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Multipotent mesenchymal stem cells in renal transplantation

https://doi.org/10.23873/2074-0506-2019-11-1-21-36

Abstract

Kidney transplantation is the most effective treatment for the end-stage chronic renal disease that has been observed to increase in the incidence consistently in recent years. Despite the achievements in immunosuppressive therapy in patients after renal transplantation, the graft survival length has remained unchangeable during the recent few decades. Bone marrow multipotent mesenchymal (stromal) stem cells (BM MMSCs) are known as a potential tool to influence this situation. Since their discovery in the middle of the XX century, their wide therapeutic potential in the transplantation of solid organs was demonstrated both in experimental and clinical trials. They have the ability to modify recipient’s immune response and improve postoperative course, however, having a low level of their own immunogenicity. MMSCs realize their properties through interactions both with the innate and adoptive immune system. Meanwhile, actual questions such as an optimal dosage and injection timing are still need answers. Actual experience of both experimental and clinical use of MMSCs in kidney transplantation has been analyzed in the present publication.

About the Authors

N. V. Borovkova
N.V. Sklifosovsky Research Institute for Emergency Medicine
Russian Federation

Natal’ya V. Borovkova - Dr. Med. Sci., Head of the Scientific Department of Biotechnologies and Tranfusiology

3 Bolshaya Sukharevskaya Sq., Moscow 129090



M. Sh. Khubutiya
N.V. Sklifosovsky Research Institute for Emergency Medicine
Russian Federation

Mogeli Sh. Khubutiya - Acad. of RAS, Prof., Dr. Med. Sci., President

3 Bolshaya Sukharevskaya Sq., Moscow 129090



O. N. Rzhevskaya
N.V. Sklifosovsky Research Institute for Emergency Medicine
Russian Federation

Ol’ga N. Rzhevskaya - Dr. Med. Sci., Leading Researcher of the Kidney and Pancreas Transplantation Department

3 Bolshaya Sukharevskaya Sq., Moscow 129090



A. V. Pinchuk
N.V. Sklifosovsky Research Institute for Emergency Medicine
Russian Federation

Aleksey V. Pinchuk - Cand. Med. Sci., Head of the Scientific Kidney and Pancreas Transplantation Scientific Department

3 Bolshaya Sukharevskaya Sq., Moscow 129090



D. A. Vasil’chenkov
A.I. Yevdokimov Moscow State University of Medicine and Dentistry
Russian Federation

Dmitriy A. Vasil’chenkov - Postgraduate in the Department of Transplantation and Artificial Organs

1 Bldg. 20 Delegatskaya St., Moscow 127473



References

1. Liyanage T., Ninomiya T., Jha V., et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet. 2015;385(9981):1975– 1982. PMID:25777665 DOI:10.1016/S0140-6736(14)61601-9

2. Webster A.C., Nagler E.V., Morton R.L., Masson P. Chronic kidney disease. Lancet. 2017;389(10075):1238–1252. PMID:27887750 DOI:10.1016/S0140-6736(16)32064-5

3. Gautier S.V., ed. Immunosuppression during solid organ transplantation. Moscow: Triada Publ., 2011. 472 p. (In Russian).

4. Bamoulid J., Staeck O., Halleck F., et al. The need for minimization strategies: current problems of immunosuppression. Transplant Int. 2015;28(8):891–900. PMID:25752992 DOI:10.1111/tri.12553

5. Casiraghi F., Perico N., Remuzzi G. Mesenchymal stromal cells for tolerance induction in organ transplantation. Hum Immunol. 2018;79(5):304– 313. PMID:29288697 DOI:10.1016/j.humimm.2017.12.008

6. Friedenstein A.J., Chailakhjan R.K., Lalykina K.S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Proliferation. 1970;3(4):393–403. PMID:5523063

7. Orkin S.H., Zon L.I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132(4):631– 644. PMID:18295580 DOI:10.1016/j.cell.2008.01.025

8. Appelbaum F.R. Hematopoietic-cell transplantation at 50. N Engl J Med. 2007;357(15):1472–1475. PMID:17928594 DOI:10.1056/NEJMp078166

9. Dominici M.L., Le Blanc K., Mueller I., et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317 PMID:16923606 DOI:10.1080/14653240600855905

10. Friedenstein A.J., Piatetzky-Shapiro I.I., Petrakova K.V. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16(3):381–390. PMID:5336210

11. Le Blanc K., Rasmusson I., Sundberg B., et al. Treatment of severe acute graftversus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363(9419):1439–1441.

12. Casiraghi F., Perico N., Remuzzi G. Mesenchymal stromal cells to promote solid organ transplantation tolerance. Curr Opin Organ Transplant. 2013;18(1):51–58. PMID:23254705 DOI:10.1097/MOT.0b013e32835c5016

13. Reinders M.E., De Fijter J.W., Zandvliet M.L., Rabelink T.J. Mesenchymal stromal cells to improve solid organ transplant outcome: lessons from the initial clinical trials. In: Orlando G., Remuzzi G., Williams D.F., eds. Kidney Transplantation, Bioengineering, and Regeneration: Kidney Transplantation in the Regenerative Medicine Era. Elsevier Science, 2017. 319–331.

14. Casiraghi F., Azzollini N., Cassis P., et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneric heart transplant through the generation of regulatory T cells. J Immunol. 2008;181(6):3933–3946. PMID:18768848 DOI:10.4049/jimmunol.181.6.3933

15. Ryan J.M., Barry F.P., Murphy J.M., Mahon B.P. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm. 2005;2(1):8. PMID:16045800 DOI:10.1186/1476-9255-2-8

16. Tu Z., Li Q., Bu H., Lin F. Mesenchymal stem cells inhibit complement activation by secreting factor H. Stem Cells Dev. 2010;19(11):1803–1809. PMID:20163251 DOI:10.1089/scd.2009.0418

17. Moll G., Jitschin R., Von Bahr L., et al. Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses. PloS One. 2011;6(7):e21703. PMID:21747949 DOI:10.1371/journal.pone.0021703

18. Brandau S., Jakob M., Hemeda H., et al. Tissue-resident mesenchymal stem cells attract peripheral blood neutrophils and enhance their inflammatory activity in response to microbial challenge. J Leukoc Biol. 2010;88(5):1005–1015. PMID:20682625 DOI:10.1189/jlb.0410207

19. Nauta A.J., Kruisselbrink A.B., Lurvink E., et al. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocytederived dendritic cells. J Immunol. 2006;177(4):2080–2087. PMID:16887966

20. Spaggiari G.M., Capobianco A., Abdelrazik H., et al. Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2, 3-dioxygenase and prostaglandin E2. Blood. 2008;111(3):1327–1333. PMID:17951526 DOI:10.1182/blood-2007-02-074997

21. Spaggiari G.M., Capobianco A., Becchetti S., et al. Mesenchymal stem cellnatural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood. 2006;107(4):1484–1490. PMID:16239427 DOI:10.1182/blood-2005-07-2775

22. Rocher B.D., Mencalha A.L., Gomes B.E., Abdelhay E. Mesenchymal stromal cells impair the differentiation of CD14++ CD16- CD64+ classical monocytes into CD14++ CD16+ CD64++ activate monocytes. Cytotherapy. 2012;14(1):12–25. PMID:21838603 DOI:10.3109/14653249.2011.594792

23. Chiesa S., Morbelli S., Morando S., et al. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Nati Acad Sci USA. 2011;108(42):17384– 17389. PMID:21960443 DOI:10.1073/pnas.1103650108

24. Kim J., Hematti P. Mesenchymal stem cell–educated macrophages: A novel type of alternatively activated macrophages. Exp Hematol. 2009;37(12):1445– 1453. PMID:19772890 DOI:10.1016/j.exphem.2009.09.004

25. Di Nicola M., Carlo-Stella C., Magni M., et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838– 3843. PMID:11986244 DOI:10.1182/blood.V99.10.3838

26. William T.T., Pendleton J.D., Beyer W.M., et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75(3):389– 397. PMID:12589164 DOI:10.1097/01.TP.0000045055.63901.A9

27. Le Blanc K., Tammik L., Sundberg B., et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57(1):11–20. PMID:12542793 DOI:10.1046/j.1365-3083.2003.01176.x

28. Glennie S., Soeiro I., Dyson P.J., et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105(7):2821–2827. PMID:15591115 DOI:10.1182/blood-2004-09-3696

29. Duffy M.M., Ritter T., Ceredig R., Griffin M.D. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther. 2011;2(4):34. PMID:21861858 DOI:10.1186/scrt75

30. Ghannam S., Pène J., Moquet-Torcy G., et al. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol. 2010;185(1);302– 312. PMID:20511548 DOI:10.4049/jimmunol.0902007

31. English K., Ryan J.M., Tobin L., et al. Cell contact, prostaglandin E2 and transforming growth factor beta 1 play nonredundant roles in human mesenchymal stem cell induction of CD4+ CD25Highforkhead box P3+ regulatory T cells. Clin Exp Immunol. 2009;156(1):149–160. PMID:19210524 DOI:10.1111/j.1365-2249.2009.03874.x

32. Tabera S., Pérez-Simón J.A., Díez-Campelo M., et al. The effect of mesenchymal stem cells on the viability, proliferation and differentiation of B-lymphocytes. Haematologica. 2008;93(9):1301–1309. PMID:18641017 DOI:10.3324/haematol.12857

33. Peng Y., Chen X., Liu Q., et al. Mesenchymal stromal cells infusions improve refractory chronic graft versus host disease through an increase of CD5 regulatory B cells producing interleukin 10. Leukemia. 2015;29(3):636– 646. PMID:25034146 DOI:10.1038/leu.2014.225

34. Franquesa M., Mensah F.K., Huizinga R., et al. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells. 2015;33(3):880–891. PMID:25376628 DOI:10.1002/stem.1881

35. Prockop D.J. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol Ther. 2009;17(6):939–946. PMID:19337235 DOI:10.1038/mt.2009.62

36. da Silva Meirelles L., Caplan A.I., Nardi N.B. In search of the in vivo identity of mesenchymal stem cells. Stem Cells. 2008;26(9):2287–2299. PMID:18566331 DOI:10.1634/stemcells.2007-1122

37. Block G.J., Ohkouchi S., Fung F., et al. Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells. 2009;27(3):670– 681. PMID:19267325 DOI:10.1002/stem.20080742

38. Lee R.H., Pulin A.A., Seo M.J., et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the antiinflammatory protein TSG-6. Cell Stem Cell. 2009;5(1):54–63. PMID:19570514 DOI:10.1016/j.stem.2009.05.003

39. Jia X., Pan J., Li X., et al. Bone marrow mesenchymal stromal cells ameliorate angiogenesis and renal damage via promoting PI3k-Akt signaling pathway activation in vivo. Cytotherapy. 2016;18(7):838–845. PMID:27210720 DOI:10.1016/j.jcyt.2016.03.300

40. Hou Y., Ryu C.H., Jun J.A., et al. IL-8 enhances the angiogenic potential of human bone marrow mesenchymal stem cells by increasing vascular endothelial growth factor. Cell Biology Int. 2014;38(9):1050–1059. PMID:24797366 DOI:10.1002/cbin.10294

41. Bartholomew A., Sturgeon C., Siatskas M., et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42–48. PMID:11823036

42. Zhou H.P., Yi D.H., Yu S.Q., et al. Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft. Transplant Proc. 2006;38(9):3046–3051. PMID:17112896 DOI:10.1016/j.transproceed.2006.10.002

43. Zhang W., Qin C., Zhou Z.M. Mesenchymal stem cells modulate immune responses combined with cyclosporine in a rat renal transplantation model. Transplant Proc. 2007;39(10):3404–3408. PMID:18089393 DOI:10.1016/j.transproceed.2007.06.092

44. De Martino M., Zonta S., Rampino T., et al. Mesenchymal stem cells infusion prevents acute cellular rejection in rat kidney transplantation. Transplant Proc. 2010;42(4):1331–1335. PMID:20534294 DOI:10.1016/j.transproceed.2010.03.079

45. Casiraghi F., Azzollini N., Todeschini M., et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant. 2012;12(9):2373–2383. PMID:22642544 DOI:10.1111/j.1600-6143.2012.04115.x

46. Ge W., Jiang J., Arp J., et al. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2, 3-dioxygenase expression. Transplantation. 2010;90(12):1312– 1320. PMID:21042238 DOI:10.1097/TP.0b013e3181fed001

47. Onishchenko N.A., Meshcherin S.S., Il’inskiy I.M., Sevast’yanov V.I. Influence of bone marrow MSCs on the development of posttransplant changes in kidnes. Russian Journal of Transplantology and Artificial Organs. 2016;18(1):45–52. (In Russian). DOI:10.15825/1995-1191-2016-1-45-52

48. Seok J., Warren H.S., Cuenca A.G., et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 2013;110(9):3507–3512. PMID:23401516 DOI:10.1073/pnas.1222878110

49. Mao F., Tu Q., Wang L., et al. Mesenchymal stem cells and their therapeutic applications in inflammatory bowel disease. Oncotarget. 2017;8(23):38008–38021. PMID:28402942 DOI:10.18632/oncotarget.16682

50. Lu D., Chen B., Liang Z., et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract. 2011;92(1):26–36. PMID:21216483 DOI:10.1016/j.diabres.2010.12.010

51. Prasad V.K., Lucas K.G., Kleiner G.I., et al. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal™) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant. 2011;17(4):534–541. PMID:20457269 DOI:10.1016/j.bbmt.2010.04.014

52. Griffin M.D., Elliman S.J., Cahill E., et al. Concise review: adult mesenchymal stromal cell therapy for inflammatory diseases: how well are we joining the dots? Stem Cells. 2013;31(10):2033–2041. PMID:23766124 DOI:10.1002/stem.1452

53. Verstockt B., Ferrante M., Vermeire S., Van Assche G. New treatment options for inflammatory bowel diseases. J Gastroenterol. 2018;53(5):585–590. PMID:29556726 DOI:10.1007/s00535-018-1449-z

54. Perico N., Casiraghi F., Introna M., et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011;6(2):412– 422. PMID:20930086 DOI:10.2215/CJN.04950610

55. Reinders M.E., de Fijter J.W., Roelofs H., et al. Autologous bone marrowderived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: Results of a phase I study. Stem Cells Transl Med. 2013;2(2):107–111. PMID:23349326 DOI:10.5966/sctm.2012-0114

56. Reinders M.E., Bank J.R., Dreyer G.J., et al. Autologous bone marrow derived mesenchymal stromal cell therapy in combination with everolimus to preserve renal structure and function in renal transplant recipients. J Transl Med. 2014;12(1):331. PMID:25491391 DOI:10.1186/s12967-014-0331-x

57. Perico N., Casiraghi F., Gotti E., et al. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transplant Int. 2013;26(9):867–878. PMID:23738760 DOI:10.1111/tri.12132

58. Perico N., Casiraghi F., Todeschini M., et al. Long-term Clinical and Immunological Profile of Kidney Transplant Patients given Mesenchymal Stromal Cell Immunotherapy. Front Immunol. 2018;9:1359. PMID:29963053 DOI:10.3389/fimmu.2018.01359

59. Mudrabettu C., Kumar V., Rakha A., et al. Safety and efficacy of autologous mesenchymal stromal cells transplantation in patients undergoing living donor kidney transplantation: a pilot study. Nephrology. 2015;20(1):25–33. PMID:25230334 DOI:10.1111/nep.12338

60. Tan J., Wu W., Xu X., et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 2012;307(11):1169– 1177. PMID:22436957 DOI:10.1001/jama.2012.316

61. Sun Q., Huang Z., Han F., et al. Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: pilot results of a multicenter randomized controlled trial. J Transl Med. 2018;16(1):52–62. PMID:29514693 DOI:10.1186/s12967-018-1422-x

62. Erpicum P., Weekers L., Detry O., et al. Infusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I-II, open-label, clinical study. Kidney Int. 2018. pii:S0085- 2538(18)30712-9. PMID:30528263 DOI:10.1016/j.kint.2018.08.046

63. Le Blanc K., Frassoni F., Ball L., et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579– 1586. PMID:18468541 DOI:10.1016/S0140-6736(08)60690-X

64. Ball L.M., Bernardo M.E., Roelofs H., et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III–IV acute graft-versus-host disease. Br J Haematol. 2013;163(4):501–509. PMID:23992039 DOI:10.1111/bjh.12545

65. Reinders M.E., van Kooten C., Rabelink T.J., de Fijter J.W. Mesenchymal stromal cell therapy for solid organ transplantation. Transplantation. 2018;102(1):35–43. PMID:28704335 DOI:10.1097/TP.0000000000001879

66. Buron F., Perrin H., Malcus C., et al. Human mesenchymal stem cells and immunosuppressive drug interactions in allogeneic responses: an in vitro study using human cells. Transplant Proc. 2009;41(8):3347–3352. PMID:19857747 DOI:10.1016/j.transproc

67. Hoogduijn M.J., Crop M.J., Korevaar S.S., et al. Susceptibility of human mesenchymal stem cells to tacrolimus, mycophenolic acid, and rapamycin. Transplantation. 2008;86(9):1283– 1291. PMID:19005411 DOI:10.1097/TP.0b013e31818aa536

68. Hajkova M., Hermankova B., Javorkova E., et al. Mesenchymal stem cells attenuate the adverse effects of immunosuppressive drugs on distinct T cell subopulations. Stem Cell Rev Rep. 2017;13(1):104–115. PMID:27866327 DOI:10.1007/s12015-016-9703-3

69. Popp F.C., Eggenhofer E., Renner P., et al. Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with lowdose mycophenolate. Transplant Immunol. 2008;20(1-2):55–60. PMID:18762258 DOI:10.1016/j.trim.2008.08.004

70. Eggenhofer E., Renner P., Soeder Y., et al. Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model. Transplant Immunol. 2011;25(2-3):141–147. PMID:21704160 DOI:10.1016/j.trim.2011.06.002

71. Fulginiti V.A., Scribner R., Groth C.G., et al. Infections in recipients of liver homografts. N Engl J Med. 1968;279(12):619–626. PMID:4299208

72. Vajdic C.M., van Leeuwen M.T. Cancer incidence and risk factors after solid organ transplantation. Int J Cancer. 2009;125(8):1747–1754. PMID:19444916 DOI:10.1002/ijc.24439

73. Casiraghi F., Remuzzi G., Abbate M., Perico N. Multipotent mesenchymal stromal cell therapy and risk of malignancies. Stem Cell Rev Rep. 2013;9(1):65–79. PMID:22237468 DOI:10.1007/s12015-011-9345-4

74. Von Bahr L., Batsis I., Moll G., et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012;30(7):1575–1578. PMID:22553154 DOI:10.1002/stem.1118

75. Moermans C., Lechanteur C., Baudoux E., et al. Impact of cotransplantation of mesenchymal stem cells on lung function after unrelated allogeneic hematopoietic stem cell transplantation following non-myeloablative conditioning. Transplantation. 2014;98(3):348– 353. PMID:24717223 DOI:10.1097/TP.0000000000000068eed.2009.08.030


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Borovkova N.V., Khubutiya M.Sh., Rzhevskaya O.N., Pinchuk A.V., Vasil’chenkov D.A. Multipotent mesenchymal stem cells in renal transplantation. Transplantologiya. The Russian Journal of Transplantation. 2019;11(1):21-36. https://doi.org/10.23873/2074-0506-2019-11-1-21-36

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