Understanding mechanisms of the umbilical cord-derived multipotent mesenchymal stromal cell-mediated recovery enhancement in rat model of limb ischemia

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Abstract

Umbilical cord-derived multipotent mesenchymal stromal cells (UC-MMSCs) are considered as a strong candidate for cell therapy of lower limb ischemia. Sustained calf muscle ischemia with aseptic inflammatory response was induced in Sprague-Dawley rats by excision of femoral and popliteal arteries. uC-MSCs were injected into the calf muscle on day 7 after surgery. The animals were sacrificed on days 3, 10, and 30 after transplantation. Animals responded to the transplantation by temporary improvement in their locomotor function as assessed by the rota-rod performance test. Measured size of the lesions was significantly smaller in the experimental group than in the control group at all time points throughout the observation. The transplantation stimulated angiogenic processes on day 10 after transplantation. Living transplanted cells were traced for up to 30 days after transplantation, during which time they migrated to the damaged area to be partially eliminated by host macrophages; none of them differentiated into endothelial or smooth muscle cells of blood vessels. Additionally, the transplantation led to the predominance of activated pro-angiogenic and anti-inflammatory M2 macrophages by inhibiting the CD68+ macrophage infiltration and stimulating the CD206+ macrophage activation at the site of injury. A single intramuscular injection of allogeneic umbilical cord-derived mesenchymal stromal cells reproducibly facilitated recovery of structural and functional properties of surgically ischemized calf muscles in a rat. No differentiation of the transplanted cells in vivo was observed. The transplantation negatively regulated inflammation and enhanced tissue repair chiefly by modulating local patterns of macrophage activation.

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About the authors

I. V Arutyunyan

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Scientific Research Institute of Human Morphology

TKh. Fatkhudinov

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Peoples' Friendship University of Russia

Email: fatkhudinov@gmail.com

A. V Elchaninov

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Scientific Research Institute of Human Morphology

A. V Makarov

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; N.I. Pirogov Russian National Research Medical University

OA. Vasyukova

Scientific Research Institute of Human Morphology

N. Y Usman

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

M. V Marey

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

M. A Volodina

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

E. Y Kananykhina

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Scientific Research Institute of Human Morphology

A. V Lokhonina

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

G. B Bolshakova

Scientific Research Institute of Human Morphology

D. V Goldshtein

Research Centre of Medical Genetics

G. T Sukhikh

V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

References

  1. Norgren L., Hiatt W.R., Harris K.A. et al. TASC II section F on revascularization in PAD. J. Endovasc. Ther. 2007; 14(5): 743-4.
  2. The Trial Register, https://clinicaltrials.gov/Accessed 04 September 2017.
  3. Ishikane S., Ohnishi S., Yamahara K. et al. Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia. Stem Cells 2008; 26(10): 2625-33.
  4. Kim Y., Kim H., Cho H. et al. Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell. Physiol. Biochem. 2007; 20(6): 867-76.
  5. Iwase T., Nagaya N., Fujii T. et al. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc. Res. 2005; 66(3): 543-51.
  6. Арутюнян И.В., Макаров А.В., Ельчанинов А.В. и соавт. Мультипотентные мезенхимальные стромальные клетки пупочного канатика: биологические свойства и клиническое применение. Гены и клетки 2015; 10(2): 30-8.
  7. Choi M., Lee H.S., Naidansaren P. et al. Proangiogenic features of Wharton's jelly-derived mesenchymal stromal/stem cells and their ability to form functional vessels. Int. J. Biochem. Cell Biol. 2013; 45(3): 560-70.
  8. Liew A., O'Brien T. Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia. Stem Cell Res. Ther. 2012; 3(4): 28.
  9. Kang W.C., Oh P.C., Lee K. et al. Increasing injection frequency enhances the survival of injected bone marrow derived mesenchymal stem cells in a critical limb ischemia animal model. Korean J. Physiol. Pharmacol. 2016; 20(6): 657-67.
  10. Santos Nascimento D., Mosqueira D., Sousa L.M. et al. Human umbilical cord tissue-derived mesenchymal stromal cells attenuate remodeling after myocardial infarction by proangiogenic, antiapoptotic, and endogenous cell-activation mechanisms. Stem Cell Res. Ther. 2014; 5(1): 5.
  11. Sabapathy V., Sundaram B., V M.S. et al. Human Wharton's Jelly Mesenchymal Stem Cells plasticity augments scar-free skin wound healing with hair growth. PLoS One 2014; 9(4): e93726.
  12. Dayan V., Yannarelli G., Billia F. et al. Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction. Basic Res. Cardiol. 2011; 106(6): 1299-310.
  13. Arutyunyan I., Fatkhudinov T., Kananykhina E. et al. Role of VEGF-A in angiogenesis promoted by umbilical cord-derived mesenchymal stromal/stem cells: in vitro study. Stem Cell Res. Ther. 2016; 7: 46.
  14. Арутюнян И.В., Ельчанинов А.В., Фатхудинов Т.Х. и соавт. Элиминация РКН26-меченных ММСК при аллогенной трансплантации. Гены и клетки 2014; 9(3А): 45-52.
  15. Schirmer S., Hoefer I., Buschmann I. Peripheral Hind Limb Ischemia Models. In: Augustin H.G., editor. Methods in Endothelial Cell Biology. Berlin: Springer-Verlag; 2004. p. 197-206.
  16. Laurila J.P., Laatikainen L.E., Castellone M.D. et al. SOD3 reduces inflammatory cell migration by regulating adhesion molecule and cytokine expression. PLoS One 2009; 4(6): e5786.
  17. Rigamonti E., Touvier T., Clementi E. et al. Requirement of inducible nitric oxide synthase for skeletal muscle regeneration after acute damage. J. Immunol. 2013; 190(4): 1767-77.
  18. Pellegrin M., Bouzourène K., Poitry-Yamate C. et al. Experimental peripheral arterial disease: new insights into muscle glucose uptake, macrophage, and T-cell polarization during early and late stages. Physiol. Rep. 2014; 2(2): e00234.
  19. Cunha F.F., Martins L., Martin P.K. et al. A comparison of the reparative and angiogenic properties of mesenchymal stem cells derived from the bone marrow of BALB/c and C57/BL6 mice in a model of limb ischemia. Stem Cell Res. Ther. 2013; 4(4): 86.
  20. Rahman M.M., Subramani J., Ghosh M. et al. CD13 promotes mesenchymal stem cell-mediated regeneration of ischemic muscle. Front. Physi ol. 2014; 4: 402.
  21. Beckermann B.M., Kallifatidis G., Groth A. et al. VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br. J. Cancer 2008; 99(4): 622-31.
  22. Taghavi S., George J.C. Homing of stem cells to ischemic myocardium. Am. J. Transl. Res. 2013; 5(4): 404-11.
  23. Germani A., Di Carlo A., Mangoni A.et al. Vascular endothelial growth factor modulates skeletal myoblast function. Am. J. Pathol. 2003; 163(4): 1417-28.
  24. Wang T., Zhou Y.T., Chen X.N. et al. Putative role of ischemic postconditioning in a rat model of limb ischemia and reperfusion: involvement of hypoxia-inducible factor-1 a expression. Braz. J. Med. Biol. Res. 2014; 47(9): 738-45.
  25. Rissanen T.T., Vajanto I., Hiltunen M.O. et al. Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration. Am. J. Pathol. 2002; 160(4): 1393-403.
  26. Carmeliet P. Angiogenesis in health and disease. Nat. Med. 2003; 9(6): 653-60.
  27. Bronckaers A., Hilkens P., Martens W. et al. Mesenchymal stem/ stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol. Ther. 2014; 143(2): 181-96.
  28. Jiang Q., Ding S., Wu J. et al. Norepinephrine stimulates mobilization of endothelial progenitor cells after limb ischemia. PLoS One 2014; 9(7): e101774.
  29. Ohta N. Umbilical Cord Matrix Stem Cells for Cytotherapy of Breast Cancer. In: Shah K., editor. Stem Cell Therapeutics for Cancer. USA, Hoboken, N.J.: Wiley-Blackwell; 2013. p. 111-26.
  30. Zordan P., Rigamonti E., Freudenberg K. et al. Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration. Cell Death Dis. 2014; 5: e1031.
  31. Contreras-Shannon V., Ochoa O., Reyes-Reyna S.M. et al. Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/- mice following ischemic injury. Am. J. Physiol. Cell Physiol. 2007; 292(2): C953-67.
  32. Gao W.H., Yu J.Y., Li H.M. et al. The Immunomodulatory Effects of Umbilical Cord Mesenchymal Stem Cell in Critical Limb Ischemia Patients. J. Stem Cell Res. Ther. 2016; 6: 349.
  33. Shohara R., Yamamoto A., Takikawa S. et al. Mesenchymal stromal cells of human umbilical cord Wharton's jelly accelerate wound healing by paracrine mechanisms. Cytotherapy 2012; 14(10): 1171-81.
  34. Prockop D.J. Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation. Stem Cells 2013; 31(10): 2042-6.
  35. Fan W., Cheng K., Qin X. et al. mTORC1 and mTORC2 play different roles in the functional survival of transplanted adipose-derived stromal cells in hind limb ischemic mice via regulating inflammation in vivo. Stem Cells 2013; 31(1): 203-14.
  36. Moon M.H., Kim S.Y., Kim Y.J. et al. Human adipose tissue-derived mesenchymal stem cells improve postnatal neovascularization in a mouse model of hindlimb ischemia. Cell. Physiol. Biochem. 2006; 17(5-6): 279-90.
  37. Bréchot N., Gomez E., Bignon M. et al. Modulation of macrophage activation state protects tissue from necrosis during critical limb ischemia in thrombospondin-1-deficient mice. PLoS One 2008; 3(12): e3950.
  38. Wu W.K., Llewellyn O.P., Bates D.O. et al. IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia. Immunobiology 2010; 215(9-10): 796-803.
  39. Jetten N., Verbruggen S., Gijbels M.J. et al. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 2014; 17(1): 109-18.
  40. Spiller K.L., Anfang R.R., Spiller K.J. et al. The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials 2014; 35(15): 4477-88.
  41. Barbay V., Houssari M., Mekki M. et al. Role of M2-like macrophage recruitment during angiogenic growth factor therapy. Angiogenesis 2015; 18(2): 191-200.

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