Absence of NUCKS augments paracrine effects of mesenchymal stem cells-mediated cardiac protection

Exp Cell Res. 2017 Jul 1;356(1):74-84. doi: 10.1016/j.yexcr.2017.04.012. Epub 2017 Apr 12.

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) contribute to myocardial repair after myocardial infarction (MI) by secreting a panel of growth factors and cytokines. This study was to investigate the potential mechanisms of the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS) in regulation of the profiles of BM-MSCs secretion and compare the therapeutic efficacy of NUCKS-/-- and wide type-BM-MSCs (WT-BM-MSCs) on MI. The secretion profiles between NUCKS-/-- and WT-BM-MSCs under hypoxia (1%O2) were analyzed. Gene function analysis showed that compared with WT-BM-MSCs-conditioned medium (CdM), some genes over-presented in NUCKS-/--BM-MSCs-CdM were closely associated with inflammatory response, regulation of cell proliferation, death, migration and secretion. Notably, VEGFa in NUCKS-/--BM-MSCs-CdM was higher than that of WT-BM-MSCs-CdM. WT-BM-MSCs and NUCKS-/--BM-MSCs were transplanted into the peri-infarct region in mice of MI. At 4 weeks after cell transplantation, NUCKS-/-- or WT-BM-MSCs group significantly improved heart function and vessels density and reduced infarction size and apoptosis of cardiomyocytes. Furthermore, NUCKS-/--BM-MSCs provided better cardioprotective effects than WT-BM-MSCs against MI. Our study demonstrates that depletion of NUCKS enhances the therapeutic efficacy of BM-MSCs for MI via regulating the secretion.

Keywords: Mesenchymal stem cells; Myocardial infarction; NF-κB; NUCKS.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cardiotonic Agents
  • Cell Hypoxia / physiology
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Cell- and Tissue-Based Therapy / methods*
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Mice, Knockout
  • Myocardial Infarction / pathology
  • Myocardial Infarction / therapy*
  • Myocytes, Cardiac / physiology*
  • NF-kappa B / metabolism
  • Nuclear Proteins / genetics*
  • Phosphoproteins / genetics*
  • Regeneration / genetics*
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Cardiotonic Agents
  • Culture Media, Conditioned
  • NF-kappa B
  • Nucks protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse