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1 Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
2 Cardiothoracic Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, United States
3 Genomic Sciences, Allegheny General Hospital, Pittsburgh, Pennsylvania, United States
4 Pathology, Allegheny General Hospital, Pittsburgh, Pennsylvania, United States
5 Department of Pediatrics, Allegheny General Hospital, Pittsburgh, Pennsylvania, United States
6 Pittsburgh, Pennsylvania, United States; Cardiothoracic Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: laframboisewa{at}upmc.edu.
Cardiac fibroblasts impact myocardial development and remodeling through intercellular contact with cardiomyocytes but less is known about non-contact, profibrotic signals whereby fibroblasts alter cardiomyocyte behavior. Fibroblasts and cardiomyocytes were harvested from newborn rat ventricles and separated by serial digestion and gradient centrifugation. Cardiomyocytes were cultured in 1) standard media, 2) standard media diluted 1:1 with phosphate buffered saline (PBS) or 3) standard media diluted 1:1 with media conditioned >72 hours by cardiac fibroblasts. Serum concentrations were held constant under all media conditions and complete media exchange performed daily. Cardiomyocytes began contracting within 24 hours at clonal or mass densities with <5% of cells expressing vimentin. Immunocytochemical analysis revealed progressive expression of a-smooth muscle actin in cardiomyocytes after 24 hours in all conditions. Only cardiomyocytes in fibroblast-conditioned media stopped contracting by 72 hours. There was a significant, sustained increase in vimentin expression specific to these cultures (X± S.D.: conditioned=46.3±6.0% vs control=5.3±2.9%, p<0.00025) typically with cardiac myosin heavy chain coexpression. Proteomics assays revealed 10 cytokines (VEGF, GRO/KC, MCP-1, leptin, MIP-1
, IL-6, IL-10, IL-12p70, IL-17, TNF-) at or below detection levels in unconditioned media that were significantly elevated in fibroblast-conditioned media. Latent-TGF-
and RANTES were present in unconditioned media but rose to higher levels in conditioned media. Only GM-CSF was present above threshold levels in standard media but decreased by fibroblast conditioning. These data indicated that, under the influence of fibroblast-conditioned media, cardiomyocytes exhibited marked hypertrophy, diminished contractile capacity and phenotype plasticity distinct from the dedifferentiation program present under standard culture conditions.
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