Defective myofibroblast formation from mesenchymal stem cells in the aging murine heart rescue by activation of the AMPK pathway

Am J Pathol. 2011 Oct;179(4):1792-806. doi: 10.1016/j.ajpath.2011.06.022. Epub 2011 Aug 3.


Aged mice in a murine model of myocardial infarction exhibit less effective myocardial repair. We hypothesized that the deficiency arises from altered lineage choice of endogenous mesenchymal stem cells (MSCs) and faulty maturation of myofibroblasts. Examination of cardiac MSCs revealed a substantial reduction in the pluripotency marker Nanog in cells from aged mice. In addition, the aged MSCs demonstrated a redirected lineage choice that favored adipocytic commitment over fibroblast or myofibroblast differentiation. Fibroblasts derived from aged MSCs demonstrated reduced expression of transforming growth factor-β (TGF-β) receptors I and II and diminished SMAD3 phosphorylation, associated with attenuated contractility and migration. Overexpression of constitutively active TGF-β receptor I in aged cardiac fibroblasts ameliorated their defective motility but did not improve their contractility. Culturing of MSCs and fibroblasts with AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside) to activate adenosine monophosphate-activated kinase resulted in TGF-β-dependent development of myofibroblasts with markedly enhanced contractility despite no reduction in adipocytic commitment or increased expression of TGF-β receptors and SMAD3 phosphorylation. The data suggest an adenosine monophosphate-activated kinase-dependent gain of function as mediated by phosphorylation of TGF-β-activated kinase 1 and p38 mitogen-activated protein kinase, which amplifies the response to TGF-β1 via a non-canonical pathway, thus compensating for the reduced expression of TGF-β receptors.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aging / drug effects
  • Aging / pathology*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation / drug effects
  • Cell Lineage / drug effects
  • Cell Separation
  • Enzyme Activation / drug effects
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / drug effects
  • Myocardium / enzymology
  • Myocardium / pathology*
  • Myofibroblasts / drug effects
  • Myofibroblasts / enzymology*
  • Myofibroblasts / pathology*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Ribonucleotides / pharmacology
  • Signal Transduction* / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Biomarkers
  • Receptors, Transforming Growth Factor beta
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide