Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis.
Using an established model of myocardial hypertrophy and fibrosis after angiotensin II (AngII) infusion, our aim was to characterize the early cellular element involved in the development of myocardial fibrosis in detail. Male Lewis rats were infused with saline or AngII (0.7 mg/kg per day) for up to seven days. Collagen deposition and cellular infiltration were identified by histology stains. Infiltrating cells were grown in vitro and examined by flow cytometry and immunostaining. Chemokine expression was measured using qRT-PCR. AngII infusion resulted in multifocal myocardial cellular infiltration (peak at three days) that preceded collagen deposition. Monocyte chemotactic protein (MCP)-1 transcripts peaked after one day of AngII exposure. Using a triple-labelling technique, the infiltrating cells were found to express markers of leucocyte (ED1(+)), mesenchymal [α-smooth muscle actin (SMA)(+)] and haematopeotic progenitor cells (CD133(+)) suggesting a fibroblast progenitor phenotype. In vitro, ED1(+)/SMA(+)/CD133(+) cells were isolated and grown from AngII-exposed animals. Comparatively few cells were cultured from untreated control hearts, and they were found to be ED1(-)/SMA(+)/CD133(-). We provide evidence that myocardial ECM deposition is preceded by infiltration into the myocardium by cells that express a combination of haematopoietic (ED1, CD133) and mesenchymal (SMA) cell markers, which is a characteristic of the phenotype of fibroblast precursor cells, termed fibrocytes. This suggests that fibrocytes rather than (as is often presumed) leucocytes may have effector functions in the initiation of myocardial fibrosis.
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Mryanda
M
Sopel
Alec
A
Falkenham
Adam
A
Oxner
Irene
I
Ma
Timothy D G
TD
Lee
Jean-Francois
JF
Légaré
D000071916:AC133 Antigen; D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D053331:Ectodysplasins / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D006023:Glycoproteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
D000071916:AC133 Antigen; C541116:ACTA2 protein, human; D000199:Actins; D015703:Antigens, CD; D015415:Biomarkers; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018925:Chemokines; C506018:EDA protein, human; D053331:Ectodysplasins; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606025:Prom1 protein, rat; D000804:Angiotensin II; D003094:Collagen