#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury


Autoři: Shani Zilberman-Itskovich aff001;  Ramzia Abu-Hamad aff001;  Rina Zarura aff001;  Marina Sova aff001;  Yafit Hachmo aff001;  Moshe Stark aff001;  Sara Neuman aff003;  Shimon Slavin aff003;  Shai Efrati aff001
Působiště autorů: Nephrology Division, Assaf-Harofeh Medical Center, Zerifin, Israel aff001;  Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel aff002;  Biotherapy International, The Center for Innovative Cancer Immunotherapy & Regenerative Medicine, Weizmann Center, Tel Aviv, Israel aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222354

Souhrn

Introduction

The primary rational for using mesenchymal stromal cells (MSCs) to rejuvenate damaged tissue is mostly based on their capacity to trans-differentiate and repair injured organs. However, previous studies have demonstrated that MSCs are beneficial even at very early stages, before differentiation and proliferation can be expected. The aim of the current study was to investigate the multifaceted immunological effects of systemically administrating MSCs in the setting of acute kidney injury (AKI) induced by ischemic-reperfusion (I/R).

Methods

A rat model of I/R induced AKI was used. The rats underwent a unilateral nephrectomy with simultaneously clamping the contralateral kidney for 60 minutes. Four treatment groups received intravenously, increasing doses of human MSCs and after 48 hours, the rats were sacrificed. Blood was taken to evaluate renal functions and to measure systemic inflammatory markers. Kidneys were taken for histopathologic examinations and evaluations of intra-renal complement activation and inflammatory mediators.

Results

Renal functions improved in U shaped dose dependent manner. Mean serum creatinine levels were 4.5, 2.9, 2.6, 1.7 and 4.1 mg/dL in I/R + placebo, I/R + 150x103 cells, I/R + 250x103 cells, I/R + 500x103 cells and I/R + 1,000x103 cells respectfully (p-values<0.05). Urea demonstrated consistent results with the same U shape improvement manner. The extensive activation of the complement system was ameliorated in the MSCs treatment groups. In addition, MSCs significantly decreased intra-renal levels of IL-1β and TNF-α. It should be noted that the highest doses of MSCs induced renal hypoxia, marked by the Hypoxy-probe staining.

Conclusions

The early beneficial effect of MSCs in the setting of AKI may be attributed to their immunomodulatory effects. Safe treatment with MSCs can block the deleterious activation of the complement cascade and alleviate the hazardous inflammatory mediator-related cascade.

Klíčová slova:

Biology and life sciences – Cell biology – Cellular types – Animal cells – Stem cells – Mesenchymal stem cells – Blood cells – White blood cells – Macrophages – Immune cells – Cell processes – Cell death – Apoptosis – Physiology – Complement system – Biochemistry – Proteins – Immune system proteins – Anatomy – Renal system – Kidneys – Developmental biology – Molecular development – Medicine and health sciences – Immune physiology – Immunology – Immune system – Innate immune system – Cytokines – Immune response – Inflammation – Diagnostic medicine – Signs and symptoms – Pathology and laboratory medicine


Zdroje

1. Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 2012;82(5):516–24. Epub 2012/06/08. doi: 10.1038/ki.2012.208 22673882.

2. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380(9843):756–66. Epub 2012/05/24. doi: 10.1016/S0140-6736(11)61454-2 22617274.

3. Chan RK, Ibrahim SI, Verna N, Carroll M, Moore FD Jr., Hechtman HB. Ischaemia-reperfusion is an event triggered by immune complexes and complement. Br J Surg. 2003;90(12):1470–8. Epub 2003/12/04. doi: 10.1002/bjs.4408 14648724.

4. McCullough JW, Renner B, Thurman JM. The role of the complement system in acute kidney injury. Semin Nephrol. 2013;33(6):543–56. Epub 2013/10/29. doi: 10.1016/j.semnephrol.2013.08.005 24161039.

5. Perico N, Casiraghi F, Remuzzi G. Clinical Translation of Mesenchymal Stromal Cell Therapies in Nephrology. J Am Soc Nephrol. 2018;29(2):362–75. Epub 2017/12/02. doi: 10.1681/ASN.2017070781 29191959.

6. Wise AF, Ricardo SD. Mesenchymal stem cells in kidney inflammation and repair. Nephrology (Carlton). 2012;17(1):1–10. Epub 2011/07/23. doi: 10.1111/j.1440-1797.2011.01501.x 21777348.

7. Milosavljevic N, Gazdic M, Simovic Markovic B, Arsenijevic A, Nurkovic J, Dolicanin Z, et al. Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells. Liver Transpl. 2017;23(8):1040–50. Epub 2017/05/10. doi: 10.1002/lt.24784 28481005.

8. Efrati S, Berman S, Hamad RA, Siman-Tov Y, Ilgiyaev E, Maslyakov I, et al. Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury. Nephrol Dial Transplant. 2012;27(1):136–45. Epub 2011/06/18. doi: 10.1093/ndt/gfr256 21680852.

9. Kezic A, Stajic N, Thaiss F. Innate Immune Response in Kidney Ischemia/Reperfusion Injury: Potential Target for Therapy. J Immunol Res. 2017;2017:6305439. Epub 2017/07/06. doi: 10.1155/2017/6305439 28676864.

10. Mulay SR, Holderied A, Kumar SV, Anders HJ. Targeting Inflammation in So-Called Acute Kidney Injury. Semin Nephrol. 2016;36(1):17–30. Epub 2016/04/18. doi: 10.1016/j.semnephrol.2016.01.006 27085732.

11. Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, et al. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A. 2007;104(26):11002–7. Epub 2007/06/16. doi: 10.1073/pnas.0704421104 17569781.

12. Du T, Zhu YJ. The regulation of inflammatory mediators in acute kidney injury via exogenous mesenchymal stem cells. Mediators Inflamm. 2014;2014:261697. Epub 2014/05/20. doi: 10.1155/2014/261697 24839354.

13. Schraufstatter IU, Discipio RG, Zhao M, Khaldoyanidi SK. C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation. J Immunol. 2009;182(6):3827–36. Epub 2009/03/07. doi: 10.4049/jimmunol.0803055 19265162.

14. Qiu Y, Marquez-Curtis LA, Janowska-Wieczorek A. Mesenchymal stromal cells derived from umbilical cord blood migrate in response to complement C1q. Cytotherapy. 2012;14(3):285–95. Epub 2012/01/24. doi: 10.3109/14653249.2011.651532 22264191.

15. Tang M, Zhang K, Li Y, He QH, Li GQ, Zheng QY, et al. Mesenchymal stem cells alleviate acute kidney injury by down-regulating C5a/C5aR pathway activation. Int Urol Nephrol. 2018;50(8):1545–53. Epub 2018/03/30. doi: 10.1007/s11255-018-1844-7 29594894.

16. Dinarello CA. A clinical perspective of IL-1beta as the gatekeeper of inflammation. Eur J Immunol. 2011;41(5):1203–17. Epub 2011/04/28. doi: 10.1002/eji.201141550 21523780.

17. Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Kohl J, et al. C3a modulates IL-1beta secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood. 2013;122(20):3473–81. Epub 2013/07/24. doi: 10.1182/blood-2013-05-502229 23878142.

18. Anders HJ. Of Inflammasomes and Alarmins: IL-1beta and IL-1alpha in Kidney Disease. J Am Soc Nephrol. 2016;27(9):2564–75. Epub 2016/08/16. doi: 10.1681/ASN.2016020177 27516236.

19. Hamidzadeh K, Christensen SM, Dalby E, Chandrasekaran P, Mosser DM. Macrophages and the Recovery from Acute and Chronic Inflammation. Annu Rev Physiol. 2017;79:567–92. Epub 2016/12/14. doi: 10.1146/annurev-physiol-022516-034348 27959619.

20. Tang PM, Nikolic-Paterson DJ, Lan HY. Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol. 2019;15(3):144–58. Epub 2019/01/30. doi: 10.1038/s41581-019-0110-2 30692665.

21. Rubio-Navarro A, Guerrero-Hue M, Martin-Fernandez B, Cortegano I, Olivares-Alvaro E, de Las Heras N, et al. Phenotypic Characterization of Macrophages from Rat Kidney by Flow Cytometry. J Vis Exp. 2016;(116). Epub 2016/11/03. doi: 10.3791/54599 27805599.

22. Wise AF, Williams TM, Kiewiet MB, Payne NL, Siatskas C, Samuel CS, et al. Human mesenchymal stem cells alter macrophage phenotype and promote regeneration via homing to the kidney following ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2014;306(10):F1222–35. Epub 2014/03/14. doi: 10.1152/ajprenal.00675.2013 24623144.

23. Kumar S. Cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int. 2018;93(1):27–40. Epub 2018/01/03. doi: 10.1016/j.kint.2017.07.030 29291820.

24. Lee C, Jang MJ, Kim BH, Park JY, You D, Jeong IG, et al. Recovery of renal function after administration of adipose-tissue-derived stromal vascular fraction in rat model of acute kidney injury induced by ischemia/reperfusion injury. Cell Tissue Res. 2017;368(3):603–13. Epub 2017/03/12. doi: 10.1007/s00441-017-2585-0 28283911.

25. Tarng DC, Tseng WC, Lee PY, Chiou SH, Hsieh SL. Induced Pluripotent Stem Cell-Derived Conditioned Medium Attenuates Acute Kidney Injury by Downregulating the Oxidative Stress-Related Pathway in Ischemia-Reperfusion Rats. Cell Transplant. 2016;25(3):517–30. Epub 2015/07/02. doi: 10.3727/096368915X688542 26132529.

26. Schubert R, Sann J, Frueh JT, Ullrich E, Geiger H, Baer PC. Tracking of Adipose-Derived Mesenchymal Stromal/Stem Cells in a Model of Cisplatin-Induced Acute Kidney Injury: Comparison of Bioluminescence Imaging versus qRT-PCR. Int J Mol Sci. 2018;19(9). Epub 2018/08/31. doi: 10.3390/ijms19092564 30158455.

27. Park SE, Lee NK, Lee J, Hwang JW, Choi SJ, Hwang H, et al. Distribution of human umbilical cord blood-derived mesenchymal stem cells in the Alzheimer’s disease transgenic mouse after a single intravenous injection. Neuroreport. 2016;27(4):235–41. Epub 2016/01/12. doi: 10.1097/WNR.0000000000000526 26752148.

28. Cai J, Yu X, Xu R, Fang Y, Qian X, Liu S, et al. Maximum efficacy of mesenchymal stem cells in rat model of renal ischemia-reperfusion injury: renal artery administration with optimal numbers. PLoS One. 2014;9(3):e92347. Epub 2014/03/19. doi: 10.1371/journal.pone.0092347 24637784.

29. Swaminathan M, Stafford-Smith M, Chertow GM, Warnock DG, Paragamian V, Brenner RM, et al. Allogeneic Mesenchymal Stem Cells for Treatment of AKI after Cardiac Surgery. J Am Soc Nephrol. 2018;29(1):260–7. Epub 2017/10/19. doi: 10.1681/ASN.2016101150 29038286.

30. Li Y, Lin F. Mesenchymal stem cells are injured by complement after their contact with serum. Blood. 2012;120(17):3436–43. Epub 2012/09/12. doi: 10.1182/blood-2012-03-420612 22966167.


Článek vyšel v časopise

PLOS One


2019 Číslo 9
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Svět praktické medicíny 1/2024 (znalostní test z časopisu)
nový kurz

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Význam metforminu pro „udržitelnou“ terapii diabetu
Autoři: prof. MUDr. Milan Kvapil, CSc., MBA

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#