Collaborative Research: RECODE: Organoid model of growth plate development

生长板是位于儿童长骨末端的软骨组织，负责骨骼生长。它开始是一群干细胞，这些干细胞变得特化，并将自己组织成柱状，形成一个功能性的生长板。这个过程是由化学线索和机械力驱动的，尽管目前还不清楚它们如何共同作用形成生长板的结构和功能。这个通过定向分化编码（RECODE）的可再生细胞和类器官项目将开发一种可再生的生长板类器官，这将使人们能够研究干细胞如何形成成熟的生长板，这可能导致骨和软骨再生的新方法，特别是在儿童中。该项目将培养一个多样化的研究生，本科生和高中生在数学建模，生物材料开发，干细胞和发育生物学，并将提供机会，以更广泛的社区通过外展活动和事件向公众开放。该RECODE项目的首要目标是获得基本的洞察力之间的联系生物物理线索，细胞分化，和细胞组织，导致功能性生长板的发展。该项目结合了实验和计算方法，以深入了解控制定向细胞分裂的局部线索（任务1），柱状组织（任务2）的软骨形成分化和肥大分化，生长板的特征表型（任务3）。该项目将揭示生物物理学线索与空间定位的生化线索相结合如何使干细胞自组装成具有适当结构和功能的生长板器官。通过利用生物学中的新工具，3D打印中的先进生物材料和基于物理的数学建模，该项目将创建迄今为止第一个生长板类器官。这种类器官将为深入研究正常和异常骨生长中的干细胞和软骨细胞分化提供模型系统。了解指导MSC分化为成熟生长板类器官的机制将有助于指导再生医学方法的新型生物材料的设计，以治疗生长板损伤，这是一个目前缺乏可行和临床接受的治疗方法的领域。土木、机械和制造创新部门的机械和工程材料集群，以及化学、生物工程、环境、该奖项反映了NSF的法定使命，并被认为是值得通过评估使用基金会的知识优点和更广泛的影响审查标准。

The growth plate is a cartilage tissue located at the end of children’s long bones that is responsible for bone growth. It begins as a cluster of stem cells that become specialized and organize themselves into columns to form a functioning growth plate. This process is driven by both chemical cues and mechanical forces, although it is unclear how they work together to form the structure and function of the growth plate. This Reproducible Cells and Organoids via Directed-Differentiation Encoding (RECODE) project will develop a reproducible growth plate organoid that will allow one to study how stem cells form a mature growth plate, which can lead to novel approaches for bone and cartilage regeneration particularly in children. This project will train a diverse group of graduate, undergraduate, and high school students in mathematical modeling, biomaterial development, and stem cell and developmental biology and will provide opportunities to the broader community through outreach activities and events open to the public.The overarching goal for this RECODE project is to gain fundamental insight into the link between biophysical cues, cellular differentiation, and cellular organization that leads to the development of a functioning growth plate. This project combines experimental and computational approaches to gain insight into the local cues that govern directional cell division (Task 1), chondrogenic differentiation followed by columnar organization (Task 2), and hypertrophic differentiation, the characteristic phenotype of the growth plate (Task 3). This project will uncover how biophysical cues combined with spatially localized biochemical cues dovetail to drive the self-assembly of stem cells into a growth plate organ with the appropriate structure and function. By utilizing novel tools in biology, advanced biomaterials in 3D printing, and physics-based mathematical modeling, this project will create the first growth plate organoid to date. This organoid will provide a model system for deeper study of stem cell and chondrocyte differentiation, in normal and abnormal bone growth. Understanding the mechanisms that direct the differentiation of MSCs into a mature growth plate organoid will help guide the design of novel biomaterials for regenerative medicine approaches to treat growth plate injury, an area that currently lacks a viable and clinically accepted treatment.This RECODE award is co-funded by the Physiological and Structural Systems Cluster in the Division of Integrative Organismal Systems, the Mechanics and Engineering Materials Cluster in the Division of Civil, Mechanical, and Manufacturing Innovation, 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.