Decoding the non-binary signaling logic that controls cell fate

解码控制细胞命运的非二进制信号逻辑

• 批准号: 10809086
• 负责人: Idse Joannes Heemskerk
• 金额: $ 1.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809086
• 关键词: Activins; Adhesions; Adult; Biological Assay; Biophysics; Cell Communication; Cell Fate Control; Cell Line; Cells; Characteristics; Complex; Computer Analysis; Computer software; Custom; Data; Data Science; Disease; Drug Targeting; Drug usage; Embryonic Development; Environment; Fibroblast Growth Factor; Fluorescence Microscopy; Foundations; Gene Combinations; Gene Expression; Goals; Health; Homeostasis; Image Analysis; Individual; Knowledge; Laboratories; Link; Logic; Maintenance; Measurement; Measures; Mechanics; Mesoderm; Methods; Nodal; Pathway interactions; Play; Population; Protocols documentation; Publishing; Recording of previous events; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Therapeutic; Time; Tissues; Visualization; Work; cell behavior; cell type; combinatorial; engineered stem cells; epithelial to mesenchymal transition; human pluripotent stem cell; improved; insight; interdisciplinary approach; mathematical model; mechanical signal; multidimensional data; nonbinary; notch protein; paracrine; pluripotency; response; stem cell differentiation; stem cell therapy; tissue regeneration

PROJECT SUMMARY / ABSTRACT Only a handful set of signaling pathways (FGF, BMP, Wnt, Hh, Notch, etc) are repeatedly utilized to control almost all aspects of cell-cell communication from early embryonic development to adult tissue homeostasis. How this small set of pathways controls such a large number of phenomena is poorly understood. We and others recently showed that signal response is not binary, and that gene expression depends on many parameters of a cell’s signaling history, including duration, timing, and rate of signal change. Therefore, different responses to the same signaling molecules may be in part attributed to different time courses of exposure. The primary goal of the proposed research is to develop a predictive understanding of how the signaling history of a cell controls its fate, focusing on early cell fate decisions in human pluripotent stem cells. To decipher how information is encoded in dynamic signals we will take a highly interdisciplinary approach that combines gene editing, quantitative fluorescence microscopy, engineering of the stem cell environment, computational analysis, and mathematical modeling. The proposed interrelated goals build on previously published work combining these approaches by the PI and recent preliminary data from the laboratory. First, we will determine population level signaling dynamics in response to FGF. The quantitative characteristics of FGF signaling are not well understood despite playing a crucial role in pluripotency maintenance and mesendoderm differentiation, and this information is important in laying the foundation for the second project. Second, we will go beyond population level dynamics of a single pathway, and measure signaling through multiple pathways simultaneously in individual cells to identify precise features of combinatorial signaling that are predictive of fate. Specifically, we will create a single cell line expressing four of our published constructs to visualize each of the paracrine pathways involved in early cell fate (Wnt, BMP, Activin/Nodal, and FGF), and utilize our custom image analysis software for tracking cells through many days of differentiation. This will generate unique high-dimensional data in the form single-cell multi- pathway signaling histories linked to cell fate. We will then use data science methods to determine signaling features that predict cell fate. Third, we will investigate the interplay between tissue mechanics and cell signaling. Mesoderm differentiation is closely linked to an epithelial-mesenchymal transition and dramatic changes in intercellular forces. By combining our signaling assays with force manipulation and force measurement, we will gain biophysical insight into how FGF regulates intercellular tension and adhesion, and how tension and adhesion modulate the Wnt response. The ultimate goal is to obtain a quantitative understanding of the complex interplay between signaling dynamics, cell mechanics, and cell fate, and exploit this knowledge for wide ranging therapeutic applications including optimized protocols for directed stem cell differentiation and more effective use of drugs that target signaling pathways.

项目摘要/摘要

项目成果

Spatial Single Cell Analysis of Proteins in 2D Human Gastruloids Using Iterative Immunofluorescence.

使用迭代免疫荧光对 2D 人类原肠胚中的蛋白质进行空间单细胞分析。

• DOI: 10.1002/cpz1.915
• 发表时间: 2023
• 期刊: Current protocols
• 作者: Freeburne,Emily;Teague,Seth;Khan,Hina;Li,Bolin;Ding,Siyuan;Chen,Bohan;Helms,Adam;Heemskerk,Idse
• 通讯作者: Heemskerk,Idse

The time integral of BMP signaling determines fate in a stem cell model for early human development.

BMP 信号传导的时间积分决定了人类早期发育干细胞模型的命运。

• DOI: 10.1101/2023.04.10.536068
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Teague,Seth;Primavera,Gillian;Chen,Bohan;Freeburne,Emily;Khan,Hina;Jo,Kyoung;Johnson,Craig;Heemskerk,Idse
• 通讯作者: Heemskerk,Idse

Extended culture of 2D gastruloids to model human mesoderm development.

二维原肠胚的扩展培养来模拟人类中胚层发育。

• DOI: 10.1101/2024.03.21.585753
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Chen,Bohan;Khan,Hina;Yu,Zhiyuan;Yao,LiAng;Freeburne,Emily;Jo,Kyoung;Johnson,Craig;Heemskerk,Idse
• 通讯作者: Heemskerk,Idse

Roadmap for the multiscale coupling of biochemical and mechanical signals during development.

• DOI: 10.1088/1478-3975/abd0db
• 发表时间: 2021-04-14
• 期刊: Physical biology
• 影响因子: 2
• 作者: Lenne PF;Munro E;Heemskerk I;Warmflash A;Bocanegra-Moreno L;Kishi K;Kicheva A;Long Y;Fruleux A;Boudaoud A;Saunders TE;Caldarelli P;Michaut A;Gros J;Maroudas-Sacks Y;Keren K;Hannezo E;Gartner ZJ;Stormo B;Gladfelter A;Rodrigues A;Shyer A;Minc N;Maître JL;Di Talia S;Khamaisi B;Sprinzak D;Tlili S
• 通讯作者: Tlili S