Mesenchymal stem cell-derived inflammatory fibroblasts promote monocyte transition into myeloid fibroblasts via an IL-6-dependent mechanism in the aging mouse heart

FASEB J. 2015 Aug;29(8):3160-70. doi: 10.1096/fj.14-268136. Epub 2015 Apr 17.


Fibrosis in the old mouse heart arises partly as a result of aberrant mesenchymal fibroblast activation. We have previously shown that endogenous mesenchymal stem cells (MSCs) in the aged heart are markedly resistant to TGF-β signaling. Fibroblasts originating from these MSCs retain their TGF-β unresponsiveness and become inflammatory. In current studies, we found that these inflammatory fibroblasts secreted higher levels of IL-6 (3-fold increase, P < 0.05) when compared with fibroblasts derived from the young hearts. Elevated IL-6 levels in fibroblasts derived from old hearts arose from up-regulated expression of Ras protein-specific guanine nucleotide releasing factor 1 (RasGrf1), a Ras activator (5-fold, P < 0.01). Knockdown of RasGrf1 by gene silencing or pharmacologic inhibition of farnesyltransferase (FTase) or ERK caused reduction of IL-6 mRNA (more than 65%, P < 0.01) and decreased levels of secreted IL-6 (by 44%, P < 0.01). In vitro, IL-6 markedly increased monocyte chemoattractant protein-1-driven monocyte-to-myeloid fibroblast formation after transendothelial migration (TEM; 3-fold, P < 0.01). In conclusion, abnormal expression of RasGrf1 promoted production of IL-6 by mesenchymal fibroblasts in the old heart. Secreted IL-6 supported conversion of monocyte into myeloid fibroblasts. This process promotes fibrosis and contributes to the diastolic dysfunction in the aging heart.

Keywords: RasGrf1; fibrosis; transendothelial migration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism*
  • Animals
  • Cells, Cultured
  • Fibroblasts / metabolism*
  • Fibroblasts / physiology
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Heart / physiopathology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Interleukin-6 / metabolism*
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism*
  • Monocytes / physiology
  • Myeloid Cells / metabolism*
  • Myeloid Cells / physiology
  • Transforming Growth Factor beta / metabolism


  • Interleukin-6
  • Transforming Growth Factor beta
  • interleukin-6, mouse