Geometric control of muscle stem cell self-renewal

成人骨骼肌组织含有常驻干细胞，称为卫星细胞，其存在于专门的位置（小生境）并在整个生命中保持组织完整性。我们的卫星细胞调节的生化利基线索，如生长因子，细胞因子和受体配体的理解是，并继续由加拿大研究人员的优雅的研究先进。生物物理生态位线索，包括生物力学（刚度），建筑和地形对成体干细胞调控的影响正在得到赞赏，但在很大程度上仍未探索。 我们先前的工作揭示了基底刚度对卫星细胞行为和命运的深刻影响。在与骨骼肌柔软度相匹配的合成生物材料（仿生）上培养的小鼠卫星细胞与在传统硬质塑料上培养的小鼠卫星细胞相比，表现出更好的存活率，并产生更多的干细胞（自我更新）。在这里，我们将整合严格的干细胞生物学，生物材料，计算机科学和显微镜方法来评估三维（3D）架构的影响，第二个生物物理特征的利基，肌肉干细胞调节。生态位结构对卫星细胞形态学施加几何约束，我们将利用这一新的观察结果（1）阐明2D仿生底物和工程化（2）2D生态位“结构阵列”指导成体干细胞命运的卫星细胞调控的细胞和分子机制;（3）3D生态位结构模型系统地评估3D卫星细胞调控。 我们的研究将提供新的工具，发现除了基础知识：一个指标，以确定自我更新事件的文化，培养平台，以诱导所需的卫星细胞的命运和成人骨骼肌组织的3D模型。我们的综合方法提供了一个理想的环境，从事和培养学术界，医学和生物技术的未来领导者;一个中心的优先事项。我们的研究计划确保商业化的机会和高素质的人才作为可交付的利益，加拿大。

Adult skeletal muscle tissue contains resident stem cells, termed satellite cells, which exist in a specialized location (niche) and maintain tissue integrity throughout life. Our understanding of satellite cell regulation by biochemical niche cues such as growth factors, cytokines and receptor ligands was and continues to be advanced by the elegant studies of Canadian researchers. The influence of biophysical niche cues including biomechanics (stiffness), architecture and topography on adult stem cell regulation is gaining appreciation, but remains largely unexplored. Our prior work revealed the profound impact of substrate stiffness on satellite cell behavior and fate. Murine satellite cells cultured on a synthetic biomaterial matching the softness of skeletal muscle (biomimetic) exhibited improved survival and generated more stem cells (self-renewed) compared with culture on traditional rigid plastic. Here we will integrate rigorous stem cell biology, biomaterials, computer science, and microscopy approaches to evaluate the influence of three-dimensional (3D) architecture, a second biophysical feature of the niche, on muscle stem cell regulation. Niche architecture imposes geometric constraints on satellite cell morphology and we will leverage this novel observation (1) to elucidate cellular and molecular mechanisms underlying satellite cell regulation by 2D biomimetic substrates and by engineering (2) 2D niche 'architecture arrays' to direct adult stem cell fate; and (3) 3D niche architecture models to systematically evaluate satellite cell regulation in 3D. Our studies will deliver novel tools for discovery in addition to fundamental knowledge: a metric to identify self-renewal events in culture, a culture platform to induce desired satellite cell fates and a 3D model of adult skeletal muscle tissue. Our integrative approach provides an ideal setting to engage and train future leaders of academia, medicine and biotech; a central priority. Our Research Program ensures commercialization opportunities and highly qualified personnel as deliverable benefits to Canada.