Preconditioning by Mitochondrial Reactive Oxygen Species Improves the Proangiogenic Potential of Adipose-Derived Cells-Based Therapy

Université de Toulouse, UPS, UMR 5241 Métabolisme, Plasticité et Mitochondrie, Toulouse Cedex 4, France.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 06/2009; 29(7):1093-9. DOI: 10.1161/ATVBAHA.109.188318
Source: PubMed


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.

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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). "
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    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 · 3.84 Impact Factor
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    • "Rotenone Complex I inhibitor, ischemic tolerance [86] Antimycin A Complex III inhibitor, ischemic tolerance [86] Diazoxide kATP channel opener, ischemic tolerance [87] Cyanide Complex IV inhibitor, ischemic tolerance [53] Cobalt chloride Chemical hypoxia/HIF-1 activation [88] [89] Carbon monoxide ROS-mediated prevention of apoptosis [61] Isoflurane Induction of pre-and postconditioning [90] [91] Short episodes of ischemia Ischemic tolerance [92] [93] [94] Hypoxia/intermittent hypoxia Ischemic tolerance [37] [95] Hyperoxia Ischemic tolerance [38] [39] Hyperthermal stress Ischemic tolerance [40] Hypothermal stress Ischemic tolerance [41] Remote preconditioning Ischemic tolerance [96] [97] [98] Physical exercise Production of beneficial ROS [50] Hydrogen peroxide Ischemic tolerance [99] [100] Ozone Ischemic tolerance [101] [102] 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 [81]. "
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    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(1). DOI:10.1016/j.redox.2014.01.002
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    • "Mitochondria generate ATP through oxidative phosphorylation and also release multiple signaling molecules, including reactive oxygen species (ROS) and calcium [8], [9], [10]. Recent studies have demonstrated the importance of mitochondrial metabolism in regulating stem cell biology. "
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    ABSTRACT: Human mesenchymal stem cells (MSCs) are adult multipotent stem cells which can be isolated from bone marrow, adipose tissue as well as other tissues and have the capacity to differentiate into a variety of mesenchymal cell types such as adipocytes, osteoblasts and chondrocytes. Differentiation of stem cells into mature cell types is guided by growth factors and hormones, but recent studies suggest that metabolic shifts occur during differentiation and can modulate the differentiation process. We therefore investigated mitochondrial biogenesis, mitochondrial respiration and the mitochondrial membrane potential during adipogenic differentiation of human MSCs. In addition, we inhibited mitochondrial function to assess its effects on adipogenic differentiation. Our data show that mitochondrial biogenesis and oxygen consumption increase markedly during adipogenic differentiation, and that reducing mitochondrial respiration by hypoxia or by inhibition of the mitochondrial electron transport chain significantly suppresses adipogenic differentiation. Furthermore, we used a novel approach to suppress mitochondrial activity using a specific siRNA-based knockdown of the mitochondrial transcription factor A (TFAM), which also resulted in an inhibition of adipogenic differentiation. Taken together, our data demonstrates that increased mitochondrial activity is a prerequisite for MSC differentiation into adipocytes. These findings suggest that metabolic modulation of adult stem cells can maintain stem cell pluripotency or direct adult stem cell differentiation.
    PLoS ONE 10/2013; 8(10):e77077. DOI:10.1371/journal.pone.0077077 · 3.23 Impact Factor
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