Principles of Cell Circuits for Tissue Repair and Fibrosis

被引：107

作者：

Adler, Miri ^{[1
,2
]}

Mayo, Avi ^{[1
]}

Zhou, Xu ^{[3
]}

Franklin, Ruth A. ^{[3
]}

Meizlish, Matthew L. ^{[3
]}

Medzhitov, Ruslan ^{[3
]}

Kallenberger, Stefan M. ^{[4
,5
,6
]}

Alon, Uri ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Immunobiol, New Haven, CT 06510 USA

[4] BIH, Digital Hlth Ctr, D-10178 Berlin, Germany

[5] Charite, D-10178 Berlin, Germany

[6] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany

来源：

ISCIENCE | 2020年 / 23卷 / 02期

基金：

以色列科学基金会;

关键词：

COLONY-STIMULATING FACTOR; LIVER FIBROSIS; CONNECTIVE-TISSUE; SENESCENT CELLS; STELLATE CELLS; MACROPHAGES; FIBROBLASTS; KELOIDS; MECHANISMS; SCAR;

D O I：

10.1016/j.isci.2020.100841

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Tissue repair is a protective response after injury, but repetitive or prolonged injury can lead to fibrosis, a pathological state of excessive scarring. To pinpoint the dynamic mechanisms underlying fibrosis, it is important to understand the principles of the cell circuits that carry out tissue repair. In this study, we establish a cell-circuit framework for the myofibroblast-macrophage circuit in wound healing, including the accumulation of scar-forming extracellular matrix. We find that fibrosis results from multistability between three outcomes, which we term "hot fibrosis" characterized by many macrophages, "cold fibrosis" lacking macrophages, and normal wound healing. This framework clarifies several unexplained phenomena including the paradoxical effect of macrophage depletion, the limited time-window in which removing inflammation leads to healing, and why scar maturation takes months. We define key parameters that control the transition from healing to fibrosis, which may serve as potential targets for therapeutic reduction of fibrosis.

引用

页数：24

共 68 条

[1]

BIOCHEMICAL-COMPOSITION OF THE CONNECTIVE-TISSUE IN KELOIDS AND ANALYSIS OF COLLAGEN-METABOLISM IN KELOID FIBROBLAST-CULTURES [J].