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Transplantation of Mesenchymal Cells Improves Peripheral Limb Ischemia in Diabetic Rats

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An Erratum to this article was published on 20 April 2014

Abstract

Adipose tissue-derived mesenchymal stromal cells (ADSCs) are a prominent cellular source for regenerative medicine. We tested whether transplantation of ADSCs into the ischemic muscular tissue of diabetic animals would attenuate impaired cell metabolism and microcirculatory function. We induced unilateral hind limb ischemia in male streptozotocin-treated rats and nondiabetic controls. One day after femoral artery ligation, six rats per group were intramuscularly injected allogeneic ADSCs (106–107–108 cells/mL); or conditioned media from ADSC cultures (CM); or saline; or allogeneic fibroblasts (107 cells/mL); or nonconditioned medium. Rats underwent magnetic resonance angiography; short time inversion recovery (STIR) edema-weighed imaging; proton MR spectroscopy (1H-MRS); immunoblotting and immunofluorescence on both hind limbs for 4 weeks. T1-weighted and STIR images showed tissue swelling and signal hyperintensity, respectively, in the ischemic tissue. The mean total ratio of creatine/water for the occluded limbs was significantly lower than for the nonoccluded limbs in both nondiabetic and diabetic rats. ADSC and CM groups had greater recovery of tCr/water in ischemic limbs in both diabetic and nondiabetic rats, with increased expression of α-sarcomeric actinin, vascular endothelial growth factor and hepatocyte growth factor, as well as increased vessel density. ADSCs improve ischemic muscle metabolism and increase neovasculogenesis in diabetic rats.

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References

  1. Barcelos, L. S., Duplaa, C., et al. (2009). Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling. Circulation Research, 104(9), 1095–1102.

    Article  CAS  Google Scholar 

  2. Beckman, J. A., Creager, M. A., et al. (2002). Diabetes and atherosclerosis: Epidemiology, pathophysiology, and management. The Journal of the American Medical Association, 287, 2570–2581.

    Article  CAS  Google Scholar 

  3. Butler, T. L., Au, C. G., et al. (2006). Cardiac aquaporin expression in humans, rats, and mice. American Journal of Physiology Heart and Circulatory Physiology, 291(2), H705–H713.

    Article  CAS  Google Scholar 

  4. Golomb, B. A., Dang, T. T., et al. (2006). Peripheral arterial disease: Morbidity and mortality implications. Circulation, 114, 688–699.

    Article  Google Scholar 

  5. Hazarika, S., Dokun, A. O., et al. (2007). Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: Differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1. Circulation Research, 101(9), 948–956.

    Article  CAS  Google Scholar 

  6. Hong, S. J., Jia, S. X., et al. (2013). Topically delivered adipose derived stem cells show an activated-fibroblast phenotype and enhance granulation tissue formation in skin wounds. PLoS One, 8(1), e55640.

    Article  CAS  Google Scholar 

  7. Kikutani, H., & Makino, S. (1992). The murine autoimmune diabetes model: NOD and related strains. Advances in Immunology, 51, 285–322.

    Article  CAS  Google Scholar 

  8. Kinnaird, T., Stabile, E., et al. (2004). Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Research, 94(5), 678–685.

    Article  CAS  Google Scholar 

  9. Li, X. D., Yang, Y. J., et al. (2012). The cardioprotection of simvastatin in reperfused swine hearts relates to the inhibition of myocardial edema by modulating aquaporins via the PKA pathway. International Journal of Cardiology, 167, 2657–2666.

    Article  Google Scholar 

  10. Lian, Q., Zhang, Y., et al. (2010). Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation, 121(9), 1113–1123.

    Article  Google Scholar 

  11. Madonna, R., & De Caterina, R. (2008). In vitro neovasculogenic potential of resident adipose tissue precursors. American Journal of Physiology. Cell Physiology, 295(5), C1271–C1280.

    Article  CAS  Google Scholar 

  12. Madonna, R., Delli Pizzi, S., et al. (2012). Non-invasive in vivo detection of peripheral limb ischemia improvement in the rat after adipose tissue-derived stromal cell transplantation. Circulation Journal, 76(6), 1517–1525.

    Article  CAS  Google Scholar 

  13. Madonna, R., Geng, Y. J., et al. (2009). Adipose tissue-derived stem cells: Characterization and potential for cardiovascular repair. Arteriosclerosis, Thrombosis, and Vascular Biology, 29(11), 1723–1729.

    Article  CAS  Google Scholar 

  14. Madonna, R., Montebello, E., et al. (2010). NA+/H+ exchanger 1- and aquaporin-1-dependent hyperosmolarity changes decrease nitric oxide production and induce VCAM-1 expression in endothelial cells exposed to high glucose. International Journal of Immunopathology and Pharmacology, 23(3), 755–765.

    CAS  Google Scholar 

  15. Madonna, R., Renna, F. V., et al. (2010). Age-dependent impairment of number and angiogenic potential of adipose tissue-derived progenitor cells. European Journal of Clinical Investigation, 41(2), 126–133.

    Article  Google Scholar 

  16. Madonna, R., Taylor, D. A., et al. (2013). Transplantation of mesenchymal cells rejuvenated by the overexpression of telomerase and myocardin promotes revascularization and tissue repair in a murine model of hindlimb ischemia. Circulation Research, 113(7), 902–914.

    Article  CAS  Google Scholar 

  17. Rahman, S., Rahman, T., et al. (2007). Diabetes-associated macrovasculopathy: Pathophysiology and pathogenesis. Diabetes, Obesity & Metabolism, 9, 767–780.

    Article  CAS  Google Scholar 

  18. Rees, D. A., & Alcolado, J. C. (2005). Animal models of diabetes mellitus. Diabetic Medicine, 22(4), 359–370.

    Article  CAS  Google Scholar 

  19. Rivard, A., Silver, M., et al. (1999). Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. American Journal of Pathology, 154(2), 355–363.

    Article  CAS  Google Scholar 

  20. Roguin, A., Nitecki, S., et al. (2003). Vascular endothelial growth factor (VEGF) fails to improve blood flow and to promote collateralization in a diabetic mouse ischemic hindlimb model. Cardiovasc Diabetol, 2, 18.

    Article  Google Scholar 

  21. Stehouwer, C. D., Lambert, J., et al. (1997). Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovascular Research, 34(1), 55–68.

    Article  CAS  Google Scholar 

  22. Tanaka, K., Yamamoto, Y., et al. (2010). The cyclooxygenase-2 selective inhibitor, etodolac, but not aspirin reduces neovascularization in a murine ischemic hind limb model. European Journal of Pharmacology, 627(1–3), 223–228.

    Article  CAS  Google Scholar 

  23. Tang, G. L., Chang, D. S., et al. (2005). The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia. Journal of Vascular Surgery, 41(2), 312–320.

    Article  Google Scholar 

  24. Umenishi, F., & Schrier, R. W. (2003). Hypertonicity-induced aquaporin-1 (AQP1) expression is mediated by the activation of MAPK pathways and hypertonicity-responsive element in the AQP1 gene. Journal of Biological Chemistry, 278(18), 15765–15770.

    Article  CAS  Google Scholar 

  25. Verkman, A. S. (2008). Mammalian aquaporins: Diverse physiological roles and potential clinical significance. Expert Reviews in Molecular Medicine, 10, e13.

    Article  CAS  Google Scholar 

  26. Waters, R. E., Terjung, R. L., et al. (2004). Preclinical models of human peripheral arterial occlusive disease: Implications for investigation of therapeutic agents. Journal of Applied Physiology, 97(2), 773–780.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Italian Ministry of University and Scientific Research (PRIN), from CARIPLO Foundation, Milan, and from the Istituto Nazionale Ricerche Cardiovascolari (INRC), to RDC and RM.

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None.

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Authors and Affiliations

  1. Department of Neuroscience and Imaging, “G. d’Annunzio” University, Chieti, Italy

    Rosalinda Madonna, Stefano Delli Pizzi, Armando Tartaro & Raffaele De Caterina

  2. Institute for Advanced Biomedical Technologies, “G. d’Annunzio” University Foundation, Chieti, Italy

    Stefano Delli Pizzi & Armando Tartaro

  3. Cardiology Division and Center of Excellence on Aging, “G. d’Annunzio” University, Chieti, Italy

    Rosalinda Madonna & Raffaele De Caterina

  4. Institute of Cardiology, “G. d’Annunzio” University Chieti, C/o Ospedale SS. Annunziata, Via dei Vestini, 66013, Chieti, Italy

    Raffaele De Caterina

Authors
  1. Rosalinda Madonna
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  2. Stefano Delli Pizzi
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  3. Armando Tartaro
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  4. Raffaele De Caterina
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Corresponding author

Correspondence to Raffaele De Caterina.

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Madonna, R., Pizzi, S.D., Tartaro, A. et al. Transplantation of Mesenchymal Cells Improves Peripheral Limb Ischemia in Diabetic Rats. Mol Biotechnol 56, 438–448 (2014). https://doi.org/10.1007/s12033-014-9735-3

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  • DOI: https://doi.org/10.1007/s12033-014-9735-3

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