Aging-related decrease of human ASC angiogenic potential is reversed by hypoxia preconditioning through ROS production

Mol Ther. 2013 Feb;21(2):399-408. doi: 10.1038/mt.2012.213. Epub 2012 Oct 16.

Abstract

Adipose stroma/stem cells (ASC) represent an ideal source of autologous cells for cell-based therapy. Their transplantation enhances neovascularization after experimental ischemic injury. Aging is associated with a progressive decrease in the regenerative potential of mesenchymal stem cells (MSCs) from bone marrow. This work aims to determine the aging effect on human ASC capacities. First, we show that aging impairs angiogenic capacities of human ASC (hASC) in a mouse ischemic hindlimb model. Although no change in hASC number, phenotype, and proliferation was observed with aging, several mechanisms involved in the adverse effects of aging have been identified in vitro combining a concomitant decrease in (i) ASC ability to differentiate towards endothelial cells, (ii) secretion of proangiogenic and pro-survival factors, and (iii) oxidative stress. These effects were counteracted by a hypoxic preconditioning that improved in vivo angiogenic capacities of hASC from older donors, while hASC from young donors that have a strong ability to manage hypoxic stress were not. Finally, we identified reactive oxygen species (ROS) generation as a key signal of hypoxia on hASC angiogenic capacities. This study demonstrates for the first time that age of donor impaired angiogenic capacities of hASC in ischemic muscle and change in ROS generation by hypoxic preconditioning reverse the adverse effect of aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Adult
  • Aged
  • Aging / physiology
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cellular Senescence*
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Hindlimb / physiopathology
  • Humans
  • Hypoxia / physiopathology*
  • Ischemia / physiopathology
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neovascularization, Physiologic*
  • Oxidative Stress
  • Phenotype
  • Reactive Oxygen Species / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Young Adult

Substances

  • HGF protein, human
  • Reactive Oxygen Species
  • Transforming Growth Factor beta2
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Hepatocyte Growth Factor