RECODE: Spatial engineering of morphogens for the reproducible formation of cortical organoids with arealization

人类的大脑由不同的区域组成，包括初级皮层、感觉皮层和运动皮层。这些区域在许多神经系统疾病中受到影响。为了更好地理解早期发育，在类器官中可重复地创造大脑区域至关重要。本项目旨在发展基于水凝胶的生物工程技术，以精确制造皮层类器官中大脑皮层的不同区域。为了实现这些目标，一个多学科团队将利用细胞和发育生物学、软材料工程和生物信息学方面的专业知识。该项目的更广泛的社会影响包括教育和推广活动，与UCI干细胞研究中心、UCI学习和记忆神经生物学中心、UCI访问和包容办公室以及OC Stem倡议合作，吸引来自服务欠缺社区的公众和学生。直接接触人体组织对于深入了解人类大脑发育和疾病的潜在机制是必不可少的。因此，皮质类器官，密切模仿胎儿皮质的许多方面，已成为易于获得和有前途的体外工具。然而，皮质类器官目前缺乏实现-可再生的细胞多样性和不同的空间组织在新皮层。为了在皮质类器官中实现这一目标，将开发一种新的响应性水凝胶平台，可以生成形态源的空间模式。该平台将利用单细胞和空间转录组学来检查潜在的信号相互作用的基因调控网络，以指定不同的区域。在这个项目中发展的方法和见解可以应用于理解形态发生和在皮质类器官以外的其他系统中产生可复制的类器官。该RECODE项目由化学、生物工程、环境和运输系统部门的工程生物学和健康集群资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The human brain is comprised of different regions, including primary, sensory, and motor cortices. These areas are affected in many neurological disorders. It is crucial to reproducibly create brain areas in organoids to better understand early development. This project aims to develop hydrogel-based bioengineering technologies to accurately make different areas of the cerebral cortex in cortical organoids. To accomplish these goals, a multidisciplinary team will leverage expertise in cell and developmental biology, soft materials engineering, and bioinformatics. The broader societal impacts of this project include educational and outreach activities that engage the public and students from underserved communities in partnership with the UCI Stem Cell Research Center, UCI Center for the Neurobiology of Learning and Memory, UCI Office of Access and Inclusion, and OC STEM Initiative. Direct access to human tissue is indispensable for deep understanding of the mechanisms underlying human brain development and disease. Therefore, cortical organoids that closely mimic many aspects of the fetal cortex have emerged as accessible and promising in vitro tools. However, cortical organoids currently lack arealization – the reproducible cellular diversity and distinct spatial organization within the neocortex. To achieve arealization in cortical organoids, a novel responsive hydrogel platform will be developed that can generate spatial patterning of morphogen sources. This platform will be leveraged for examining gene regulatory networks underlying signaling interactions for specifying different areas, using single-cell and spatial transcriptomics. The approaches and insights developed in this project can be applied towards understanding morphogenesis and generating reproducible organoids in other systems beyond cortical organoids. This RECODE project is funded by the Engineering Biology and Health Cluster in the Division of Chemical, Bioengineering, Environmental, and Transport Systems.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.