCs from patients with Marfan Syndrome, we aim to: (1) fully characterized both ECs and contractile vSMCs from hiPSCs derived from Marfan patients, (2) study the responses of hiPSC-ECs to shear force and hiPSC-vSMCs to circumferential strain, (3) study the impacts of mechanical forces (i.e. shear force and circumferential strain) and paracrine signaling in a co-culture model, specifically reactive oxygen species(ROS), on vSMC phenotype and rate of graft degradation using the fibrin-based vascular graft. Our multidisciplinary approach underpinning this project will elucidate key mediators of MFS disease progression towards early detection and therapeutic targets.