Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

Peder Öhman Fuchs; Carlemi Calitz; Nataša Pavlović; François Binet; Sara Marie Øie Solbak; U Helena Danielson; Johan Kreuger; Femke Heindryckx; Pär Gerwins

doi:10.1016/j.cellsig.2020.109661

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

Cell Signal. 2020 Aug:72:109661. doi: 10.1016/j.cellsig.2020.109661. Epub 2020 Apr 22.

Authors

Peder Öhman Fuchs¹, Carlemi Calitz¹, Nataša Pavlović¹, François Binet¹, Sara Marie Øie Solbak², U Helena Danielson³, Johan Kreuger¹, Femke Heindryckx⁴, Pär Gerwins⁵

Affiliations

¹ Dept. of Medical Cell Biology, Uppsala University, P.O. Box 571, SE-751 23 Uppsala, Sweden.
² Dept. of Chemistry-BMC, Uppsala University, P.O. Box 576, SE-751 23 Uppsala, Sweden.
³ Dept. of Chemistry-BMC, Uppsala University, P.O. Box 576, SE-751 23 Uppsala, Sweden; Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
⁴ Dept. of Medical Cell Biology, Uppsala University, P.O. Box 571, SE-751 23 Uppsala, Sweden. Electronic address: femke.heindryckx@mcb.uu.se.
⁵ Dept. of Medical Cell Biology, Uppsala University, P.O. Box 571, SE-751 23 Uppsala, Sweden; Dept. of Radiology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.

PMID: 32334027
DOI: 10.1016/j.cellsig.2020.109661

Abstract

Fibrin is an essential constituent of the coagulation cascade, and the formation of hemostatic fibrin clots is central to wound healing. Fibrin clots are over time degraded into fibrin degradation products as the injured tissue is replaced by granulation tissue. Our goal was to study the role of the fibrin degradation product fragment E (FnE) in fibroblast activation and migration. We present evidence that FnE is a chemoattractant for fibroblasts and that FnE can potentiate TGF-β-induced myofibroblast formation. FnE forms a stable complex with α_Vβ₃ integrin, and the integrin β₃ subunit is required both for FnE-induced fibroblast migration and for potentiation of TGF-β-induced myofibroblast formation. Finally, subcutaneous infusion of FnE in mice results in a fibrotic response in the hypodermis. These results support a model where FnE released from clots in wounded tissue promote wound healing and fibrosis by both recruitment and activation of fibroblasts. Fibrin fragment E could thus represent a therapeutic target for treatment of pathological fibrosis.

Keywords: Fibrinolysis; Fibroblasts; Fibrosis; Inflammation; Wound healing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Cell Proliferation / drug effects
Chemotaxis / drug effects
Female
Fibrin Fibrinogen Degradation Products / metabolism*
Fibrosis
Humans
Integrin alphaVbeta3 / metabolism
Male
Membrane Proteins / metabolism
Mice, Inbred C57BL
Myofibroblasts / drug effects
Myofibroblasts / pathology*
Protein Binding / drug effects
Rats
Subcutaneous Tissue / drug effects
Subcutaneous Tissue / pathology
Toll-Like Receptor 4 / metabolism
Transforming Growth Factor beta / pharmacology*

Substances

BAMBI protein, human
Fibrin Fibrinogen Degradation Products
Integrin alphaVbeta3
Membrane Proteins
Toll-Like Receptor 4
Transforming Growth Factor beta
fibrin fragment E-2