Collaborative Research: RECODE: Directed Differentiation of Human Liver Organoids via Computational Analysis and Engineering of Gene Regulatory Networks

类器官是由干细胞分化产生的一组细胞，它们具有与人体器官相似的结构和功能。类器官可用于模拟人类疾病的发展和测试新生产的药物。然而，需要产生具有更好功能和更少变异性的人类类器官。该项目旨在使用基于遗传的分析和工程来控制干细胞向人类肝细胞的分化，并改善肝脏类器官的最终制造结果。作为该项目活动的一部分，研究生和本科生将接受培训，并将制作简短的教育视频剪辑用于在线教育和公众参与。该RECODE项目将解决体外肝脏类器官工程的生物技术挑战，如成熟度，血管形成和可重复性。为此，合成生物学、干细胞工程和系统生物学将被整合，以开发人类诱导多能干细胞自主分化为肝脏类器官的平台。研究将在两个独立的目标中进行：1）开发用于肝脏类器官中多步分化的合成基因电路，2）在分化期间鉴定谱系可塑性调节剂，以控制工程类器官中的最终细胞命运。通过这项工作获得的理解将解决适用于细胞分化，人类肝脏成熟和血管形成的知识差距。该项目还将通过围绕干细胞工程的新颖在线教育和公共宣传活动，为发展强大的STEM劳动力提供支持。该RECODE奖由分子和细胞生物科学部的系统和合成生物学集群以及化学，生物工程，环境，环境和生物工程部的工程生物学和健康集群共同资助。该奖项反映了NSF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。

Organoids are group of cells produced from stem cells that mimic closely structure and functions of human organs. Organoids can be used for modeling the development of human diseases and for testing newly produced medicines. However, there is a need for generation of human organoids with better function and less variability. This project aims to use genetic based analysis and engineering to control stem cell differentiation towards human liver cells and improve the final manufacturing outcome of liver organoids. As part of the activities in this project, graduate and undergraduate students will be trained and short educational video clips will be made for online education and public engagement.This RECODE project will address biotechnology challenges of in vitro liver organoid engineering such as maturity, vascular formation, and reproducibility. To this end, synthetic biology, stem cell engineering, and systems biology will be integrated to develop a platform for autonomous differentiation of human induced pluripotent stem cells to liver organoids. Studies will be performed in two independent objectives to: 1) develop synthetic gene circuits for multistep differentiation in liver organoids and 2) identify lineage plasticity regulators during differentiation to control final cell fates in engineered organoids. The understanding gained through this work will address knowledge gaps applicable to cellular differentiation, human liver maturation, and vascular formation. This project will also provide support for the development of a strong STEM workforce through novel online education and public outreach activities surrounding stem cell engineering.This RECODE award is co-funded by the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biosciences and 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.