Preconditioning by Mitochondrial Reactive Oxygen Species Improves the Proangiogenic Potential of Adipose-Derived Cells-Based Therapy
ABSTRACT Transplantation of adipose-derived stroma cells (ADSCs) stimulates neovascularization after experimental ischemic injury. ADSC proangiogenic potential is likely mediated by their ability to differentiate into endothelial cells and produce a wide array of angiogenic and antiapoptotic factors. Mitochondrial reactive oxygen species (ROS) have been shown to control ADSC differentiation. We therefore hypothesized that mitochondrial ROS production may change the ADSC proangiogenic properties.
The use of pharmacological strategies (mitochondrial inhibitors, antimycin, and rotenone, with or without antioxidants) allowed us to specifically and precisely modulate mitochondrial ROS generation in ADSCs. We showed that transient stimulation of mitochondrial ROS generation in ADSCs before their injection in ischemic hindlimb strongly improved revascularization and the number of ADSC-derived CD31-positive cells in ischemic area. Mitochondrial ROS generation increased the secretion of the proangiogenic and antiapoptotic factors, VEGF and HGF, but did not affect ADSC ability to differentiate into endothelial cells, in vitro. Moreover, mitochondrial ROS-induced ADSC preconditioning greatly protect ADSCs against oxidative stress-induced cell death.
Our study demonstrates that in vitro preconditioning by moderate mitochondrial ROS generation strongly increases in vivo ADSC proangiogenic properties and emphasizes the crucial role of mitochondrial ROS in ADSC fate.
- SourceAvailable from: Maria Giovanna Scioli
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- "Further studies are needed to investigate if the chronic insulin resistance and high levels of circulating insulin may contribute to adipose tissue remodeling by ROS-mediated reduction of resident ASCs in vivo. Under normal conditions, ASCs contribute to tissue regeneration and angiogenesis through the release of angiogenic growth factors and endothelial differentiation (Carrière et al., 2009). It is possible to hypothesize that the negative effect of the chronic exposure to high insulin levels on ASC survival is partially responsible for the impaired healing of ulcers, as described in diabetic patients (Aghdam et al., 2012). "
ABSTRACT: Homeostasis of adipose tissue requires highly coordinated response between circulating factors and cell population. Human adult adipose tissue-derived stem cells (ASCs) display multiple differentiation properties and are sensitive to insulin stimulation. Insulin resistance and high level of circulating insulin characterize patients with type 2 diabetes and obesity. At physiological concentration, insulin promoted proliferation and survival of ASCs in vitro, whereas high insulin level induced their dose-dependent proliferative arrest and apoptosis. Insulin-induced apoptotic commitment depended on the down-regulation of Erk-1, insulin growth factor-1 receptor (IGF-1R), and fibroblast growth factor receptor-1 (FGFR-1)-mediated signaling. Specific inhibition of Erk-1/2, IGF-1R, and FGFR activity promoted ASC apoptosis but did not increase insulin effects, whereas EGFR and ErbB2 inhibition potentiated insulin-induced apoptosis. FGFRs and EGFR inhibition reduced ASC adipogenic differentiation, whereas Erk-1/2 and IGF-1R inhibition was ineffective. Insulin-induced apoptosis associated to reactive oxygen species (ROS) accumulation and inhibition of NADPH oxidase 4 (Nox4) activity prevented ASC apoptosis. Moreover, specific inhibition of Erk-1/2, IGF-1R, and FGFR-1 activity promoted ROS generation and this effect was not cumulative with that of insulin alone. Our data indicate that insulin concentration is a critical regulatory switch between proliferation and survival of ASCs. High insulin level-induced apoptotic machinery involves Nox4-generated oxidative stress and the down-regulation of a complex receptor signaling, partially distinct from that influencing adipogenic differentiation of ASCs. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.Journal of Cellular Physiology 12/2014; 229(12). DOI:10.1002/jcp.24667 · 3.87 Impact Factor
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- "Rotenone Complex I inhibitor, ischemic tolerance  Antimycin A Complex III inhibitor, ischemic tolerance  Diazoxide kATP channel opener, ischemic tolerance  Cyanide Complex IV inhibitor, ischemic tolerance  Cobalt chloride Chemical hypoxia/HIF-1 activation   Carbon monoxide ROS-mediated prevention of apoptosis  Isoflurane Induction of pre-and postconditioning   Short episodes of ischemia Ischemic tolerance    Hypoxia/intermittent hypoxia Ischemic tolerance   Hyperoxia Ischemic tolerance   Hyperthermal stress Ischemic tolerance  Hypothermal stress Ischemic tolerance  Remote preconditioning Ischemic tolerance    Physical exercise Production of beneficial ROS  Hydrogen peroxide Ischemic tolerance   Ozone Ischemic tolerance   Beneficial effect of a cholesterol oxidation product 24-S-hydroxycholesterol (24-SOHC) is endogenously produced in the brain and plays an important role in brain cholesterol homeostasis. Okabe et al. recently showed that 24-SOHS could elicit an adaptive response in human neuroblastoma SH-SY5Y cells . "
ABSTRACT: It is now well established that reactive oxygen species (ROS), reactive nitrogen species (RNS), and a basal level of oxidative stress are essential for cell survival. It is also well known that while severe oxidative stress often leads to widespread oxidative damage and cell death, a moderate level of oxidative stress, induced by a variety of stressors, can yield great beneficial effects on adaptive cellular responses to pathological challenges in aging and aging-associated disease tolerance such as ischemia tolerance. Here in this review, I term this moderate level of oxidative stress as positive oxidative stress, which usually involves imprinting molecular signatures on lipids and proteins via formation of lipid peroxidation by-products and protein oxidation adducts. As ROS/RNS are short-lived molecules, these molecular signatures can thus execute the ultimate function of ROS/RNS. Representative examples of lipid peroxidation products and protein oxidation adducts are presented to illustrate the role of positive oxidative stress in a variety of pathological settings, demonstrating that positive oxidative stress could be a valuable prophylactic and/or therapeutic approach targeting aging and aging-associated diseases.01/2014; 2. DOI:10.1016/j.redox.2014.01.002
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ABSTRACT: Adipose tissue is the final tissue to develop and is strongly involved in energy homeostasis. It can represent up to 50% of body weight in obesity. Beside its metabolic role, endocrine functions appeared to play a key role in interconnecting adipose tissue with other tissues of the organism and in numerous physiological functions. The presence of adipocyte progenitors has long been demonstrated throughout life in the stromal fraction of adipose tissue. Now, it appears that these cells are multipotent and share numerous features with mesenchymal stem cells (MSC) derived from bone marrow. They also display some specificities and a strong pro-angiogenic potential. Altogether, these data emphasize the need to reconsider the potential of adipose tissue. Moreover, since fat pads are easy to sample, numerous and promising perspectives are now opening up in regenerative medicine, particularly in ischemic situations.Current Stem Cell Research & Therapy 11/2009; 5(2):141-4. DOI:10.2174/157488810791268546 · 2.86 Impact Factor