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Mesenchymal stem cell-derived inflammatory fibroblasts mediate interstitial fibrosis in the aging heart

JoAnn Trial1, Mark L Entman2, Katarzyna A Cieslik1

  • 1Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, TX, United States.

Journal of Molecular and Cellular Cardiology
|January 1, 2016
PubMed

Insights

Aging heart fibrosis stems from stem cell dysfunction. Aged mesenchymal stem cells (MSCs) differentiate into inflammatory fibroblasts, secreting collagen and inflammatory factors, driving cardiac fibrosis.

Area of Science:

  • Cardiovascular Biology
  • Stem Cell Biology
  • Aging Research

Background:

  • Pathologic fibrosis in aging hearts is linked to resident mesenchymal stem cells (MSCs).
  • Aging impairs MSC stemness and promotes differentiation into dysfunctional inflammatory fibroblasts.
  • These aged fibroblasts contribute to cardiac fibrosis and inflammation.

Purpose of the Study:

  • To investigate the role of aging resident mesenchymal stem cells (MSCs) in cardiac fibrosis.
  • To identify molecular mechanisms driving fibroblast dysfunction in aging hearts.
  • To explore potential therapeutic targets for age-related cardiac fibrosis.

Main Methods:

  • Analysis of resident mesenchymal stem cells (MSCs) from aging mouse hearts.
  • Characterization of fibroblast differentiation and secretory profiles.
  • Investigation of the farnesyltransferase (FTase)-Ras-Erk pathway.

Main Results:

  • Aging MSCs exhibit reduced stemness and aberrant differentiation into inflammatory fibroblasts.
  • These fibroblasts secrete elevated collagen type 1 (Col1), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6).
  • The FTase-Ras-Erk pathway mediates transcriptional activation of these fibrotic and inflammatory factors.
  • Defects are specific to cardiac MSCs, not bone wall MSCs (BW-MSCs).

Conclusions:

  • Dysfunctional aging cardiac MSCs drive fibrosis through inflammatory fibroblast activation.
  • The FTase-Ras-Erk pathway is a key regulator of this process.
  • Targeting this pathway may offer novel therapeutic strategies for age-related cardiac fibrosis.
Keywords:
AgingFibrocyteInflammatory fibroblastMSCMyeloid fibroblastsRasGrf1

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