Mechanical Mapping of Neural Stem Cell Differentiation

神经退行性疾病如阿尔茨海默氏症和帕金森氏症的特征是神经元的不可逆损失，这可能导致严重的认知和运动缺陷。这些疾病给社会带来了巨大的负担，仅在美国就有数千亿美元的医疗费用。目前的治疗方案通常不能治愈，只能暂时缓解症状。干细胞治疗是一种新兴技术，具有永久替代或修复神经退行性疾病中丢失的神经细胞的潜力。提高干细胞治疗的疗效需要了解影响干细胞分化的因素，干细胞分化是干细胞产生新神经元的过程。虽然大多数研究工作都是针对分析分化过程中涉及的生化和遗传因素，但最近的发现突出了细胞环境机械特性的贡献。本项目将通过采用一种新的技术，布里渊显微镜，可以在细胞水平上提供组织生物力学特性的三维信息，来研究干细胞分化的这一方面。目的是确定机械线索在指导干细胞分化中的重要性，并为提高再生疗法的有效性提供关键信息。该项目提供了一个很好的机会，教育和培训研究生和博士后研究人员在工程和生命科学之间的接口。除了高级学生外，哈佛-麻省理工学院暑期生物医学光学研究所的本科生也将有机会参加。目前对干细胞生物力学特性的认识大多基于细胞培养研究，表明细胞外环境的力学参数如刚度对指导分化有重要影响。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。其中一个主要障碍是缺乏研究组织弹性特性的技术，三维分辨率下降到细胞和亚细胞水平。布里渊成像由于其非接触性质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工具，提供可靠的测量神经细胞和组织的弹性模量。该技术将被用来映射在小鼠大脑中的机械性能的异质性，无论是在不同的大脑结构的水平，并在不同的区域，在细胞水平，以了解这种空间变化的起源。然后通过将引入脑中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这种机械异质性对分化的影响

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