Small extracellular vesicles from HO-1 modified BMMSCs alleviate steatotic liver grafts ischemia-reperfusion injury by delivering PDIA4 to promote reparative macrophage polarization

  • Biochim Biophys Acta Mol Basis Dis. 2025 Jun 9;1871(7):167947. doi: 10.1016/j.bbadis.2025.167947.
Huaiwen Zuo  1 ,  Yilin Pi  1 ,  Yuxin Wang  2 ,  Weiping Zheng  3 ,  Xinru Zhang  1 ,  Huiyuan Zhou  1 ,  Hongli Song  4
Affiliations
  • 1. Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, PR China.
  • 2. School of Medicine, Nankai University, Tianjin, PR China.
  • 3. Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, 300192 Tianjin, PR China; NHC Key Laboratory of Critical Care Medicine, Tianjin 300192, PR China.
  • 4. Department of Liver Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, 300192 Tianjin, PR China; Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Tianjin, PR China. Electronic address: [email protected].
PMID: 40494182 DOI: 10.1016/j.bbadis.2025.167947
Abstract

Utilizing steatotic liver donors presents a viable strategy to mitigate the donor shortage in liver transplantation. However, severe steatosis increases the susceptibility of livers to ischemia-reperfusion injury (IRI) during transplantation, and regulating hepatic macrophage polarization can suppress liver inflammation and alleviate IRI. This study investigates the effects of small extracellular vesicles (sEVs) from heme oxygenase-1 (HO-1) modified bone marrow mesenchymal stem cells (BMMSCs), termed HM-sEVs, on IRI and macrophage polarization in steatotic liver grafts. We found that HM-sEVs significantly alleviated steatotic liver grafts IRI compared to sEVs from BMMSCs (M-sEVs). Further experiments have demonstrated that HM-sEVs can be internalized by macrophages and possess a greater capacity to promote reparative macrophage polarization and inhibit inflammatory responses, compared to M-sEVs. Mechanistically, protein disulfide-isomerase A4 (PDIA4) was found to be highly enriched in HM-sEVs. HM-sEVs can deliver PDIA4 to macrophages, activating the PDIA4/HSP90/MYC axis. This activation inhibits MYC ubiquitination and degradation, thereby promoting reparative macrophage polarization. In summary, our results indicated HM-sEVs can promote hepatic reparative macrophage polarization by activating the PDIA4/HSP90/MYC axis, providing a theoretical foundation for the application of HM-sEVs in alleviating steatotic liver grafts IRI and mitigating donor liver shortages.

Keywords
BMMSCs; Ischemia-reperfusion injury; Liver transplantation; Macrophage polarization; Small extracellular vesicles; Steatotic donor liver.
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