期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 8, 页码 E1926-E1935出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1714377115
关键词
mathematical models; tissue biology; systems medicine; cell circuits; bistability
资金
- Broad Institute-Israel Science Foundation [2389/17]
- Blavatnik Family Foundation
- Else Kroner-Fresenius Foundation
- Scleroderma Research Foundation
- Biogen Inc.
- Howard Hughes Medical Institute (HHMI)
- Jane Coffin Childs Memorial Fund Postdoctoral Fellowship
- Cancer Research Institute Donald Gogel Postdoctoral Fellowship
- NIH Medical Scientist Training Program T32 Training Grant [T32GM007205]
- National Research Service Award National Cancer Institute Fellowship [1F30CA189926-01]
Cells in tissues communicate by secreted growth factors (GF) and other signals. An important function of cell circuits is tissue homeostasis: maintaining proper balance between the amounts of different cell types. Homeostasis requires negative feedback on the GFs, to avoid a runaway situation in which cells stimulate each other and grow without control. Feedback can be obtained in at least two ways: endocytosis in which a cell removes its cognate GF by internalization and cross-inhibition in which a GF down-regulates the production of another GF. Here we ask whether there are design principles for cell circuits to achieve tissue homeostasis. We develop an analytically solvable framework for circuits with multiple cell types and find that feedback by endocytosis is far more robust to parameter variation and has faster responses than cross-inhibition. Endocytosis, which is found ubiquitously across tissues, can even provide homeostasis to three and four communicating cell types. These design principles form a conceptual basis for how tissues maintain a healthy balance of cell types and how balance may be disrupted in diseases such as degeneration and fibrosis.
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