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

类器官是由干细胞产生的一组细胞，与人体器官的结构和功能非常相似。有机化合物可用于模拟人类疾病的发展和测试新生产的药物。然而，需要产生功能更好、变异性更小的人类有机化合物。该项目旨在利用基于基因的分析和工程技术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，将对研究生和本科生进行培训，并将制作教育短片用于在线教育和公共活动。该RECODE项目将解决体外肝脏有机体工程的生物技术挑战，如成熟度、血管形成和重复性。为此，合成生物学、干细胞工程和系统生物学将整合在一起，开发一个将人诱导的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下进行：1)开发肝脏类器官的多步分化的合成基因电路；2)识别分化过程中的谱系可塑性调节因子，以控制工程类器官的最终细胞命运。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空白。该项目还将通过新颖的在线教育和围绕干细胞工程的公共推广活动，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小组以及化学、生物工程、环境和运输系统部门的工程生物学和健康小组共同资助。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。

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.