Mesenchymal Stem Cells Prevent SLC39A14-Dependent Hepatocyte Ferroptosis through Exosomal miR-16-5p in Liver Graft.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Ferroptosis*/genetics ; Hepatocytes*/metabolism ; MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Mesenchymal Stem Cells*/metabolism ; Exosomes*/metabolism ; Exosomes*/genetics ; Cation Transport Proteins*/genetics ; Cation Transport Proteins*/metabolism ; Reperfusion Injury*/metabolism ; Reperfusion Injury*/genetics; Mice ; Animals ; Humans ; Disease Models, Animal ; Liver Transplantation/methods ; Male

Ischemia-reperfusion injury (IRI) is the leading cause of hepatic graft dysfunction, resulting from hepatocyte damage. Nevertheless, given the few specialized therapeutics available in hepatic IRI, additional mechanistic insights into hepatocyte damage are required. Here, the protein solute carrier family 39 member 14 (SLC39A14) is identified as a pro-ferroptosis target in hepatocytes of human liver allografts through single-cell RNA sequencing analysis. SLC39A14 knockdown significantly mitigated hepatic IRI by preventing hepatocyte ferroptosis in vivo and in vitro. Mechanistically, the inhibition of SLC39A14 suppressed non-transferrin-bound iron (NTBI) uptake by hepatocytes, thereby reducing iron overload and cell ferroptosis. Moreover, human bone marrow-derived mesenchymal stem cells (hBMSCs) are found to exhibit a notable therapeutic effect on hepatic IRI by downregulating SLC39A14 expression. Exosomes derived from hBMSCs delivered abundant miR-16-5p into hepatocytes, which post-transcriptionally suppressed the expression of SLC39A14 and reduced cell ferroptosis induced by hepatic IRI. In conclusion, SLC39A14 triggers hepatic IRI by mediating NTBI uptake into hepatocytes and inducing hepatocyte ferroptosis. Moreover, hBMSC-based therapy is promising to reverse this progression of hepatic IRI.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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82072216 National Natural Science Foundation of China; 2022A1515011556 Guangdong Basic and Applied Basic Research Foundation; U22A20276 Joint Funds of the National Natural Science Foundation of China; 2023B110006 Science and Technology Planning Project of Guangdong Province-Regional Innovation Capacity and Support System Construction; 2021B1515230012 Provincial-enterprise Joint Funds of Guangdong Basic and Applied Basic Research Foundation; 202201020429 Science and Technology Program of Guangzhou, China; 2023WW501 The "Five and five" Project of the Third Affiliated Hospital of Sun Yat-Sen University

Keywords: MiR‐16‐5p; SLC39A14; ferroptosis; hepatic ischemia‐reperfusion injury; mesenchymal stem cells

0 (MicroRNAs)
0 (Cation Transport Proteins)
0 (SLC39A14 protein, human)

Date Created: 20241216 Date Completed: 20250210 Latest Revision: 20250212

20250212

PMC11809355

10.1002/advs.202411380

39680749