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Mesenchymal stem cell‐derived inflammatory fibroblasts promote monocyte transition into myeloid fibroblasts via an IL‐6‐dependent mechanism in the aging mouse heart
Author(s) -
Cieslik Katarzyna A.,
Trial JoAnn,
Entinan Mark L.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-268136
Subject(s) - mesenchymal stem cell , fibroblast , monocyte , microbiology and biotechnology , biology , chemistry , cancer research , immunology , in vitro , biochemistry
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.—Cieslik, K. A., Trial, J., Entonan, M. L. 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. 29, 3160‐3170 (2015). www.fasebj.org