Understanding the mechanobiology of stem cells in a microengineered 3D cardiac tissue environment with cardiomyopathy

了解心肌病微工程 3D 心脏组织环境中干细胞的力学生物学

• 批准号: 8883616
• 负责人: Arghya Paul
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883616
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Myocardial infarction and hypertrophic cardiomyopathy followed by heart failure is a major cause of death worldwide. As the terminally differentiated adult cardiomyocytes (CMs) possess a very limited innate ability to regenerate, much research has focused on exploring the potential of mesenchymal stem cells (MSC) and induced pluripotent stem cells (iPSC) to repair the damaged myocardium. However with regards to benefits till date, experimental and clinical trials have shown sub-optimal to modest results. The main drawback for this is that the mechanisms involved for the in vivo therapy is not well understood. Suggested pathways include permanent or partial cell fusion between stem cells and resident cardiac cells, transdifferentiation of stem cells into cardiac and vascular cells and secretion of pro-angiogenic paracrine factors. However, none of them have considered the fact that the continuously beating cardiac microenvironment can also induce significant mechanobiological effects on the transplanted stem cells that can influence their overall fate and functionality. In this project we aim to study, for the first time, the fundamental mechanobiological interactions between stem cells (iPSC and MSC) and contractile cardiomyocytes (under normal and diseased conditions) in a continuously beating 3D cardiac tissue environment. In pursuit of this research goal, we will develop a microscale device using human iPSC-derived beating CMs to assay the combined effects of mechanical, biochemical and architectural factors on mechanobiology of transplanted stem cells and their therapeutic potential in cardiomyopathy. We expect this novel miniaturized biomimetic cardiac tissue model will help decipher the specific roles of individual biomechanical forces imposed by the spontaneously beating cardiac microenvironment on the transplanted stem cells. The study will also help identify the role of rhythmic mechanical environments, ECM stiffness, focal adhesion signal molecules and their cross-talks to regulate MSC mechanotranduction, paracrine signaling, epigenetic profile, differentiation abilities and cell fate. As a broader impact, this study will provide better understanding of stem cell fate in vivo, enabling highly safe and efficacious cell-based myocardial therapy.

心肌梗死和肥厚性心肌病紧随心力衰竭是全球死亡的主要原因。由于终端分化的成年心肌细胞（CMS）具有非常有限的先天能力，因此许多研究重点是探索间充质干细胞（MSC）和诱导多能干细胞（IPSC）修复受损的心肌的潜力。然而，关于迄今为止的收益，实验和临床试验表现出了次优至中等结果。这样做的主要缺点是，对体内疗法所涉及的机制尚不清楚。建议的途径包括干细胞和常驻心脏细胞之间的永久性或部分细胞融合，将干细胞转变为心脏和血管细胞，以及促血管生成旁分泌因子的分泌。但是，他们都没有考虑到不断跳动的心脏微环境还可以引起对移植的干细胞的显着机械生物学作用，从而影响其整体命运和功能。在这个项目中，我们旨在首次研究干细胞（IPSC和MSC）和收缩性心肌细胞（在正常和患病的情况下）之间的基本机械生物学相互作用，这是在连续击败3D心脏组织环境中。为了实现这一研究目标，我们将使用人类IPSC衍生的Beat CMS开发一种微观设备，以分析机械，生化和建筑因素对移植干细胞机械生物学的合并作用及其在心肌病中的治疗潜力。我们预计，这种新型的微型仿生心脏组织模型将有助于解读由自发击败心脏微环境在移植的干细胞上施加的个体生物力学力的特定作用。这项研究还将有助于确定节奏机械环境，ECM刚度，局灶性信号分子及其交叉对话的作用，以调节MSC机械辅助，旁分泌信号传导，表观遗传谱，分化能力和细胞命运。作为更广泛的影响，这项研究将更好地了解体内干细胞命运，从而实现高度安全有效的基于细胞的心肌治疗。