CAREER: Mechanisms Underlying Temporal Integration of BMP Signaling in Cell Fate Decisions

Heemskerk实验室之前表明，对于被称为骨形态发生蛋白(BMP)的细胞信号，细胞将随着时间的推移而看到的信号量相加，以决定是否专门针对一种特定的细胞类型。这个项目将结合实验和计算方法，以了解细胞如何跟踪过去的信号，并确定其他细胞类型的后来特化事件是否遵循相同的规则。多名本科生和研究生将接受进行这项研究的培训，为他们的职业生涯做好准备，这些职业越来越需要整合计算和实验方法来解决科学问题。与密歇根大学自然历史博物馆(UMMNH)的一项合作将向不同的受众传播干细胞研究及其社会效益。为了接触到更年轻的观众，研究人员将与UMMNH合作，为底特律大都会代表不足的社区的中学生制定教学课程，并在博物馆举办为期一年的小型展览和额外的外联活动。为了接触到成年人，研究小组将在公共科学咖啡馆活动中讨论干细胞研究和人类发育，并为研究生扩展课程模块，教授该项目中应用的方法。BMP是一种典型的信号分子，在早期发育中发挥保守作用。该项目使用人类多能干细胞(HPSCs)作为体外模型，以解决BMP在人类早期发育过程中控制细胞命运的机制。初步研究表明，hPSC向羊膜样细胞的分化不依赖于信号的水平或持续时间，而仅取决于时间积分，即随着时间的推移，信号的总量。这与普遍认为信号水平是细胞反应的主要决定因素的假设相反，并暗示了不同的信号处理分子机制。初步筛选出其水平与信号的时间积分呈线性相关的基因，提供了一种简单的潜在机制，但这些基因如何受BMP调控，以及它们如何控制其他基因尚不清楚。我们也不知道BMP整合是否在不同的背景下是保守的。因此，本项目的目标是1)揭示羊膜样分化过程中BMP信号时间整合的机制，2)了解信号响应如何依赖于细胞的初始状态，3)确定这些机制是否在不同的细胞命运决定和物种中保守。总之，这项工作将对多能干细胞中的BMP信号产生更深刻的理解，并有助于揭示动态信号控制细胞命运的一般原理，使干细胞在体外能够更具重复性。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。

The Heemskerk lab previously showed that for the cell signal called Bone Morphogenetic Protein (BMP), cells add up the amount of signal they see over time to decide whether to specialize to one specific cell type. This project will combine experimental and computational methods to understand how cells keep track of the past signaling and determine if later specialization events to other cell types follow the same rules. Multiple undergraduate and graduate students will be trained to perform this research, preparing them for careers that increasingly demand integration of computational and experimental approaches to tackle scientific problems. A collaboration with the University of Michigan Museum of Natural History (UMMNH) will communicate stem cell research and its societal benefits to diverse audiences. To reach younger audiences, the researchers will partner with the UMMNH to develop a curriculum for teaching middle school students in underrepresented communities from metro-Detroit, as well as a small year-long exhibit and additional outreach activities at the museum. To reach adults, the research team will discuss stem cell research and human development in public Science Café events and expand a course module for graduate students to teach the methods applied in this project.BMP is a quintessential signaling molecule that plays a conserved role in early development. This project uses human pluripotent stem cells (hPSCs) as an in vitro model to address the mechanisms by which BMP controls cell fate decisions in early human development. Preliminary work revealed that differentiation of hPSCs to amnion-like cells does not depend on the level or duration of signaling separately, but only on the time integral, i.e. the total amount of signaling over time. This is contrary to the common assumption that signaling level is the main determinant of cell response and implies different molecular mechanisms for signal processing. A preliminary screen yielded genes whose levels are linearly related to the time integral of signaling, providing a simple potential mechanism, but how these genes are regulated by BMP and how they in turn control other genes is unclear. We also do not know if BMP integration is conserved across different contexts. Therefore, this project aims to 1) reveal the mechanisms underlying temporal integration of BMP signaling during amnion-like differentiation, 2) understand how signal response depends on the initial state of the cell, 3) determine if these mechanisms are conserved across different cell fate decisions and species. Together, this work will yield a more profound understanding of BMP signaling in pluripotent stem cells and contribute to revealing general principles by which dynamic signaling controls cell fate, enabling more reproducible stem cell differentiation in vitro.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.