Bone marrow-derived cells contribute to fibrosis in the chronically failing heart.
Cardiac fibrosis contributes significantly to the phenotype of the chronically failing heart. It is not clear whether in this setting the fibrosis is contributed by native cardiac fibroblasts or alternatively by recruitment of cells arising from the bone marrow. We aimed to determine the contribution of bone marrow-derived cells to cardiac fibrosis in the failing heart and to investigate potentially contributing cytokines. Bone marrow-derived fibrocyte recruitment to the failing heart was studied in a transgenic (Mst1 mice) model of dilated cardiomyopathy. In conjunction, we examined the role of stromal-derived factor-1 (SDF-1), a key chemoattractant, by assessing myocardial expression and secretion by cardiomyocytes and in clinical samples. Bone marrow-derived cells were recruited in significantly greater numbers in Mst1 versus control mice (P < 0.001), contributing 17 +/- 4% of the total fibroblast load in heart failure. Patients with heart failure had higher plasma levels of SDF-1 than healthy control subjects (P < 0.01). We found that cardiomyocytes constitutively secrete SDF-1, which is significantly up-regulated by angiotensin II. SDF-1 was shown to increases cardiac fibroblast migration by 59% (P < 0.05). Taken together, our data suggest that recruitment of bone marrow-derived cells under the influence of factors, including SDF-1, may play an important role in the pathogenesis of cardiac fibrosis in heart failure.
Chu
Po-Yin
PY
Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Central, Melbourne, VIC 8008, Australia.
Mariani
Justin
J
Finch
Samara
S
McMullen
Julie R
JR
Sadoshima
Junichi
J
Marshall
Tanneale
T
Kaye
David M
DM
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002311:Cardiomyopathy, Dilated / Q000473:pathology; D017690:Cell Transplantation; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology*; D005434:Flow Cytometry; D006333:Heart Failure / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse