Wnt/frizzled signalling modulates the migration and differentiation of immortalized cardiac fibroblasts.
OBJECTIVE
The Wnt/frizzled (Fzd) signal transduction cascade has been implicated in the proliferation, differentiation, and migration of many cell types, but the role of this pathway in cardiac fibroblast differentiation is not known. Our lab previously showed an up-regulation of Fzd-1 and -2 expression in myofibroblasts after myocardial infarction (MI), indicating a potential role for the Fzd receptor in fibroblast-myofibroblast differentiation. The present study was performed to further define the role of specific Wnt and Fzd proteins in the proliferation, migration, and differentiation of cardiac fibroblasts.


RESULTS
Because primary fibroblasts become senescent after a few passages and are difficult to transfect, we immortalized rat cardiac fibroblasts with telomerase [cardiac fibroblasts immortalized with telomerase (CFIT)]. Proliferation of CFIT was not significantly influenced by Wnt/Fzd signalling. The migration, however, was attenuated by all Wnt/Fzd combinations tested. Also, specific Wnt/Fzd combinations modulated the expression of the following myofibroblast markers: collagen Ialpha1, collagen III, fibronectin and its splice variants, and alpha-smooth muscle actin.


CONCLUSIONS
The results indicate that myofibroblast migration and differentiation, but not proliferation, can be modulated by interventions in Wnt/Fzd signalling. Therefore, Wnt/Fzd signalling may serve as a novel therapeutic target to ameliorate wound healing after MI.
Laeremans
Hilde
H
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, 50 Universiteitssingel, PO Box 616, 6200 MD Maastricht, The Netherlands.
Rensen
Sander S
SS
Ottenheijm
Harry C J
HC
Smits
Jos F M
JF
Blankesteijn
W Matthijs
WM
D000199:Actins / Q000378:metabolism; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein
D000199:Actins; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D024042:Collagen Type I; D024061:Collagen Type III; D005353:Fibronectins; D051157:Frizzled Receptors; D043562:Receptors, G-Protein-Coupled; D019098:Telomerase; D051153:Wnt Proteins; D060508:Wnt3 Protein; C489739:Fzd1 protein, mouse; C489743:Fzd2 protein, mouse; C498862:Acta2 protein, rat; C509186:TERT protein, human