Mechanical Mapping of Neural Stem Cell Differentiation

阿尔茨海默氏症和帕金森氏症等神经退行性疾病的特点是神经元不可逆转的丧失，可能导致严重的认知和运动障碍。这些疾病给社会带来了巨大的负担，仅在美国，医疗成本就高达数千亿美元。目前的治疗方案通常不能治愈，只能暂时缓解症状。干细胞治疗是一项新兴技术，具有永久取代或修复在神经退行性疾病中丢失的神经细胞的潜力。提高干细胞治疗的有效性需要了解影响干细胞分化的因素，干细胞通过这个过程产生新的神经元。虽然大多数研究工作都集中在分析分化过程中涉及的生化和遗传因素，但最近的发现强调了细胞环境的机械特性的贡献。这个项目将通过使用一种新的技术-布里渊显微镜来研究干细胞分化的这一方面，该技术可以在细胞水平上提供组织生物力学特性的三维信息。其目的是确定机械信号在指导干细胞分化中的重要性，并为提高再生治疗的有效性提供关键信息。这个项目提供了一个很好的机会来教育和培训工程学和生命科学之间的研究生和博士后研究人员。除了高级学生，哈佛-麻省理工学院夏季生物医学光学研究所的本科生将有机会参加。目前对干细胞生物力学特性的了解大多基于细胞培养研究，表明细胞外环境的机械参数，如硬度，对定向分化有显著影响。然而，这些结果在多大程度上代表了脑组织中干细胞的行为尚不清楚。主要障碍之一是缺乏以细胞和亚细胞水平的三维分辨率研究组织的弹性特性的技术。布里渊成像由于其非接触性和高空间分辨率，可以弥补这一差距。在这项研究中，布里渊成像将被验证为一种提供可靠的神经细胞和组织弹性模数测量的工具。这项技术将被用来绘制小鼠大脑机械特性的异质性图谱，既在不同的大脑结构水平上，也在不同区域的细胞水平上，以了解这种空间差异的起源。这种机械异质性对分化的影响将通过将引入大脑的干细胞谱系与用布里渊成像测量的局部微环境的弹性特性相关联来评估。

Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterized by an irreversible loss of neurons that can lead to severe cognitive and motor deficits. These disorders generate an enormous burden on society, with healthcare costs of hundreds of billions of dollars in the U.S. alone. Current treatment options are generally not curative and can only provide temporary relief from symptoms. Stem cell therapy is an emerging technology with the potential of permanently replacing or repairing neural cells lost in neurodegenerative disorders. Improving the efficacy of stem cell therapy requires understanding of the factors that influence stem cell differentiation, the process by which stem cells generate new neurons. While most research efforts have been directed to analyzing the biochemical and genetic factors involved in the differentiation process, recent discoveries have highlighted contributions from mechanical properties of the cellular environment. This project will investigate this aspect of stem cell differentiation by employing a novel technique, Brillouin microscopy that can provide three-dimensional information on biomechanical properties of tissues at the cellular level. The objective is to determine the importance of mechanical cues in directing stem cell differentiation, and provide critical information for improving the effectiveness of regenerative therapies. This project provides an excellent opportunity to educate and train graduate students and postdoctoral researchers at the interface between engineering and life sciences. In addition to advanced students, undergraduate students enrolled in the Harvard-MIT Summer Institute for Biomedical Optics will be given the opportunity to participate.The current understanding of biomechanical properties of stem cells is mostly based on cell culture studies, showing that the mechanical parameters of the extracellular environment such as stiffness have a significant influence in directing differentiation. However, the extent to which these results represent the behavior of stem cells in brain tissues is unclear. One of the major obstacles is the lack of techniques for investigating the elastic properties of tissues with three-dimensional resolution down to the cellular and subcellular level. Brillouin imaging can bridge this gap given its non-contact nature and high spatial resolution. In this research, Brillouin imaging will be validated as a tool to provide reliable measurements of elastic modulus of neural cells and tissues. The technique will be used to map the heterogeneity of mechanical properties in the mouse brain, both at the level of the different brain structures and, in the different regions, at the cellular level to understand the origin of such spatial variations. The effect of this mechanical heterogeneity on differentiation will then be assessed by correlating the lineage of stem cells introduced into the brain with the elastic properties of the local microenvironment measured with Brillouin imaging