CAREER: Understanding the Effects of Mechanical Dosing on Mesenchymal Stem Cell Identity

这个教师早期职业发展（CAREER）补助金将研究如何通过周围材料的机械性能来保持干细胞的“身份”。干细胞的身份是由它们的分裂，适应和分化的能力定义的。这项工作将重点关注间充质干细胞，这是通常来源于骨髓并通过组织培养技术扩增的成体干细胞。控制间充质干细胞身份对于细胞制造和再生医学是重要的。该项目的研究目标是通过开发具有独立可控的刚度，粘附性和细胞-细胞信号传导特性的材料来克服目前间充质干细胞细胞培养环境的限制。该项目的教育目标是将研究与正在进行的教育活动相结合，以提高科学素养和公平性。这项工作将涉及计划，为代表性不足的高中和本科生进行亲自暑期研究，并参加虚拟互动模块，旨在灌输细胞生物学和材料科学的热情。这项研究的中心假设是，机械剂量策略可以利用来控制间充质干细胞增殖，适应动态材料，并在3D水凝胶内分化。该假设将通过以下方式进行测试：（i）确定体外扩增期间基质机械感测对间充质干细胞增殖和干性的显著性，（ii）阐明粘附肽和细胞-细胞模拟肽对间充质干细胞机械适应的作用，以及（iii）鉴定增加间充质干细胞在3D可注射水凝胶中的分化潜力的机械给药参数。从这些研究中获得的基础知识有望导致当前间充质干细胞培养环境的范式转变，并导致细胞制造，干细胞机械生物学和再生医学的重大进步。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

This Faculty Early Career Development (CAREER) grant will study how the “identity” of stem cells can be preserved by the mechanical properties of the materials that surround them. Stem cell identity is defined by their ability to divide, adapt, and differentiate. This work will focus on mesenchymal stem cells, which are adult stem cells typically sourced from bone marrow and expanded with tissue culture techniques. Controlling mesenchymal stem cell identity is important for cell manufacturing and regenerative medicine. The research goal of this project is to overcome current limitations in the cell culture environment of mesenchymal stem cells by developing materials with independently controllable properties of stiffness, adhesion, and cell-cell signaling. The educational goal of this project is to integrate research with ongoing educational activities to increase scientific literacy and equity. The work will involve programs for underrepresented high school and undergraduate students to conduct in-person summer research and attend virtual interactive modules designed to instill a passion for cell biology and materials science.The central hypothesis of this research is that mechanical dosing strategies can be leveraged to control mesenchymal stem cell proliferation, adaptation to dynamic materials, and differentiation within 3D hydrogels. This hypothesis will be tested by: (i) determining the significance of matrix mechanosensing during in vitro expansion on mesenchymal stem cell proliferation and stemness, (ii) elucidating the role of adhesive and cell-cell mimetic peptides on mesenchymal stem cell mechanical adaptation, and (iii) identifying mechanical dosing parameters that increase the differentiation potential of mesenchymal stem cells in 3D injectable hydrogels. The fundamental knowledge gained from these studies is expected to lead to a paradigm shift in current mesenchymal stem cell culture environments and result in significant advances in cell manufacturing, stem cell mechanobiology, and regenerative medicine.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.