RECODE: New technologies to illuminate and harness cadherins for the reproducible production of cortical tissue in human cerebral organoids

大脑类器官是模仿人类大脑许多特征的细胞簇。当人类干细胞分化为脑细胞时，这些簇就会形成。对人脑进行实验提出了许多挑战。因此，在早期大脑发育、神经系统疾病和药物发现研究的许多研究中，大脑类器官被用来代替大脑。脑类器官产生的高度变异性限制了这些研究的实用性。该项目的目标是通过在类器官发育过程中控制细胞间粘附来减少变异性。预期的结果将是一系列细胞间粘附干预措施，广泛提高大脑类器官生产的可重复性，从而使它们可以用作人类神经发育和疾病的可靠模型。作为该项目的一部分，研究生和本科生将在干细胞生物学和工程学不同领域的团队领导方面接受指导。细胞粘附在发育过程中动态重塑大脑。我们的中心假设是，细胞间粘附的调节可以从任何人类干细胞系中制造可重复的大脑类器官。将开发和实施系统地询问和调节脑类器官分化不同阶段的细胞间粘附的新工具。这将通过三个具体目标来实现：（1）开发一套技术来控制人类多能干细胞的细胞间粘附； (2) 确定细胞间粘附调节神经元分化的机制； (3) 使用新的细胞间粘附调节方案测量分化时再现性的变化。该项目的预期成果包括关于细胞间粘附在人类神经元分化早期阶段的作用的基础知识；调节细胞间粘附的新技术；培养和监测类器官的新技术；以及跨人类多能干细胞系脑类器官发育的可行分化策略。这些新工具和见解可能会转化为理解脑类器官以外的许多细胞类型分化中基于粘附的形态发生。该项目由 ENG/CBET 的工程生物学和健康集群以及 ENG/CMMI 的生物力学和力学生物学项目共同支持。该奖项反映了 NSF 的法定使命，并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，被认为值得支持。

Brain organoids are clusters of cells that mimic many features of the human brain. As human stem cells differentiate into brain cells, these clusters form. Experimenting on human brains poses many challenges. As a result, brain organoids are used in place of the brain in many studies of early brain development, neurological disorders, and drug discovery research. High variability in the production of brain organoids limits the usefulness in these studies. The goal of this project is to reduce variability through control of cell-cell adhesion during organoid development. The expected outcome will be a collection of cell-cell adhesion interventions that broadly improve the reproducibility of brain organoids production so they can be used as reliable models for human neural development and disease. As part of the project, graduate and undergraduate students will be mentored in team leadership across diverse fields of stem cell biology and engineering.Cell-cell adhesion dynamically remodels the brain during development. Our central hypothesis is that modulation of cell-cell adhesion can manufacture reproducible cerebral organoids from any human stem cell line. New tools to systematically interrogate and modulate cell-cell adhesion at different stages of cerebral organoid differentiation will be developed and implemented. This will be achieved with three specific aims: (1) Develop a suite of technologies to control cell-cell adhesion in human pluripotent stem cells; (2) Identify mechanisms by which cell-cell adhesion regulates neuronal differentiation; and (3) Measure changes in reproducibility upon differentiation with new cell-cell adhesion modulation protocols. The expected outcomes of this project include fundamental knowledge of the role of cell-cell adhesion at early stages of human neuronal differentiation; new technologies to modulate cell-cell adhesion; new technologies to culture and monitor organoids; and a workable differentiation strategy for cerebral organoid development across human pluripotent stem cell lines. These new tools and insights can likely be translated to understand adhesion-based morphogenesis in the differentiation of many cell types beyond cerebral organoids.This project is being jointly supported by the Engineering Biology and Health Cluster in ENG/CBET and the Biomechanics and Mechanobiology Program in ENG/CMMI.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.