Measurement of Forces and Their Role in Stem Cell Differentiation Using Suspended Fiber Networks

使用悬挂光纤网络测量力及其在干细胞分化中的作用

• 批准号: 1437101
• 负责人: Amrinder Nain
• 金额: $ 37.5万
• 依托单位: Virginia Polytechnic Institute and State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1437101&HistoricalAwards=false
• 关键词: Measurement; Forces; Their; Role; Stem

Stem cells are the essential bridge connecting embryos to the adult life span through amazing capability of unlimited self-renewal and commitment to become (differentiate into) specialized cells representing tissues and organs. In addition, they are key players in repair mechanisms as impairment of stem cell functionality is directly related to disease models including cancer. Cells in their native environment are constantly subjected to both biochemical and biophysical signals. While the role of biochemical cues on stem cell behavior is well documented, only recently have we begun to understand the role of biophysical cues. In this context, very little is known on the role of ubiquitous forces cells feel or exert constantly during differentiation. This award funds fundamental research in determining these forces and their role in stem cell differentiation. The new knowledge will allow development of scaffolds capable of providing simultaneous biochemical and biophysical factors specific to a cell type, thus impacting both developmental and disease biology. This research involves multiple disciplines including engineering (mechanical, biomedical), polymer physics, biology and mathematics under the umbrella of rapidly growing mechanobiology. The knowledge from this research will benefit the U.S. economy and society, while also providing pathways for increased participation of underrepresented groups in research and engineering.This research plans to build extracellular matrix (ECM)-mimicking nanofiber-based scaffolds called 'nanonets' as force measurement probes. Nanonets are composed of aligned and suspended nanofibrous assemblies of a mix of diameters, lengths, and spacing in double layer configuration. Furthermore, nanonets contain fused fiber intersections, which allow migrating single cells to deflect fiber segments, thus providing a measure of forces using inverse methods. This multiscale approach will permit simultaneous investigations on the role of biophysical (curvature, structural stiffness (N/m)) and biochemical (growth factor concentrations) cues on differentiation of single human bone-marrow derived mesenchymal stem cells (h-MSCs) attached to suspended nanonets. This will allow development of a set of force-differentiation (F-D) master curves calibrating the optimal biophysical and biochemical contributions to mesenchymal stem cell differentiation. The fundamental knowledge will contribute significantly by unraveling the role of cell-ECM mechanobiological interactions at the single-cell level and provide insights in development of implantable platforms for tissue regeneration, wound healing sutures, single cell force measurement assays for early diagnosis and drug testing for a wide variety of diseases including cancer.

干细胞是通过无限制的自我更新和承诺成为代表组织和器官的专用细胞（分化为（区分）的特殊细胞的惊人能力，是将胚胎连接到成人生活的必不可少的桥梁。此外，由于干细胞功能的损害与包括癌症在内的疾病模型直接相关，因此它们是维修机制的关键参与者。本地环境中的细胞经常受到生化和生物物理信号的影响。尽管生化线索对干细胞行为的作用有充分的文献证明，但直到最近我们才开始了解生物物理提示的作用。在这种情况下，关于无处不在的力细胞在分化过程中不断感觉或发挥作用的作用很少。该奖项为确定这些力及其在干细胞分化中的作用而提供了基本研究。新知识将允许开发能够提供特定于细胞类型的生化和生物物理因素的脚手架，从而影响发育和疾病生物学。这项研究涉及多个学科，包括工程（机械，生物医学），聚合物物理学，生物学和数学，在快速增长的机械生物学的保护下。这项研究的知识将使美国的经济和社会受益，同时还为增加代表性群体参与研究和工程的参与提供了途径。这项研究计划构建细胞外矩阵（ECM）的研究计划 - 模仿基于纳米纤维的支架，称为“纳米纳米人”作为力量测量探测器。纳米人由直径，长度和间距的混合物组合的对齐和悬浮的纳米纤维组成组成。此外，纳米体包含融合的纤维交叉点，允许迁移的单个细胞偏转纤维段，从而使用逆方法提供了一定的力量。这种多尺度方法将允许同时研究生物物理（曲率，结构刚度（N/M））和生化（生长因子浓度）线索对单个人骨衍生的间质干细胞（H-MSC）与悬浮液的单个人骨衍生的间质干细胞（H-MSC）的分化的作用。这将允许发展一组力分化（F-D）主曲线，以校准对间充质干细胞分化的最佳生物物理和生化贡献。基本知识将通过阐明单细胞水平上的细胞ECM机械生物学相互作用的作用，并为开发可植入的平台开发用于组织再生，伤口愈合缝合线，单细胞力量测量测定法，以早期诊断和药物测试包括各种疾病在内的各种疾病。