Adler M, Mayo A, Zhou X, Franklin RA, Jacox JB, Medzhitov R, Alon U. 2018. Endocytosis as a stabilizing mechanism for tissue homeostasis. Proceedings of the National Academy of Sciences of the United States of America. 115(8):E1926-E1935. Pubmed: 29429964 DOI:10.1073/pnas.1714377115


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.
Copyright © 2018 the Author(s). Published by PNAS.

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Ruth Franklin’s laboratory explores the role of the innate immune system in tissue repair and homeostasis, with a focus on the communication between macrophages and non-immune cells within tissues.

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