AMSC-EVs attenuate acute kidney injury through TXNIP-IKKα/NFκB signaling-mediated renal CX3CR1 ⁺ macrophage polarization.

Publisher: BioMed Central Country of Publication: England NLM ID: 101527581 Publication Model: Electronic Cited Medium: Internet ISSN: 1757-6512 (Electronic) Linking ISSN: 17576512 NLM ISO Abbreviation: Stem Cell Res Ther Subsets: MEDLINE

Original Publication: London : BioMed Central

Acute Kidney Injury*/therapy ; Acute Kidney Injury*/metabolism ; Acute Kidney Injury*/chemically induced ; Acute Kidney Injury*/pathology ; CX3C Chemokine Receptor 1*/metabolism ; CX3C Chemokine Receptor 1*/genetics ; Macrophages*/metabolism ; Carrier Proteins*/metabolism ; Mesenchymal Stem Cells*/metabolism ; Mesenchymal Stem Cells*/cytology; Animals ; Mice ; NF-kappa B/metabolism ; Signal Transduction ; Cisplatin ; I-kappa B Kinase/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Disease Models, Animal ; Thioredoxins

Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were conducted in accordance with the ARRIVE 2.0 guidelines and approved by the Animal Ethical and Welfare Committee of Nanjing Medical University (Title: Mechanistic Study of Adipose-derived Mesenchymal Stem Cells Promoting Repair after Acute Kidney Injury; Approval No.: IACUC-2001017; Date: March 4, 2022). This study strictly adhered to the Declaration of Helsinki, and adipose tissue collection was performed after obtaining written informed consent from the participants. The study protocol was approved by the Ethics Committee of Sir Run Run Shaw Hospital, Nanjing Medical University (Title: Protective Effects of Human Adipose-derived Mesenchymal Stem Cell-derived Extracellular Vesicles on Acute Kidney Injury in Mice; Approval No.: 2024-SR-007; Date: January 18, 2024). The THP-1 cell line (RRID: CVCL_0006) was obtained from Shanghai Zhongqiao Xinzou Biotechnology Co., Ltd. (originally purchased from ATCC, USA). For detailed information regarding compliance and prior ethical approval of the cell line, please visit the ATCC official website: https://www.atcc.org . Competing interests: The authors declare no competing interests.
Background: Extracellular vesicles generated from mesenchymal stem cells (MSC-EVs) have garnered significant attention as a cell-free treatment option for acute kidney injury (AKI). The fundamental processes and capabilities of MSC-EVs in attenuating kidney injury are still largely unclear.
Methods: The AKI mouse model was established by intraperitoneal injection of cisplatin. AKI mice were further randomized to receive Phosphate- Buffered Saline, adipose-derived mesenchymal stem cell-extracellular vesicles (AMSC-EVs (50 µg), or AMSC-EVs (100 µg) into the tail vein. Following a 96-hour post-injury period, the mice were euthanized, and kidney tissues together with blood samples were procured for paraffin embedding and immunoblotting. To investigate the relationship between AMSC-EVs and renal CX3CR1 ⁺ macrophages, CX3CR1 ⁺ macrophage-specific conditional knockout mice (CX3CR1-Cre+/-; Rosa26-LSL-DTR+/-) were generated. Additionally, overexpression of experiments of thioredoxin-interacting protein (TXNIP) were conducted to analyze macrophage polarization and TXNIP-IKKα/NFκB signaling pathway expression.
Results: In mice, AMSC-EVs reduced the renal tubule damage and ameliorated cisplatin-induced AKI in a dose-dependent manner. However, in the CX3CR1 ⁺ macrophage ablated group, AKI mice exhibited more severe renal tubular pathology compared to littermate controls, suggesting diminished therapeutic efficacy of AMSC-EVs post CX3CR1 ⁺ macrophage ablation. Meanwhile, AMSC-EVs promoted polarization of renal CX3CR1 ⁺ macrophages towards reparative M2 macrophages, leading to increased production of anti-inflammatory factors and subsequent alteration of the inflammatory microenvironment in renal tubular cells, thereby facilitating the self-repair process in AKI mice. Mechanistically, AMSC-EVs suppressed the protein expression of TXNIP-IKKα/NFκB in renal CX3CR1 ⁺ macrophages. Finally, overexpression of TXNIP appeared to attenuate the protective effects of AMSC-EVs in renal CX3CR1 ⁺ macrophages.
Conclusions: Our study findings suggest that AMSC-EVs modulate the polarization of renal CX3CR1 ⁺ macrophages and promote renal self-recovery following cisplatin-induced AKI through the TXNIP-IKKα/NFκB signaling pathway.
(© 2025. The Author(s).)

Circ Res. 2021 Dec 3;129(12):1086-1101. (PMID: 34645281)
J Thromb Thrombolysis. 2010 May;29(4):443-8. (PMID: 19915801)
Stem Cell Res Ther. 2022 Apr 8;13(1):149. (PMID: 35395782)
Radiology. 2006 Jan;238(1):200-10. (PMID: 16373768)
Cell Mol Immunol. 2020 Dec;17(12):1245-1256. (PMID: 31673056)
Cell. 2020 Oct 1;183(1):94-109.e23. (PMID: 32937105)
EBioMedicine. 2018 Oct;36:140-150. (PMID: 30197023)
Ren Fail. 2024 Dec;46(1):2330629. (PMID: 38494199)
Sci Immunol. 2020 Apr 10;5(46):. (PMID: 32276965)
Free Radic Biol Med. 2023 Jan;194:12-22. (PMID: 36436727)
Life Sci. 2022 Aug 1;302:120646. (PMID: 35595070)
Chem Biol Interact. 2017 Dec 25;278:212-221. (PMID: 29108777)
Cell Rep. 2020 Aug 4;32(5):107979. (PMID: 32755573)
Front Immunol. 2014 Jan 09;4:514. (PMID: 24409188)
Acta Pharmacol Sin. 2020 Jun;41(6):771-781. (PMID: 31937929)
Nutrients. 2017 Sep 29;9(10):. (PMID: 28961169)
Stem Cell Res Ther. 2025 Mar 05;16(1):111. (PMID: 40038808)
Thromb Res. 2020 Sep;193:45-52. (PMID: 32521334)
Exp Clin Transplant. 2015 Apr;13 Suppl 1:207-13. (PMID: 25894156)
Stem Cells. 2004;22(7):1338-45. (PMID: 15579651)
Int J Mol Sci. 2023 May 04;24(9):. (PMID: 37175935)
Science. 2013 Sep 20;341(6152):1387-90. (PMID: 24030490)
Nat Commun. 2020 May 8;11(1):2280. (PMID: 32385245)
J Nanobiotechnology. 2024 Jun 6;22(1):316. (PMID: 38844939)
Front Immunol. 2023 May 15;14:1082078. (PMID: 37256130)
Kidney Int. 2023 Jun;103(6):1105-1119. (PMID: 37097268)
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023 Jul 28;48(7):957-966. (PMID: 37724398)
Am J Respir Crit Care Med. 2015 Feb 15;191(4):437-47. (PMID: 25536148)
Proc Natl Acad Sci U S A. 2022 Aug 30;119(35):e2116505119. (PMID: 35994650)
Inflammation. 2021 Feb;44(1):217-228. (PMID: 32892306)
Kidney Int. 2003 Oct;64(4):1273-82. (PMID: 12969145)
Annu Rev Physiol. 2017 Feb 10;79:449-469. (PMID: 28192060)
Int J Biochem Cell Biol. 2018 May;98:43-53. (PMID: 29477360)
Pharmacol Ther. 2022 Mar;231:107989. (PMID: 34492237)
Stem Cell Res Ther. 2021 Mar 31;12(1):219. (PMID: 33789750)
Biochem Biophys Res Commun. 2025 Mar 25;754:151425. (PMID: 40023991)
J Am Soc Nephrol. 2015 Apr;26(4):896-906. (PMID: 25266072)
Cells. 2020 Oct 13;9(10):. (PMID: 33065974)
Adv Sci (Weinh). 2022 May;9(15):e2103222. (PMID: 35332686)
Cell. 2002 Apr;109 Suppl:S81-96. (PMID: 11983155)
Eur J Immunol. 2020 Jun;50(6):795-808. (PMID: 32068249)
J Interferon Cytokine Res. 2018 Dec;38(12):566-577. (PMID: 30523751)
Int J Mol Sci. 2022 Oct 14;23(20):. (PMID: 36293111)
Ageing Res Rev. 2024 Aug;99:102391. (PMID: 38914266)
Research (Wash D C). 2025 Jun 02;8:0716. (PMID: 40458609)
J Hematol Oncol. 2021 Feb 12;14(1):24. (PMID: 33579329)
J Immunol Res. 2021 Dec 7;2021:5521051. (PMID: 34917688)
Lab Invest. 2018 Sep;98(9):1211-1224. (PMID: 29884908)
Int Immunopharmacol. 2017 Mar;44:26-37. (PMID: 28068647)
Nature. 2020 Jan;577(7790):405-409. (PMID: 31775156)
Kidney Int. 2013 Mar;83(3):372-6. (PMID: 23302721)
J Am Soc Nephrol. 2009 Apr;20(4):730-41. (PMID: 19211714)
Immunol Lett. 2021 Nov;239:23-31. (PMID: 34418490)
Crit Care. 2018 Dec 27;22(1):359. (PMID: 30591070)
J Control Release. 2016 Aug 10;235:337-351. (PMID: 27297779)
J Cell Sci. 2006 Jun 1;119(Pt 11):2204-13. (PMID: 16684817)
Adv Sci (Weinh). 2023 Jul;10(20):e2207334. (PMID: 37162248)
Oxid Med Cell Longev. 2016;2016:2386068. (PMID: 27867451)
Stem Cells Transl Med. 2021 Nov;10(11):1516-1529. (PMID: 34327849)
Stem Cells. 2013 Sep;31(9):1840-56. (PMID: 23666768)
Int Immunopharmacol. 2024 May 30;133:112001. (PMID: 38608443)
Immunology. 2023 Jan;168(1):120-134. (PMID: 36053796)
Free Radic Biol Med. 2021 Mar;165:54-66. (PMID: 33476797)
Toxicol In Vitro. 2018 Feb;46:265-272. (PMID: 29054699)

20212BAB216071 Youth Science Foundation of Jiangxi Province; BKJP1220240788 Health Commission of Jiangxi Province; 2025_000694 Jiujiang City Key Research and Development Program Project; 82170698 National Natural Science Foundation of China

Keywords: Acute kidney injury; CX3CR1+ macrophages; Extracellular vesicles; Mesenchymal stem cell; TXNIP-IKKα/NFκB

0 (CX3C Chemokine Receptor 1)
0 (NF-kappa B)
0 (Txnip protein, mouse)
0 (Carrier Proteins)
Q20Q21Q62J (Cisplatin)
EC 2.7.11.10 (I-kappa B Kinase)
0 (Cx3cr1 protein, mouse)
52500-60-4 (Thioredoxins)

Date Created: 20251114 Date Completed: 20251115 Latest Revision: 20251117

20251117

PMC12619428

10.1186/s13287-025-04754-z

41239483