Role and mechanism of mesenchymal stem cell-derived exosomes on renal ischemia-reperfusion injury_West China Medical Journal

Authors：

LIU Yi ¹ ,  ZHANG Peng ² , SUN Shiren ² ,  BAI Ming ²

1. Xi’an Medical University, Xi’an, Shaanxi 710021, P. R. China;
2. Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi 710032, P. R. China;

Corresponding author：

ZHANG Peng, Email: zhangpeng@fmmu.edu.cn; BAI Ming, Email: mingbai1983@126.com

Keywords：

Acute kidney injury; ischemia-reperfusion injury; mesenchymal stem cells; exosome

DOI：

10.7507/1002-0179.202205144

Video：

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Abstract Full text Figures/Tables Video References Cited by

Acute kidney injury (AKI) is characterized by a sudden and rapid decline of renal function and associated with high morbidity and mortality. AKI can be caused by various factors, and ischemia-reperfusion injury (IRI) is one of the most common causes of AKI. An increasing number of studies found out that exosomes of mesenchymal stem cells (MSCs) could alleviate IRI-AKI by the adjustment of the immune response, the suppression of oxidative stress, the reduction of cell apoptosis, and the promotion of tissue regeneration. This article summarizes the effect and mechanism of MSC-derived exosomes in the treatment of renal ischemia-reperfusion injury, in order to provide useful information for the researches on this field.

Citation： LIU Yi, ZHANG Peng, SUN Shiren, BAI Ming. Role and mechanism of mesenchymal stem cell-derived exosomes on renal ischemia-reperfusion injury. West China Medical Journal, 2022, 37(7): 1081-1087. doi: 10.7507/1002-0179.202205144 Copy

1.	Mehta RL, Cerdá J, Burdmann EA, et al. International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet, 2015, 385(9987): 2616-2643.
2.	Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest, 2011, 121(11): 4210-4221.
3.	Ricci Z, Cruz DN, Ronco C. Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nat Rev Nephrol, 2011, 7(4): 201-208.
4.	Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol, 2009, 130(1): 41-50.
5.	Smith SF, Hosgood SA, Nicholson ML. Ischemia-reperfusion injury in renal transplantation: 3 key signaling pathways in tubular epithelial cells. Kidney Int, 2019, 95(1): 50-56.
6.	Pefanis A, Ierino FL, Murphy JM, et al. Regulated necrosis in kidney ischemia-reperfusion injury. Kidney Int, 2019, 96(2): 291-301.
7.	Klinker MW, Wei CH. Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. World J Stem Cells, 2015, 7(3): 556-567.
8.	Wang Y, Chen X, Cao W, et al. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol, 2014, 15(11): 1009-1016.
9.	Zhao M, Liu S, Wang C, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate mitochondrial damage and inflammation by stabilizing mitochondrial DNA. ACS Nano, 2021, 15(1): 1519-1538.
10.	Tang TT, Wang B, Wu M, et al. Extracellular vesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI. Sci Adv, 2020, 6(33): eaaz0748.
11.	Zhang C, Shang Y, Chen X, et al. Supramolecular nanofibers containing arginine-glycine-aspartate (RGD) peptides boost therapeutic efficacy of extracellular vesicles in kidney repair. ACS Nano, 2020, 14(9): 12133-12147.
12.	Collino F, Bruno S, Incarnato D, et al. AKI recovery induced by mesenchymal stromal cell-derived extracellular vesicles carrying microRNAs. J Am Soc Nephrol, 2015, 26(10): 2349-2360.
13.	Eitan E, Tosti V, Suire CN, et al. In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles. Aging Cell, 2017, 16(6): 1430-1433.
14.	Danielson KM, Shah R, Yeri A, et al. Plasma Circulating extracellular RNAs in left ventricular remodeling post-myocardial infarction. EBio Medicine, 2018, 32: 172-181.
15.	Yu HA, Perez L, Chang Q, et al. A phase 1/2 trial of ruxolitinib and erlotinib in patients with EGFR-mutant lung adenocarcinomas with acquired resistance to erlotinib. J Thorac Oncol, 2017, 12(1): 102-109.
16.	An T, Qin S, Xu Y, et al. Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. J Extracell Vesicles, 2015, 4: 27522.
17.	Jia Y, Ding X, Zhou L, et al. Mesenchymal stem cells-derived exosomal microRNA-139-5p restrains tumorigenesis in bladder cancer by targeting PRC1. Oncogene, 2021, 40(2): 246-261.
18.	Li CX, Song J, Li X, et al. Circular RNA 0001273 in exosomes derived from human umbilical cord mesenchymal stem cells (UMSCs) in myocardial infarction. Eur Rev Med Pharmacol Sci, 2020, 24(19): 10086-10095.
19.	Yan Y, Jiang W, Tan Y, et al. hucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury. Mol Ther, 2017, 25(2): 465-479.
20.	Liu B, Hu D, Zhou Y, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against renal interstitial fibrosis through ROS-mediated P38MAPK/ERK signaling pathway. Am J Transl Res, 2020, 12(9): 4998-5014.
21.	Stroo I, Stokman G, Teske GJ, et al. Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase. Int Immunol, 2010, 22(6): 433-442.
22.	Jang HR, Ko GJ, Wasowska BA, et al. The interaction between ischemia-reperfusion and immune responses in the kidney. J Mol Med (Berl), 2009, 87(9): 859-864.
23.	Jang HR, Rabb H. Immune cells in experimental acute kidney injury. Nat Rev Nephrol, 2015, 11(2): 88-101.
24.	Tammaro A, Kers J, Scantlebery AML, et al. Metabolic flexibility and innate immunity in renal ischemia reperfusion injury: the fine balance between adaptive repair and tissue degeneration. Front Immunol, 2020, 11: 1346.
25.	Sutton TA, Mang HE, Campos SB, et al. Injury of the renal microvascular endothelium alters barrier function after ischemia. Am J Physiol Renal Physiol, 2003, 285(2): F191-198.
26.	Brodsky SV, Yamamoto T, Tada T, et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol, 2002, 282(6): F1140-1149.
27.	Malek M, Nematbakhsh M. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev, 2015, 4(2): 20-27.
28.	Cao CC, Ding XQ, Ou ZL, et al. In vivo transfection of NF-kappaB decoy oligodeoxynucleotides attenuate renal ischemia/reperfusion injury in rats. Kidney Int, 2004, 65(3): 834-845.
29.	Eickelberg O, Seebach F, Riordan M, et al. Functional activation of heat shock factor and hypoxia-inducible factor in the kidney. J Am Soc Nephrol, 2002, 13(8): 2094-2101.
30.	Daha MR, van Kooten C. Is the proximal tubular cell a proinflammatory cell?. Nephrol Dial Transplant, 2000, 15(Suppl 6): 41-43.
31.	Takada M, Nadeau KC, Shaw GD, et al. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest, 1997, 99(11): 2682-2690.
32.	Vilaysane A, Chun J, Seamone ME, et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol, 2010, 21(10): 1732-1744.
33.	Vallés PG, Lorenzo AG, Bocanegra V, et al. Acute kidney injury: what part do toll-like receptors play?. Int J Nephrol Renovasc Dis, 2014, 7: 241-251.
34.	Kurts C, Panzer U, Anders HJ, et al. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol, 2013, 13(10): 738-753.
35.	Bolisetty S, Agarwal A. Neutrophils in acute kidney injury: not neutral any more. Kidney Int, 2009, 75(7): 674-676.
36.	Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature, 2010, 464(7293): 1357-1361.
37.	Li L, Huang L, Sung SS, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int, 2008, 74(12): 1526-1537.
38.	Furuichi K, Wada T, Iwata Y, et al. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol, 2003, 14(10): 2503-2515.
39.	Bruno S, Grange C, Collino F, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One, 2012, 7(3): e33115.
40.	Shen B, Liu J, Zhang F, et al. CCR2 positive exosome released by mesenchymal stem cells suppresses macrophage functions and alleviates ischemia/reperfusion-induced renal injury. Stem Cells Int, 2016, 2016: 1240301.
41.	Cao J, Wang B, Tang T, et al. Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury. Stem Cell Res Ther, 2020, 11(1): 206.
42.	Asea A, Kraeft SK, Kurt-Jones EA, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med, 2000, 6(4): 435-442.
43.	Ullah M, Liu DD, Rai S, et al. HSP70-mediated NLRP3 inflammasome suppression underlies reversal of acute kidney injury following extracellular vesicle and focused ultrasound combination therapy. Int J Mol Sci, 2020, 21(11): 4085.
44.	Alzahrani FA. Melatonin improves therapeutic potential of mesenchymal stem cells-derived exosomes against renal ischemia-reperfusion injury in rats. Am J Transl Res, 2019, 11(5): 2887-2907.
45.	Betteridge DJ. What is oxidative stress?. Metabolism, 2000, 49(2 Suppl 1): 3-8.
46.	Emma F, Montini G, Parikh SM, et al. Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol, 2016, 12(5): 267-280.
47.	Brooks C, Wei Q, Cho SG, et al. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest, 2009, 119(5): 1275-1285.
48.	Ruiz S, Pergola PE, Zager RA, et al. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int, 2013, 83(6): 1029-1041.
49.	Sanz AB, Santamaría B, Ruiz-Ortega M, et al. Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol, 2008, 19(9): 1634-1642.
50.	Zhang G, Zou X, Miao S, et al. The anti-oxidative role of micro-vesicles derived from human Wharton-Jelly mesenchymal stromal cells through NOX2/gp91(phox) suppression in alleviating renal ischemia-reperfusion injury in rats. PLoS One, 2014, 9(3): e92129.
51.	Chen W, Yan Y, Song C, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal fibrosis by releasing from G₂/M cell cycle arrest. Biochem J, 2017, 474(24): 4207-4218.
52.	Zhang G, Zou X, Huang Y, et al. Mesenchymal stromal cell-derived extracellular vesicles protect against acute kidney injury through anti-oxidation by enhancing Nrf2/ARE activation in rats. Kidney Blood Press Res, 2016, 41(2): 119-128.
53.	Qi H, Wang Y, Fa S, et al. Extracellular vesicles as natural delivery carriers regulate oxidative stress under pathological conditions. Front Bioeng Biotechnol, 2021, 9: 752019.
54.	Cao H, Cheng Y, Gao H, et al. In vivo tracking of mesenchymal stem cell-derived extracellular vesicles improving mitochondrial function in renal ischemia-reperfusion injury. ACS Nano, 2020, 14(4): 4014-4026.
55.	Ruiz-Ortega M, Rayego-Mateos S, Lamas S, et al. Targeting the progression of chronic kidney disease. Nat Rev Nephrol, 2020, 16(5): 269-288.
56.	Sancho-Martínez SM, López-Novoa JM, López-Hernández FJ. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury. Clin Kidney J, 2015, 8(5): 548-559.
57.	Tang C, Ma Z, Zhu J, et al. P53 in kidney injury and repair: mechanism and therapeutic potentials. Pharmacol Ther, 2019, 195: 5-12.
58.	Zhang D, Liu Y, Wei Q, et al. Tubular p53 regulates multiple genes to mediate AKI. J Am Soc Nephrol, 2014, 25(10): 2278-2289.
59.	Cao JY, Wang B, Tang TT, et al. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics, 2021, 11(11): 5248-5266.
60.	Lindoso RS, Collino F, Bruno S, et al. Extracellular vesicles released from mesenchymal stromal cells modulate miRNA in renal tubular cells and inhibit ATP depletion injury. Stem Cells Dev, 2014, 23(15): 1809-1819.
61.	Natalicchio A, Laviola L, De Tullio C, et al. Role of the p66Shc isoform in insulin-like growth factor I receptor signaling through MEK/Erk and regulation of actin cytoskeleton in rat myoblasts. J Biol Chem, 2004, 279(42): 43900-43909.
62.	Zhu H, Shyh-Chang N, Segrè AV, et al. The Lin28/let-7 axis regulates glucose metabolism. Cell, 2011, 147(1): 81-94.
63.	Zhang K, Chen S, Sun H, et al. In vivo two-photon microscopy reveals the contribution of Sox9 + cell to kidney regeneration in a mouse model with extracellular vesicle treatment. J Biol Chem, 2020, 295(34): 12203-12213.
64.	Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol, 2009, 20(5): 1053-1067.
65.	Tomasoni S, Longaretti L, Rota C, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev, 2013, 22(5): 772-780.
66.	Ju GQ, Cheng J, Zhong L, et al. Microvesicles derived from human umbilical cord mesenchymal stem cells facilitate tubular epithelial cell dedifferentiation and growth via hepatocyte growth factor induction. PLoS One, 2015, 10(3): e0121534.
67.	Zou X, Zhang G, Cheng Z, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther, 2014, 5(2): 40.

1. Mehta RL, Cerdá J, Burdmann EA, et al. International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet, 2015, 385(9987): 2616-2643.
2. Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest, 2011, 121(11): 4210-4221.
3. Ricci Z, Cruz DN, Ronco C. Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nat Rev Nephrol, 2011, 7(4): 201-208.
4. Jang HR, Rabb H. The innate immune response in ischemic acute kidney injury. Clin Immunol, 2009, 130(1): 41-50.
5. Smith SF, Hosgood SA, Nicholson ML. Ischemia-reperfusion injury in renal transplantation: 3 key signaling pathways in tubular epithelial cells. Kidney Int, 2019, 95(1): 50-56.
6. Pefanis A, Ierino FL, Murphy JM, et al. Regulated necrosis in kidney ischemia-reperfusion injury. Kidney Int, 2019, 96(2): 291-301.
7. Klinker MW, Wei CH. Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. World J Stem Cells, 2015, 7(3): 556-567.
8. Wang Y, Chen X, Cao W, et al. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol, 2014, 15(11): 1009-1016.
9. Zhao M, Liu S, Wang C, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate mitochondrial damage and inflammation by stabilizing mitochondrial DNA. ACS Nano, 2021, 15(1): 1519-1538.
10. Tang TT, Wang B, Wu M, et al. Extracellular vesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI. Sci Adv, 2020, 6(33): eaaz0748.
11. Zhang C, Shang Y, Chen X, et al. Supramolecular nanofibers containing arginine-glycine-aspartate (RGD) peptides boost therapeutic efficacy of extracellular vesicles in kidney repair. ACS Nano, 2020, 14(9): 12133-12147.
12. Collino F, Bruno S, Incarnato D, et al. AKI recovery induced by mesenchymal stromal cell-derived extracellular vesicles carrying microRNAs. J Am Soc Nephrol, 2015, 26(10): 2349-2360.
13. Eitan E, Tosti V, Suire CN, et al. In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles. Aging Cell, 2017, 16(6): 1430-1433.
14. Danielson KM, Shah R, Yeri A, et al. Plasma Circulating extracellular RNAs in left ventricular remodeling post-myocardial infarction. EBio Medicine, 2018, 32: 172-181.
15. Yu HA, Perez L, Chang Q, et al. A phase 1/2 trial of ruxolitinib and erlotinib in patients with EGFR-mutant lung adenocarcinomas with acquired resistance to erlotinib. J Thorac Oncol, 2017, 12(1): 102-109.
16. An T, Qin S, Xu Y, et al. Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. J Extracell Vesicles, 2015, 4: 27522.
17. Jia Y, Ding X, Zhou L, et al. Mesenchymal stem cells-derived exosomal microRNA-139-5p restrains tumorigenesis in bladder cancer by targeting PRC1. Oncogene, 2021, 40(2): 246-261.
18. Li CX, Song J, Li X, et al. Circular RNA 0001273 in exosomes derived from human umbilical cord mesenchymal stem cells (UMSCs) in myocardial infarction. Eur Rev Med Pharmacol Sci, 2020, 24(19): 10086-10095.
19. Yan Y, Jiang W, Tan Y, et al. hucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury. Mol Ther, 2017, 25(2): 465-479.
20. Liu B, Hu D, Zhou Y, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against renal interstitial fibrosis through ROS-mediated P38MAPK/ERK signaling pathway. Am J Transl Res, 2020, 12(9): 4998-5014.
21. Stroo I, Stokman G, Teske GJ, et al. Chemokine expression in renal ischemia/reperfusion injury is most profound during the reparative phase. Int Immunol, 2010, 22(6): 433-442.
22. Jang HR, Ko GJ, Wasowska BA, et al. The interaction between ischemia-reperfusion and immune responses in the kidney. J Mol Med (Berl), 2009, 87(9): 859-864.
23. Jang HR, Rabb H. Immune cells in experimental acute kidney injury. Nat Rev Nephrol, 2015, 11(2): 88-101.
24. Tammaro A, Kers J, Scantlebery AML, et al. Metabolic flexibility and innate immunity in renal ischemia reperfusion injury: the fine balance between adaptive repair and tissue degeneration. Front Immunol, 2020, 11: 1346.
25. Sutton TA, Mang HE, Campos SB, et al. Injury of the renal microvascular endothelium alters barrier function after ischemia. Am J Physiol Renal Physiol, 2003, 285(2): F191-198.
26. Brodsky SV, Yamamoto T, Tada T, et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol, 2002, 282(6): F1140-1149.
27. Malek M, Nematbakhsh M. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev, 2015, 4(2): 20-27.
28. Cao CC, Ding XQ, Ou ZL, et al. In vivo transfection of NF-kappaB decoy oligodeoxynucleotides attenuate renal ischemia/reperfusion injury in rats. Kidney Int, 2004, 65(3): 834-845.
29. Eickelberg O, Seebach F, Riordan M, et al. Functional activation of heat shock factor and hypoxia-inducible factor in the kidney. J Am Soc Nephrol, 2002, 13(8): 2094-2101.
30. Daha MR, van Kooten C. Is the proximal tubular cell a proinflammatory cell?. Nephrol Dial Transplant, 2000, 15(Suppl 6): 41-43.
31. Takada M, Nadeau KC, Shaw GD, et al. The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. J Clin Invest, 1997, 99(11): 2682-2690.
32. Vilaysane A, Chun J, Seamone ME, et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol, 2010, 21(10): 1732-1744.
33. Vallés PG, Lorenzo AG, Bocanegra V, et al. Acute kidney injury: what part do toll-like receptors play?. Int J Nephrol Renovasc Dis, 2014, 7: 241-251.
34. Kurts C, Panzer U, Anders HJ, et al. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol, 2013, 13(10): 738-753.
35. Bolisetty S, Agarwal A. Neutrophils in acute kidney injury: not neutral any more. Kidney Int, 2009, 75(7): 674-676.
36. Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature, 2010, 464(7293): 1357-1361.
37. Li L, Huang L, Sung SS, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int, 2008, 74(12): 1526-1537.
38. Furuichi K, Wada T, Iwata Y, et al. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol, 2003, 14(10): 2503-2515.
39. Bruno S, Grange C, Collino F, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One, 2012, 7(3): e33115.
40. Shen B, Liu J, Zhang F, et al. CCR2 positive exosome released by mesenchymal stem cells suppresses macrophage functions and alleviates ischemia/reperfusion-induced renal injury. Stem Cells Int, 2016, 2016: 1240301.
41. Cao J, Wang B, Tang T, et al. Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury. Stem Cell Res Ther, 2020, 11(1): 206.
42. Asea A, Kraeft SK, Kurt-Jones EA, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med, 2000, 6(4): 435-442.
43. Ullah M, Liu DD, Rai S, et al. HSP70-mediated NLRP3 inflammasome suppression underlies reversal of acute kidney injury following extracellular vesicle and focused ultrasound combination therapy. Int J Mol Sci, 2020, 21(11): 4085.
44. Alzahrani FA. Melatonin improves therapeutic potential of mesenchymal stem cells-derived exosomes against renal ischemia-reperfusion injury in rats. Am J Transl Res, 2019, 11(5): 2887-2907.
45. Betteridge DJ. What is oxidative stress?. Metabolism, 2000, 49(2 Suppl 1): 3-8.
46. Emma F, Montini G, Parikh SM, et al. Mitochondrial dysfunction in inherited renal disease and acute kidney injury. Nat Rev Nephrol, 2016, 12(5): 267-280.
47. Brooks C, Wei Q, Cho SG, et al. Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest, 2009, 119(5): 1275-1285.
48. Ruiz S, Pergola PE, Zager RA, et al. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int, 2013, 83(6): 1029-1041.
49. Sanz AB, Santamaría B, Ruiz-Ortega M, et al. Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol, 2008, 19(9): 1634-1642.
50. Zhang G, Zou X, Miao S, et al. The anti-oxidative role of micro-vesicles derived from human Wharton-Jelly mesenchymal stromal cells through NOX2/gp91(phox) suppression in alleviating renal ischemia-reperfusion injury in rats. PLoS One, 2014, 9(3): e92129.
51. Chen W, Yan Y, Song C, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal fibrosis by releasing from G₂/M cell cycle arrest. Biochem J, 2017, 474(24): 4207-4218.
52. Zhang G, Zou X, Huang Y, et al. Mesenchymal stromal cell-derived extracellular vesicles protect against acute kidney injury through anti-oxidation by enhancing Nrf2/ARE activation in rats. Kidney Blood Press Res, 2016, 41(2): 119-128.
53. Qi H, Wang Y, Fa S, et al. Extracellular vesicles as natural delivery carriers regulate oxidative stress under pathological conditions. Front Bioeng Biotechnol, 2021, 9: 752019.
54. Cao H, Cheng Y, Gao H, et al. In vivo tracking of mesenchymal stem cell-derived extracellular vesicles improving mitochondrial function in renal ischemia-reperfusion injury. ACS Nano, 2020, 14(4): 4014-4026.
55. Ruiz-Ortega M, Rayego-Mateos S, Lamas S, et al. Targeting the progression of chronic kidney disease. Nat Rev Nephrol, 2020, 16(5): 269-288.
56. Sancho-Martínez SM, López-Novoa JM, López-Hernández FJ. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury. Clin Kidney J, 2015, 8(5): 548-559.
57. Tang C, Ma Z, Zhu J, et al. P53 in kidney injury and repair: mechanism and therapeutic potentials. Pharmacol Ther, 2019, 195: 5-12.
58. Zhang D, Liu Y, Wei Q, et al. Tubular p53 regulates multiple genes to mediate AKI. J Am Soc Nephrol, 2014, 25(10): 2278-2289.
59. Cao JY, Wang B, Tang TT, et al. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics, 2021, 11(11): 5248-5266.
60. Lindoso RS, Collino F, Bruno S, et al. Extracellular vesicles released from mesenchymal stromal cells modulate miRNA in renal tubular cells and inhibit ATP depletion injury. Stem Cells Dev, 2014, 23(15): 1809-1819.
61. Natalicchio A, Laviola L, De Tullio C, et al. Role of the p66Shc isoform in insulin-like growth factor I receptor signaling through MEK/Erk and regulation of actin cytoskeleton in rat myoblasts. J Biol Chem, 2004, 279(42): 43900-43909.
62. Zhu H, Shyh-Chang N, Segrè AV, et al. The Lin28/let-7 axis regulates glucose metabolism. Cell, 2011, 147(1): 81-94.
63. Zhang K, Chen S, Sun H, et al. In vivo two-photon microscopy reveals the contribution of Sox9 + cell to kidney regeneration in a mouse model with extracellular vesicle treatment. J Biol Chem, 2020, 295(34): 12203-12213.
64. Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol, 2009, 20(5): 1053-1067.
65. Tomasoni S, Longaretti L, Rota C, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev, 2013, 22(5): 772-780.
66. Ju GQ, Cheng J, Zhong L, et al. Microvesicles derived from human umbilical cord mesenchymal stem cells facilitate tubular epithelial cell dedifferentiation and growth via hepatocyte growth factor induction. PLoS One, 2015, 10(3): e0121534.
67. Zou X, Zhang G, Cheng Z, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther, 2014, 5(2): 40.

West China Medical Journal

Role and mechanism of mesenchymal stem cell-derived exosomes on renal ischemia-reperfusion injury

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