期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 44, 页码 17969-17973出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105901108
关键词
biological engineering; mathematical modeling; synthetic biology
资金
- Japan Science and Technology
- Ministry of Education, Culture, Sports, Science, and Technology [14085101, 14085203, 23119005, 23119008]
- Japan Society for the Promotion of Science [21650018, 23680031]
- Grants-in-Aid for Scientific Research [23650066, 23300084, 21650018, 09J09649, 23680031, 23650069, 14085203, 14085101] Funding Source: KAKEN
Phenotypic diversification of cells is crucial for developmental and regenerative processes in multicellular organisms. The diversification concept is described as the motion of marbles rolling down Waddington's landscape, in which the number of stable states changes as development proceeds. In contrast to this simple concept, the complexity of natural biomolecular processes prevents comprehension of their design principles. We have constructed, in Escherichia coli, a synthetic circuit with just four genes, which programs cells to autonomously diversify as the motion on the landscape through cell-cell communication. The circuit design was based on the combination of a bistable toggle switch with an intercellular signaling system. The cells with the circuit diversified into two distinct cell states, high and low, in vivo and in silico, when all of the cells started from the low state. The synthetic diversification was affected by not only the shape of the landscape determined by the circuit design, which includes the synthesis rate of the signaling molecule, but also the number of cells in the experiments. This cell-number dependency is reminiscent of the community effect: The fates of developing cells are determined by their number. Our synthetic circuit could be a model system for studying diversification and differentiation in higher organisms. Prospectively, further integrations of our circuit with different cellular functions will provide unique tools for directing cell fates on the population level in tissue engineering.
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