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

  • Stem Cell Res Ther. 2025 Nov 14;16(1):639. doi: 10.1186/s13287-025-04754-z.
Wei-Juan Deng  #  1  2 ,  Rui Tang  #  1 ,  Meng-Qing Ma  #  3 ,  Hao Zhang  3 ,  Chang-Chun Cao  4
Affiliations
  • 1. Department of Nephrology, Sir Run Run hospital, Nanjing Medical University, No. 109 Longmian Road, Nanjing, 211112, China.
  • 2. Department of Nephrology, Jiujiang No.1 People's Hospital, Jiujiang, China.
  • 3. Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 4. Department of Nephrology, Sir Run Run hospital, Nanjing Medical University, No. 109 Longmian Road, Nanjing, 211112, China. [email protected].
  • # Contributed equally.
PMID: 41239483 DOI: 10.1186/s13287-025-04754-z
Abstract

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.

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