Excellence in Research: Human Stem Cell-Derived Polarized Dorsoventral Forebrain Organoid: Effect of Matrix Stiffness and Mechanical Stimulus

该奖项将支持促进我们对决定干细胞命运的生物物理线索的理解的研究。所有的组织和器官都来自干细胞，一系列复杂的信号会影响干细胞发育成特定的组织类型。干细胞的“命运”，意味着它最终成为哪种特定的细胞类型，取决于器官发育过程中细胞的线索。这些线索可以是生化的，也可以是生物物理的，或者是它们的组合。这项工作将集中在大脑的发育和影响这一过程的生物物理信号上。这项工作将使用“类器官”--在实验室中生长的小型三维细胞结构，以模拟完整大小器官的生理和功能。许多研究使用脑器官来检查影响干细胞发育为脑组织的生化线索。然而，相对较少的研究在静态(恒定)和动态(变化)刺激下干细胞分化的生物物理调节。这项工作将首先开发一种微型装置，以产生一致的、可控的静态和动态力。这个装置将被用来描述器官发育的机械生物学。了解决定脑器官干细胞命运的机械线索最终可以为研究神经或神经退行性疾病、个性化治疗、癌症以及创伤性脑损伤的影响和治疗提供新的机会。这项研究涉及多个学科，包括微器件开发、机械生物学、干细胞工程、材料科学和计算医学。这个项目最终将促进我们在脑组织工程、再生医学、生物制造和药理学方面的知识，并将引起下一批前沿劳动力的浓厚兴趣，导致此类工程系统的临床和工业成功。了解调节干细胞特定谱系分化的生物线索的作用对于极化类器官结构的发展至关重要。然而，目前的许多文献都集中在生化刺激在产生区域特异性脑器官方面的作用，而不是这项工作的重点-生物物理刺激。这项工作将通过发现形态发生化学物质、细胞外基质(ECM)硬度和机械刺激如何在时空上影响背腹侧极化和皮质前脑有机体的发育来解决这种失衡问题。这项工作将提供关于可溶性形态发生因子和梯度、ECM机制、机械刺激和信号通路在无缝调节有机物分化和组织中的作用的新知识。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award will support research that advances our understanding of the biophysical cues that determine stem cell fate. All tissues and organs are derived from stem cells, and a complex array of signals influence the development of stem cells into specific tissue types. The “fate” of a stem cell, which means the specific cell type it ultimately becomes, depends on cues to the cells during organ development. These cues can be biochemical, biophysical or a combination. This work will focus on the development of the brain and the biophysical signals that influence this process. This work will use “organoids” – small three-dimensional cellular structures grown in a lab to mimic the physiology and function of the full-sized organ. Many studies have used brain organoids to examine the biochemical cues that influence the development of stem cells into brain tissue. However, relatively few have studied the biophysical regulation of stem cell differentiation under both static (constant) and dynamic (varying) stimuli. This work will first develop a micro-device to generate consistent and controllable static and dynamic forces. This device will be used to characterize the mechanobiology of organ development. Understanding the mechanical cues that determine the brain organoid’s stem cell fate can ultimately provide new opportunities for studying neurological or neurodegenerative disorders, personalized treatment, cancer, and the effects and treatments of traumatic brain injury. This research involves several disciplines, including micro-device development, mechanobiology, stem cell engineering, materials science, and computational medicine. This project will ultimately advance our knowledge of brain tissue engineering, regenerative medicine, biomanufacturing, and pharmacology, and will be of significant interest to the next-frontier workforce, leading to the clinical and industrial success of such engineering systemsUnderstanding the roles of the biological cues that regulate lineage-specific differentiation of stem cells is critical to the development of polarized organoid structures. However, much of the current literature has focused on the role of biochemical stimuli to generate region-specific brain organoids, rather than on biophysical stimuli, the focus of this work. This work will address this imbalance by discovering how morphogenetic chemicals, extracellular matrix (ECM) stiffness, and mechanical stimuli affect the development of dorsoventral polarized and cortical forebrain organoids in a spatiotemporal manner. This work will provide new knowledge addressing the roles of soluble morphogenetic factors and gradients, ECM mechanics, mechanical stimuli, and signaling pathways in seamlessly regulating organoid differentiation and organization.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.