期刊
MOLECULAR SYSTEMS BIOLOGY
卷 14, 期 1, 页码 -出版社
WILEY
DOI: 10.15252/msb.20177733
关键词
cellular heterogeneity; mathematical modeling; signaling dynamics; single-cell analysis; TGF beta-SMAD signaling
资金
- NIH [NIH 1R01DK090347]
- e:bio junior group program of the German Federal Ministry of Education and Research (BMBF) [FKZ 0316196]
- Virtual Liver Network of the German Federal Ministry of Education and Research (BMBF) [FKZ 0316054]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK090347] Funding Source: NIH RePORTER
The cytokine TGF beta provides important information during embryonic development, adult tissue homeostasis, and regeneration. Alterations in the cellular response to TGFb are involved in severe human diseases. To understand how cells encode the extracellular input and transmit its information to elicit appropriate responses, we acquired quantitative time-resolved measurements of pathway activation at the single-cell level. We established dynamic time warping to quantitatively compare signaling dynamics of thousands of individual cells and described heterogeneous single-cell responses by mathematical modeling. Our combined experimental and theoretical study revealed that the response to a given dose of TGFb is determined cell specifically by the levels of defined signaling proteins. This heterogeneity in signaling protein expression leads to decomposition of cells into classes with qualitatively distinct signaling dynamics and phenotypic outcome. Negative feedback regulators promote heterogeneous signaling, as a SMAD7 knock-out specifically affected the signal duration in a subpopulation of cells. Taken together, we propose a quantitative framework that allows predicting and testing sources of cellular signaling heterogeneity.
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