Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction

Biomaterials. 2015 Aug;60:130-40. doi: 10.1016/j.biomaterials.2015.04.046. Epub 2015 May 16.

Abstract

Stem cell therapy has been proved to be an effective approach to ameliorate the heart remodeling post myocardial infarction (MI). However, poor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating MI. Here, we sought to transplant adipose derived-mesenchymal stem cells (AD-MSCs) with a hydrogel (NapFF-NO), naphthalene covalently conjugated a short peptide, FFGGG, and β-galactose caged nitric oxide (NO) donor, which can release NO molecule in response to β-galactosidase. AD-MSCs, either from transgenic mice that constitutively express GFP and firefly luciferase (Fluc), or express Fluc under the control of VEGFR2 promoter, were co-transplanted with NapFF-NO hydrogel into murine MI models. Improved cell survival and enhanced cardiac function were confirmed by bioluminescence imaging (BLI) and echocardiogram respectively. Moreover, increasing VEGFR2-luc expression was also tracked in real-time in vivo, indicating NapFF-NO hydrogel stimulated VEGF secretion of AD-MSCs. To investigate the therapeutic mechanism of NapFF-NO hydrogel, cell migration assay, paracrine action of AD-MSCs, and histology analysis were carried out. Our results revealed that condition medium from AD-MSCs cultured with NapFF-NO hydrogel could promote endothelial cell migration. Additionally, AD-MSCs showed significant improvement secretion of angiogenic factors VEGF and SDF-1α in the presence of NapFF-NO hydrogel. Finally, postmortem analysis confirmed that transplanted AD-MSCs with NapFF-NO hydrogel could ameliorate heart function by promoting angiogenesis and attenuating ventricular remodeling. In conclusion, NapFF-NO hydrogel can obviously improve therapeutic efficacy of AD-MSCs for MI by increasing cell engraftment and angiogenic paracrine action.

Keywords: Adipose-derived mesenchymal stem cells (AD-MSCs); Angiogenesis; Hydrogel; Molecular imaging; Myocardial infarction; Nitric oxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology
  • Animals
  • Cells, Cultured
  • Delayed-Action Preparations / chemistry
  • Delayed-Action Preparations / metabolism*
  • Galactose / chemistry
  • Galactose / metabolism
  • Heart / drug effects
  • Hydrogel, Polyethylene Glycol Dimethacrylate / chemistry
  • Hydrogel, Polyethylene Glycol Dimethacrylate / metabolism*
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / pathology
  • Myocardial Infarction / therapy*
  • Myocardium / pathology
  • NIH 3T3 Cells
  • Naphthalenes / chemistry
  • Naphthalenes / metabolism
  • Neovascularization, Physiologic
  • Nitric Oxide Donors / administration & dosage*
  • Nitric Oxide Donors / therapeutic use
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Optical Imaging
  • Ventricular Remodeling
  • beta-Galactosidase / metabolism

Substances

  • Delayed-Action Preparations
  • Naphthalenes
  • Nitric Oxide Donors
  • Oligopeptides
  • naphthalene
  • Hydrogel, Polyethylene Glycol Dimethacrylate
  • beta-Galactosidase
  • Galactose