Collaborative Research: Mechanoregulation of Amnion Patterning through Activation of Bone Morphogenetic Protein Signaling

本项目旨在支持利用干细胞衍生的人类发育模型研究羊膜发育的基础研究。羊膜作为胎膜的最内层，在介导营养运输和产生对维持妊娠重要的多种细胞因子方面起着至关重要的作用。该项目产生的见解将推进我们对人类早期发展的认识。该方法将有助于疾病建模，细胞替代治疗和生殖医学的三维干细胞培养系统的合理设计。这项研究将促进基础科学的进步，促进孕产妇健康。推广和教育活动包括高中和本科课程开发，这将通过提供实践研究机会，丰富研讨会和指导计划来实现。将特别强调扩大代表性不足的群体对研究活动的参与。该项目的目标是解决在人类早期发育过程中，在理解羊膜发育的机械生物学方面的重大挑战。这项工作将是第一次尝试引导形成干细胞衍生的多细胞组织与可调的生物力学环境。该项目的成功完成将为三维人类多能干细胞培养带来新的创新平台。所研究的定量形态学和基因表达表征将提供有价值的知识，以更好地了解机械线索如何控制羊膜图案和人类胚胎囊的形成，以及在这一过程中所涉及的形态学和基因表达动态。该方法将是非常有价值的表征复杂的干细胞衍生的组织，类似于人类胚胎（胚状体）和器官（类器官）一般的发展。本项目的机制研究将阐明骨形态发生蛋白信号通路及其与机械信号的交叉调节如何调节羊膜发育，并将为推进我们对涌现自我的理解奠定重要基础，组织原则和发展机制。该奖项反映了NSF的法定使命，并已被认为是值得支持的，通过评估使用基金会的智力价值，更广泛的影响审查标准。

This project is to support the fundamental research to study amnion development using a stem cell-derived human development model. As the innermost layer of the fetal membrane, amnion plays a crucial role in mediating nutrient transportation and producing a variety of cytokines that are important for maintaining pregnancy. The insights generated by this project will advance our knowledge in early human development. The methods will assist in the rational design of three-dimensional stem cell culture systems for disease modeling, cell replacement therapy, and reproductive medicine. This research will promote the progress of fundamental science and advance maternal health. Outreach and educational activities include high school and undergraduate curriculum development, which will be achieved by offering hands-on research opportunities, enrichment workshops, and mentoring program. Special emphasis will be placed on broadening participation of underrepresented groups in the researched activities. The objective of this project is set to address the significant challenge in understanding the mechanobiology governing amnion development during early human development. This work will be the first attempt to guide the formation of stem cell-derived multicellular tissues with tunable biomechanical environments. Successful completion of the project will lead to new innovative platforms for three-dimensional human pluripotent stem cell culture. The researched quantitative morphological and gene expression characterizations will provide valuable knowledge towards a better understanding on how mechanical cues control amnion patterning and the formation of the human embryonic sac, and the morphological and gene expression dynamics involved in this process. The methodologies will be highly valuable for characterizing the development of complex stem cell-derived tissues that resemble human embryos (embryoid) and organs (organoid) in general. Mechanistic investigations researched in this project will elucidate how the bone morphogenetic protein signaling pathway and its cross-regulations with mechanical signals regulate amnion development, and will lay important foundations for advancing our understanding of the emergent self-organizing principles and developmental mechanisms.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.