In vivo effects of allogeneic mesenchymal stem cells in a rat model of acute ischemic kidney injury

Document Type: Original Article

Authors

1 Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Vascular Surgery, Vascular and Endovascular Surgery Research Center, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

4 Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

5 Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture and Research (ACECR), Mashhad Branch, Mashhad, Iran

6 Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

7 Neurogenic Inflammation Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

8 Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran

Abstract

Objective(s): Renal ischemia-reperfusion injury (IRI) as a severe condition of acute kidney injury (AKI) is the most common clinical problem with high mortality rates of 35-60% deaths in hospital. Mesenchymal stem cells (MSC) due to unique regenerative characteristics are ideal candidates for the treatment of the ischemic injuries. This work is focused on the administration of MSC to IRI-induced AKI Wistar rats and evaluating their significance in AKI treatment.
Material and Methods: Animals underwent surgical procedure and AKI was induced by 40 min bilateral renal pedicle clamping. Immediately after reperfusion, 2×106 rat bone marrow derived MSCs were injected via intra-parenchymal or intra-aortic route.
Results: Animals subjected to AKI after days 1 and 3 showed significant increase in the serum creatinine and blood urea nitrogen (BUN) concentration along with a declined glomerular filtration rate (GFR) when compared with non-ischemic animals. On the other hand, treated animals showed a significant enhanced regeneration as compared to ischemic animals in both administration route groups.
Conclusion: According to the results concluded from the renoprotective effects of MSC in IRI/AKI, MSCs could be considered as promising therapeutic approach for AKI in clinical applications.

Keywords

Main Subjects


1. Rewa O, Bagshaw SM. Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol 2014;10:193–207.
2. Taal M, Brenner B, Rector F. Brenner & Rector’s the kidney. 9th edition. Philadelphia, PA: Elsevier/Saunders; 2012.
3. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. AJP Ren Physiol 2005;289:31–42.
4. Lee P-Y, Chien Y, Chiou G-Y, Lin C-H, Chiou C-H, Tarng D-C. Induced pluripotent stem cells without c-Myc attenuate acute kidney injury via down regulating the signaling of oxidative stress and inflammation in ischemia-reperfusion rats. Cell Transplant 2012;21:2569–2585.
5. Reule S, Gupta S. Kidney regeneration and resident stem cells. Organogenesis 2011;7:135–139.
6. Tian H, Lu Y, Shah SP, Wang Q, Hong S. 14S,21R-dihydroxy-docosahexaenoic acid treatment enhances mesenchymal stem cell amelioration of renal ischemia/reperfusion injury. Stem Cells Dev 2012;21:1187–1199.
7. Neshati V, Mollazadeh S, Fazly Bazzaz BS, Iranshahi M, Mojarrad M, Naderi-Meshkine H, et al. Cardiogenic effects of characterized Geum urbanum extracts on adipose-derived human mesenchymal stem cells. Biochem Cell Biol 2018; 24. 10.1139/bcb-2017-0313. [Epub ahead of print]
8. Mollazadeh S, Neshati V, Fazly Bazzaz BS, Iranshahi M, Mojarrad M, Naderi-Meshkine H, et al. Standardized Sophora pachycarpa root extract enhances osteogenic differentiation in adipose-derived human mesenchymal stem cells. Phytother Res 2017;31:792-800.
9. Togel F, Westenfelder C. The role of multipotent marrow stromal cells (MSCs) in tissue regeneration. Organogenesis 2011;7:96-100.
10. Shahzad U, Li G, Zhang Y, Yau TM. Transmyocardial revascularization induces mesenchymal stem cell engraftment in infarcted hearts. Ann Thorac Surg 2012;94:556-5562.
11. Nayan M, Paul A, Chen G, Chiu RCJ, Prakash S, Shum-Tim D. Superior therapeutic potential of young bone marrow mesenchymal stem cells by direct intramyocardial delivery in aged recipients with acute myocardial infarction: in vitro and in vivo investigation. J Tissue Eng 2011.
12. Neshati V, Mollazadeh S, Fazly Bazzaz BS, de Vries AAF, Mojarrad M, Naderi-Meshkine H, et al. MicroRNA-499a-5p promotes differentiation of human bone marrow-derived mesenchymal stem cells to cardiomyocytes. Appl Biochem Biotechnol 2018; 24. doi: 10.1007/s12010-018-2734-2. [Epub ahead of print]
13. Mathiasen AB, Jorgensen E, Qayyum AA, Haack-Sorensen M, Ekblond A, Kastrup J. Rationale and design of the first randomized, double-blind, placebo-controlled trial of intramyocardial injection of autologous bone-marrow derived Mesenchymal Stromal Cells in chronic ischemic Heart Failure (MSC-HF Trial). Am Heart J 2012;164:285-291.
14. Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Yin Z, et al. Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med 2012;10:3.
15. Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 2003 Dec;48:3464-3474.
16. Perasso L, Cogo CE, Giunti D, Gandolfo C, Ruggeri P, Uccelli A, et al. Systemic administration of mesenchymal stem cells increases neuron survival after global cerebral ischemia in vivo ( 2VO ). Neural Plast 2010.
17. Edalatmanesh MA, Bahrami AR, Hosseini E, Hosseini M, Khatamsaz S. Bone marrow derived mesenchymal stem cell transplantation in cerebellar degeneration: A behavioral study. Behav Brain Res 2011;225:63-70.
18. Morando S, Vigo T, Esposito M, Casazza S, Novi G, Principato MC, et al. The therapeutic eff ect of mesenchymal stem cell transplantation in experimental autoimmune encephalomyelitis is mediated by peripheral and central mechanisms. Stem Cell Res Ther 2012;3:1-7.
19. Aboushwareb T, Atala A. Stem cells in urology. Nat Clin Pract Urol 2008;5:621–631.
20. Tsuda H, Yamahara K, Otani K, Okumi M, Yazawa K, Kaimori JY, et al. Transplantation of allogenic fetal membrane-derived mesenchymal stem cells protects against ischemia/reperfusion-induced acute kidney injury. Cell Transplant 2014;23:889-899.
21. Ende N, Chen R, Reddi AS. Transplantation of human umbilical cord blood cells improves glycemia and glomerular hypertrophy in type 2 diabetic mice. Biochem Biophys Res Commun 2004;321:168-171.
22. Morigi M, Rota C, Montemurro T, Montelatici E, Lo Cicero V, Imberti B, et al. Life-sparing effect of human cord blood-mesenchymal stem cells in experimental acute kidney injury. Stem Cells 2010;28:513-522.
23. Tögel F, Cohen A, Zhang P, Yang Y, Hu Z, Westenfelder C. Autologous and allogeneic marrow stromal cells are safe and effective for the treatment of acute kidney injury. Stem Cells Dev 2009;18:475-485.
24. Kunter U, Rong S, Djuric Z, Boor P, Müller-Newen G, Yu D, et al. Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. J Am Soc Nephrol 2006;17:2202-2212.
25. Geng Y, Zhang L, Fu B, Zhang J, Hong Q, Hu J, et al. Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages. Stem Cell Res Ther 2014;5:80.
26. Havakhah S, Sadeghnia HR, Hajzadeh MR, Roshan NM, Shafiee S, Hosseinzadeh H, et al. Effect of Nigella sativa on ischemia-reperfusion induced rat kidney damage. Iran J Basic Med Sci 2014;17:986-992.
27. Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, et al. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: Feasibility, cell migration, and body distribution. Circulation 2003;108:863-868.
28. Naderi-meshkin Hojjat. "Improving the homing capacity of mesenchymal stem cells (MSCs) through pretreatment and use of an injectable scaffold percutaneously in rat animal model." PhD thesis, Ferdowsi University of Mashhad, 2013.
29. Khalid U, Pino-Chavez G, Nesargikar P, Jenkins RH, Bowen T, Fraser DJ, et al. Kidney ischaemia reperfusion injury in the rat: the EGTI scoring system as a valid and reliable tool for histological assessment. J Histol Histopathol 2016 Jan; 3:1.
30. Bagul A, Frost JH, Drage M. Stem cells and their role in renal ischaemia reperfusion injury. Am J Nephrol 2013;37:16-29.
31. Berry MF, Engler AJ, Woo YJ, Pirolli TJ, Bish LT, Jayasankar V, et al. Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. Am J Physiol Heart Circ Physiol 2006;290:H2196-203.
32. Liu Y, Lai WH, Liao SY, Siu CW, Yang YZ, Tse HF. Lack of cardiac nerve sprouting after intramyocardial transplantation of bone marrow-derived stem cells in a swine model of chronic ischemic myocardium. J Cardiovasc Transl Res 2012;5:359-364.
33. Ko SF, Yip HK, Lee CC, Sheu JJ, Sun CK, Ng SH, et al. Immediate intramyocardial bone marrow-derived mononuclear cells implantation in minipig myocardium after permanent coronary artery ligation: Magnetic resonance imaging with histopathologic and immunochemical correlation. Invest Radiol 2011;46:495-503.
34. Wang CC, Chen CH, Lin WW, Hwang SM, Hsieh PCH, Lai PH, et al. Direct intramyocardial injection of mesenchymal stem cell sheet fragments improves cardiac functions after infarction. Cardiovasc Res 2008;77:515-524.
35. Furuichi K, Shintani H, Sakai Y, Ochiya T, Matsushima K, Kaneko S, et al. Effects of adipose-derived mesenchymal cells on ischemia-reperfusion injury in kidney. Clin Exp Nephrol. 2012;16:679-689.
36. Tögel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 2007;292:F1626-F1635.
37. Cao H, Qian H, Xu W, Zhu W, Zhang X, Chen Y, et al. Mesenchymal stem cells derived from human umbilical cord ameliorate ischemia/reperfusion-induced acute renal failure in rats. Biotechnol Lett 2010;32:725-732.
38. Altun B, Yilmaz R, Aki T, Akoglu H, Zeybek D, Piskinpasa S, et al. Use of mesenchymal stem cells and darbepoetin Improve Ischemia-Induced Acute Kidney Injury Outcomes. Am J Nephrol 2012;35:531-539.
39. Gao J, Liu R, Wu J, Liu Z, Li J, Zhou J, et al. The use of chitosan based hydrogel for enhancing the therapeutic benefits of adipose-derived MSCs for acute kidney injury. Biomaterials 2012;33:3673-3681.
40. Quimby JM, Webb TL, Gibbons DS, Dow SW. Evaluation of intrarenal mesenchymal stem cell injection for treatment of chronic kidney disease in cats: A pilot study. J Feline Med Surg 2011;13:418-426.
41. Pino CJ, Humes HD. Stem cell technology for the treatment of acute and chronic renal failure. Transl Res 2010;156:161-168.
42. Perin L, Giuliani S, Sedrakyan S, Da Sacco S, De Filippo RE. Stem cell and regenerative science applications in the development of bioengineering of renal tissue. Pediatr Res 2008;63:467-471.
43. Tögel FE, Westenfelder C. Treatment of acute kidney injury with allogeneic mesenchymal stem cells: preclinical and initial clinical data. In Regenerative Nephrology. Elsevier Inc; 2011.p. 315-339.
44. Westenfelder C, Togel FE. Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials. Kidney Int Suppl 2011;1:103-106.
45. Wise AF, Ricardo SD. Mesenchymal stem cells in kidney inflammation and repair. Nephrology 2012;17:1-10.