Related Experiment Video
Updated: Oct 15, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial
Fumiya Ito1, Katsuhiro Kato2, Izumi Yanatori1
1Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Abstract:
Asbestos-associated diseases remain a social burden worldwide. Our previous studies identified asbestos-induced iron-rich milieu for mesothelial cells with ceaseless macrophage ferroptosis. However, molecular mechanisms how this mutagenic milieu influences mesothelial cells have not been elucidated yet. Here, we propose a novel mechanism that extracellular vesicles (EVs) mediate asbestos-associated mutagenic factors to mesothelial cells. In a mice model of intraperitoneal crocidolite injection, mutagenic milieu highly expressed CD63, an exosomal marker. We then used a GFP-CD63 labeled THP-1 macrophage model exposed to crocidolite/iron, which generated EVs under ferroptotic process. We observed that MeT-5A mesothelial cells can receive and internalize these EVs. Furthermore, we comprehensively analyzed the ferroptosis-dependent EVs (FedEVs) for transported proteins and identified ferritin heavy/light chains as major components. Therefore, we inferred that FedEVs transport iron from ferroptotic macrophages to mesothelial cells. RNA sequencing revealed that the mesothelial cells receiving higher amounts of the FedEVs were mitotic, especially at the S and G2/M phases, by the use of Fucci mesothelial cells. Nuclear 8-hydroxy-2'-deoxyguanosine and γ-H2AX were significantly increased in the recipient mesothelial cells after exposure to FedEVs. Collectively, we here demonstrate a novel mechanism that FedEVs act as a key mutagenic mediator by transporting iron, which contribute to asbestos-induced mesothelial carcinogenesis.
Insights
Extracellular vesicles (EVs) transport iron from dying macrophages to mesothelial cells, promoting cell division and DNA damage, contributing to asbestos-induced cancer.
Area of Science:
- Cell Biology
- Toxicology
- Oncology
Background:
- Asbestos exposure causes diseases due to an iron-rich environment and macrophage ferroptosis.
- The molecular mechanisms linking this environment to mesothelial cell transformation are unclear.
Purpose of the Study:
- To elucidate the role of extracellular vesicles (EVs) in mediating asbestos-associated mutagenic factors to mesothelial cells.
- To investigate the mechanism of iron transport from ferroptotic macrophages to mesothelial cells via EVs.
Main Methods:
- Mice model with intraperitoneal crocidolite injection.
- GFP-CD63 labeled THP-1 macrophage model exposed to crocidolite/iron.
- Analysis of EVs from ferroptotic macrophages (FedEVs) for protein content.
- RNA sequencing and cell cycle analysis of mesothelial cells exposed to FedEVs.
- Measurement of DNA damage markers (8-hydroxy-2'-deoxyguanosine and γ-H2AX).
Main Results:
- Ferroptosis-dependent EVs (FedEVs) were generated and characterized, containing ferritin heavy/light chains.
- Mesothelial cells internalized FedEVs, receiving iron from ferroptotic macrophages.
- FedEVs induced mitotic activity in mesothelial cells, particularly in S and G2/M phases.
- Significant increases in DNA damage markers were observed in mesothelial cells exposed to FedEVs.
Conclusions:
- FedEVs act as a novel mediator, transporting iron from ferroptotic macrophages to mesothelial cells.
- This iron transport by FedEVs contributes to asbestos-induced mesothelial cell proliferation and DNA damage.
- The findings reveal a new mechanism in asbestos-related mesothelial carcinogenesis.
Related Concept Videos
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
01:28The Early Endosome: Endocytosis of Transferrin