Gene expression of colony-stimulating factors and stem cell factor after myocardial infarction in the mouse

Stem cell factor (SCF) and its receptor c-kit have been implicated in inflammation, tissue remodeling, and fibrosis. Ingenuity Integrated Pathway Analysis of gene expression array data sets showed an upregulation of SCF transcripts in idiopathic pulmonary fibrosis (IPF) lung biopsies compared with tissue from nonfibrotic lungs that are further increased in rapid progressive disease. SCF248, a cleavable isoform of SCF, was abundantly and preferentially expressed in human lung fibroblasts and fibrotic mouse lungs relative to the SCF220 isoform. In fibroblast-mast cell coculture studies, blockade of SCF248 using a novel isoform-specific anti-SCF248 monoclonal antibody (anti-SCF248), attenuated the expression of COL1A1, COL3A1, and FN1 transcripts in cocultured IPF but not normal lung fibroblasts. Administration of anti-SCF248 on days 8 and 12 after bleomycin instillation in mice significantly reduced fibrotic lung remodeling and col1al, fn1, acta2, tgfb, and ccl2 transcript expression. In addition, bleomycin increased numbers of c-kit+ mast cells, eosinophils, and ILC2 in lungs of mice, whereas they were not significantly increased in anti-SCF248-treated animals. Finally, mesenchymal cell-specific deletion of SCF significantly attenuated bleomycin-mediated lung fibrosis and associated fibrotic gene expression. Collectively, these data demonstrate that SCF is upregulated in diseased IPF lungs and blocking SCF248 isoform significantly ameliorates fibrotic lung remodeling in vivo suggesting that it may be a therapeutic target for fibrotic lung diseases.

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Abstract 1504: Increased Expression of Stem Cell Factor and its Receptor Following LVAD: A Potential Novel Target for Therapeutic Interventions In Heart Failure

Circulation ◽

10.1161/circ.116.suppl_16.ii_310-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Jama Jahanyar ◽

Keith A Youker ◽

George P Noon ◽

Guillermo Torre-Amione ◽

Michael M Koerner ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Stem Cell ◽

In Situ Hybridization ◽

Mast Cells ◽

Cardiac Remodeling ◽

Stem Cell Factor ◽

Therapeutic Interventions ◽

Circulatory Support

Introduction: Previous studies have demonstrated the involvement of mast cells (MCs) in cardiac remodeling during heart failure. LVADs cause an influx of MCs into the failing heart, but the underlying mechanism is unknown. We hypothesize that stem cell factor (SCF) induces migration of MCs to the heart. This study investigates the potential role of SCF and its receptor (C-Kit) in promoting the recruitment of stem cell derived MCs during heart failure and following LVAD support. Methods: Myocardial samples were collected from 10 patients undergoing LVAD implantation (Pre-LVAD) paired with samples taken at the time of heart transplantation (Post-LVAD). Biopsies of 4 normal hearts served as controls. We assessed gene expression of SCF and C-Kit. Additionally, we stained for SCF, C-Kit and tryptase protein and utilized In-situ hybridization to determine the origin of SCF. Results: Real-time PCR: SCF mRNA is significantly increased (P<0.01) following mechanical circulatory support as compared to paired heart failure tissue. C-Kit mRNA was significantly increased post-LVAD, as compared to normal tissues (p<0.05). Immunohistochemistry: The C-Kit protein was only expressed on cardiac mast cells. In-Situ hybridization: SCF mRNA was found in endothelial cells, myocytes and interstitial cells. This was confirmed by antibody staining for the SCF protein. Conclusions: LVADs cause an increase of SCF and C-Kit gene expression during unloading. SCF appears to be an important mechanism for the recruitment and maturation of MCs involved in cardiac remodeling, and we suggest that pharmacologic or biologic modification of SCF may provide a new therapeutic path for heart failure treatment.

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