CAREER: Regulation of Stem Cell Migration by Extracellular Matrix Plasticity

干细胞迁移是骨折和伤口愈合的关键方面，许多新兴的治疗系统需要干细胞迁移到植入的生物材料或从植入的生物材料迁移。 在通过组织迁移的过程中，干细胞必须穿过细胞外基质，这些细胞外基质的孔隙有时比细胞本身小100到1,000倍。 生理组织及其细胞外基质通常表现出机械可塑性，在机械力的作用下发生不可逆的变形。 在这些组织中，细胞产生的力可以永久地或塑性地扩张基质中的孔隙。 因此，细胞外基质的机械性质，包括基质的机械塑性或永久变形程度，可以在调节干细胞迁移中发挥关键作用。细胞外基质可塑性在调节干细胞迁移中的作用将在这个教师早期职业发展计划（CAREER）研究项目中进行研究。 这项研究将与涉及研究生、本科生和高中教师培训的教育和推广活动相结合。研究成果将纳入本科和研究生课程。教学模块，包括动手活动，适合高中教室和更广泛的公众将开发生物材料，刚度，可塑性和活组织的工程模型的主题。 这一综合努力将扩大对组织力学和干细胞迁移的理解。 本项目将研究组织的机械可塑性如何调节干细胞迁移。 研究人员假设，通过产生力，细胞可以塑性地打开基质中的孔以促进迁移。 使用生物材料进行3D培养，2D培养和基于微通道的迁移试验，该奖项将通过三个研究目标来验证这一假设。目的1将研究基质机械可塑性对干细胞迁移的影响，在可调的三维水凝胶基质开发的藻酸盐和透明质酸-胶原共聚物。 将跟踪细胞迁移，并量化HA-col基质中胶原结构的变化。 目的2将建立机械可塑性对干细胞迁移的影响，在2D表面和微通道中使用共聚焦荧光显微镜，以评估迁移以及细胞和核形态的测量。 目的3将阐明干细胞在不同机械可塑性基质中迁移的生物物理和分子机制。 特别是，将在迁移过程中测量基质应变，并将其与肌动蛋白动力学、细胞形态和体积以及核形态相关联。 最后，将重复3D迁移测定，同时扰动分子以确定它们如何影响迁移。 这些研究将揭示干细胞迁移的基本新见解，这将促进自然再生过程的知识，然后可以应用于推进再生医学。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。

Stem cell migration is a critical aspect of fracture and wound healing, and many emerging treatment systems require the migration of stem cells to or from implanted biomaterials. During migration through tissues, stem cells must crawl through an extracellular matrix with pores that are sometimes 100 to 1,000 times smaller than the cells themselves. Physiological tissues and their extracellular matrix often exhibit mechanical plasticity, undergoing irreversible deformations in response to mechanical force. In these tissues, cell generated forces can permanently -- or plastically -- expand pores in the matrix. Thus, the mechanical properties of the extracellular matrix, including how mechanically plastic or permanently deformable the matrix is, could play a critical role in regulating stem cell migration. The role of extracellular matrix plasticity in regulating stem cell migration will be investigated in this Faculty Early Career Development Program (CAREER) research project. The research will be integrated with both educational and outreach activities that involve the training of graduate students, undergraduates, and high school teachers. Research results will be incorporated into both undergraduate and graduate level courses. Teaching modules, including hands-on activities, suitable for high school classrooms and the broader public will be developed on the topics of biomaterials, stiffness, plasticity, and engineering models of living tissues. This integrated effort will broaden understanding regarding tissue mechanics and stem cell migration. This project will investigate how tissue mechanical plasticity regulates stem cell migration. The researcher hypothesizes that cells, through the generation of forces, can plastically open up pores in the matrix to facilitate migration. Using biomaterials for 3D culture, 2D culture, and microchannel-based migration assays, this award will test this hypothesis through three research objectives. Objective 1 will examine the impact of matrix mechanical plasticity on stem cell migration in tunable 3D hydrogel matrices developed from both alginate and hyaluronic acid-collagen copolymers. Cell migration will be tracked and changes to the collagen architecture in the HA-col matrices will be quantified. Objective 2 will establish the impact of mechanical plasticity on stem cell migration on 2D surfaces and in microchannels using confocal fluorescence microscopy to assess measurements of migration as well as cellular and nuclear morphology. Objective 3 will elucidate the biophysical and molecular mechanisms that stem cells utilize to migrate through matrices with different levels of mechanical plasticity. In particular, matrix strains will be measured during migration and correlated with actin dynamics, cell morphologies and volume, and nuclear morphologies. Finally, 3D migration assays will be repeated while perturbing molecules to determine how they affect migration. These studies will reveal fundamental new insights into stem cell migration, which will advance knowledge of natural regenerative processes that can then be applied to advance regenerative medicineThis 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.