The Alchemist's Nightmare: Might Mesenchymal Stem Cells That Are Recruited to Repair the Injured Heart Be Transformed Into Fibroblasts Rather Than Cardiomyocytes?

Circulation. 2018 May 8;137(19):2068-2073. doi: 10.1161/CIRCULATIONAHA.117.032190.


The injection of mesenchymal stem cells into the injured myocardium to induce cardiac regeneration has yielded disappointing results, conceivably because cells with cardioreparative potential must be supplied for long periods of time to produce a salutary effect. Accordingly, investigators have devised ways of directing such cells to the heart on an ongoing basis: by enhancing the action of endogenous peptides that function as cardiac homing signals (eg, stromal cell-derived factor-1). Stromal cell-derived factor-1 is released during acute cardiac injury and heart failure, but it has a short half-life because of degradation by dipeptidyl peptidase-4. Inhibition of dipeptidyl peptidase-4 potentiates the actions of stromal cell-derived factor-1 and, theoretically, could enhance cardiac recovery. However, in large-scale trials in patients with type 2 diabetes mellitus, dipeptidyl peptidase-4 inhibitors have not reduced the risk of atherosclerotic ischemic events, and they have unexpectedly increased the risk of heart failure, most probably heart failure with a preserved ejection fraction. Such an outcome might be explained if the channeling of mesenchymal stem cells to the heart by the actions of stromal cell-derived factor-1 (especially from nearby adipose tissue) were followed by the transformation of these cells into fibroblasts rather than cardiomyocytes. This concern has been supported by experimental studies; the resulting fibrosis would be expected to exacerbate the pathophysiological derangements that lead to heart failure with a preserved ejection fraction. Given the widespread use of dipeptidyl peptidase-4 inhibitors, the possibility that these drugs potentiate the cardiac homing of mesenchymal stem cells that cause myocardial fibrosis (rather than repair) warrants further study.

Keywords: cardiac regeneration; dipeptidyl peptidase-4 inhibitors; mesenchymal stem cells; stromal cell-derived factor-1.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Chemokine CXCL12 / metabolism
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetic Cardiomyopathies / etiology*
  • Diabetic Cardiomyopathies / metabolism
  • Diabetic Cardiomyopathies / pathology
  • Diabetic Cardiomyopathies / physiopathology
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects*
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis
  • Heart Failure / chemically induced*
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Humans
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Risk Factors


  • CXCL12 protein, human
  • Chemokine CXCL12
  • Dipeptidyl-Peptidase IV Inhibitors