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Adriamycin 유발 신병증에서 중간엽 줄기세포의 완화 효과

Mesenchymal Stem Cells Ameliorate Adriamycin Induced Proteinuric Nephropathy

  • 강희경 (서울대학교 의과대학 소아과학교실) ;
  • 박소연 (서울대학교 의과대학 병리학교실) ;
  • 하일수 (서울대학교 의과대학 소아과학교실) ;
  • 정해일 (서울대학교 의과대학 소아과학교실) ;
  • 최용 (서울대학교 의과대학 소아과학교실)
  • Kang, Hee-Gyung (Department of Pediatrics, Seoul National University Hospital) ;
  • Park, So-Yeon (Department of Pathology, Seoul National University College of Medicine) ;
  • Ha, Il-Soo (Department of Pediatrics, Seoul National University Hospital) ;
  • Cheong, Hae-Il (Department of Pediatrics, Seoul National University Hospital) ;
  • Choi, Yong (Department of Pediatrics, Seoul National University Hospital)
  • 투고 : 2010.03.26
  • 심사 : 2010.04.13
  • 발행 : 2010.04.30

초록

목 적 : 사구체신염은 흔히 단백뇨를 보이며 특이 치료법이 없고, 만성 신부전으로 발전하는 경우가 많다. 몇몇 연구에서 중간엽 줄기세포(Mesenchymal stem cell, MSC)를 실험적 사구체신염에 투여하여 단백뇨가 호전된 것을 보고한 바 있으나, 이는 신염을 일으키는 약제와 중간엽 줄기세포를 함께 투여하거나 신장에 직접 투여한 것이었다. 본 연구에서는 실험적 신병증에서 단백뇨가 발현된 시점에서 정주 요법으로 MSC를 투여함으로써 MSC의 임상적인 적용 가능성을 탐색하였다. 방 법 : 실험용 생쥐에 Adriamycin을 투여하여 신병증(ADR-GN)을 유발한 후, 2주 후에 대량의 단백뇨를 확인하고 MSC를 생쥐 꼬리의 정맥에 주사하였다. MSC에 의한 질병 완화의 기전을 확인하기 위한 in vitro 실험으로 mixed lymphocyte culture(MLC)에 MSC를 투여하였을 때의 염증 관련 cytokine인 IFN-$\gamma$ and IL-10의 변화를 측정하였다. 결 과 : 실험용 생쥐에 ADR-GN를 유발하고 단백뇨가 보일 때 MSC를 정주한 군에서는 단백뇨의 소실이 더 먼저 관찰되었다. 또한 MSC를 투여받은 군에서의 생존률이 더 나은 경향이 관찰되었다. MLC 에 MSC를 투여하였을 때, 염증을 유발하는 cytokine인 IFN-$\gamma$ 는 감소하고 염증을 억제하는 cytokine인 IL-10는 증가하였다. 결 론 : 이 연구는 이전의 보고들에서 관찰되었던 사구체신염에서의 MSC의 질병완화 효과가 좀더 임상적으로 적용 가능한 방법으로 투여된 경우, 즉 단백뇨가 있을 때 정주 요법으로 투여한 경우에도 관찰됨을 확인하였다. 이러한 효과의 기전과 임상적용에 요구되는 안전성 등에 대한 확인을 위해서는 추가 연구가 필요하겠다.

Purpose : Glomerulonephropathy (GN) often manifests as proteinuria and progresses to chronic renal failure without specific therapy. Mesenchymal stem cell (MSC) has been tried as a therapeutic agent in experimental GN, and previous studies showed that administration of MSC concomitantly to the insult inducing GN or via intra-renal administration ameliorated proteinuria. The purpose of this study was to test the therapeutic potential of MSC administered via intravenous route at the time of clinically evident proteinuria. Methods : MSCs were administered intravenously via tail vain into the mice with adriamycin (ADR) induced nephropathy (ADR-GN), two weeks after ADR injection when massive proteinuria was evident. To test the capacity of MSC modulate the cytokine production in the inflammatory milieu, the concentrations of IFN-$\gamma$ and IL-10 were measured in the supernatant of in vitro mixed lymphocyte culture (MLC) with or without additional MSC. Results : MSCs administered intravenously into the proteinuric mice with ADR-GN accelerated the recovery of this experimental GN with disappearance of proteinuria in two weeks when the saline treated (control) mice still showed significant proteinuria. The mice treated with MSC also had a tendency of better survival. Addition of MSC decreased IFN-$\gamma$ and increased IL-10 in the supernatant of MLC. Conclusion : This study showed that MSC had a therapeutic potential even when administered in a more clinically relevant setting into a proteinuric glomerulonephropathy model. Further study to verify the mechanism and long-term safety of this phenomenon is required.

키워드

참고문헌

  1. Eddy AA. Interstitial nephritis induced by protein-overload proteinuria. Am J Pathol 1989;135:719-33.
  2. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006;116:288-96. https://doi.org/10.1172/JCI27699
  3. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, et al. Mesenchymal stem cells modified with akt prevent remodeling and restore performance of infarcted hearts. Nat Med 2003;9:1195-201. https://doi.org/10.1038/nm912
  4. 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;108:863-8. https://doi.org/10.1161/01.CIR.0000084828.50310.6A
  5. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105: 1815-22. https://doi.org/10.1182/blood-2004-04-1559
  6. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce t-cell unresponsiveness. Blood 2005;105:2214-9. https://doi.org/10.1182/blood-2004-07-2921
  7. Frank MH, Sayegh MH. Immunomodulatory functions of mesenchymal stem cells. Lancet 2004;363:1411-2. https://doi.org/10.1016/S0140-6736(04)16134-5
  8. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: A phase ii study. Lancet 2008;371:1579-86. https://doi.org/10.1016/S0140-6736(08)60690-X
  9. Togel 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;18:475-85. https://doi.org/10.1089/scd.2008.0092
  10. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiationindependent mechanisms. Am J Physiol Renal Physiol 2005;289:F31-42. https://doi.org/10.1152/ajprenal.00007.2005
  11. Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G. Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 2004;14:1035-41.
  12. Kunter U, Rong S, Djuric Z, Boor P, Muller-Newen G, Yu D, et al. Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. J Am Soc Nephrol 2006;17:2202-12. https://doi.org/10.1681/ASN.2005080815
  13. Kunter U, Rong S, Boor P, Eitner F, Muller-Newen G, Djuric Z, et al. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes. J Am Soc Nephrol 2007; 18:1754-64. https://doi.org/10.1681/ASN.2007010044
  14. Magnasco A, Corselli M, Bertelli R, Ibatici A, Peresi M, Gaggero G, et al. Mesenchymal stem cells protective effect in adriamycin model of nephropathy. Cell Transplant 2008;17:1157-67. https://doi.org/10.3727/096368908787236567
  15. Wang Y, Mahajan D, Tay YC, Bao S, Spicer T, Kairaitis L, et al. Partial depletion of macrophages by ed7 reduces renal injury in adriamycin nephropathy. Nephrology (Carlton) 2005;10:470-7. https://doi.org/10.1111/j.1440-1797.2005.00438.x
  16. Wang Y, Feng X, Bao S, Yi S, Kairaitis L, Tay YC, et al. Depletion of cd4(+) t cells aggravates glomerular and interstitial injury in murine adriamycin nephropathy. Kidney Int 2001;59:975-84. https://doi.org/10.1046/j.1523-1755.2001.059003975.x
  17. Rangan GK, Wang Y, Tay YC, Harris DC. Cytokine gene expression in adriamycin nephropathy: Effects of antioxidant nuclear factor kappab inhibitors in established disease. Nephron 2000;86:482-90. https://doi.org/10.1159/000045838
  18. Morigi M, Benigni A, Remuzzi G, Imberti B. The regenerative potential of stem cells in acute renal failure. Cell Transplant 2006; 15 Suppl 1:S111-7. https://doi.org/10.3727/000000006783982449
  19. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ. Adult stem cells from bone marrow (mscs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 2004;103:1662-8. https://doi.org/10.1182/blood-2003-09-3070
  20. Wells AD, Gudmundsdottir H, Turka LA. Following the fate of individual t cells throughout activation and clonal expansion. Signals from t cell receptor and cd28 differentially regulate the induction and duration of a proliferative response. J Clin Invest 1997;100:3173-83. https://doi.org/10.1172/JCI119873
  21. Okuda S, Languino LR, Ruoslahti E, Border WA. Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J Clin Invest 1990;86: 453-62. https://doi.org/10.1172/JCI114731
  22. Degauque N, Mariat C, Kenny J, Zhang D, Gao W, Vu MD, et al. Immunostimulatory tim-1-specific antibody deprograms tregs and prevents transplant tolerance in mice. J Clin Invest 2008;118:735-41. https://doi.org/10.1172/JCI32562
  23. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: The pulmonary first-pass effect. Stem Cells Dev 2009;18:683-92. https://doi.org/10.1089/scd.2008.0253
  24. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001;169:12-20. https://doi.org/10.1159/000047856
  25. Ninichuk V, Gross O, Segerer S, Hoffmann R, Radomska E, Buchstaller A, et al. Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen 4a3-deficient mice. Kidney Int 2006;70: 121-9. https://doi.org/10.1038/sj.ki.5001521
  26. Togel F, Yang Y, Zhang P, Hu Z, Westenfelder C. Bioluminescence imaging to monitor the in vivo distribution of administered mesenchymal stem cells in acute kidney injury. Am J Physiol Renal Physiol 2008;295: F315-21. https://doi.org/10.1152/ajprenal.00098.2008