Targeting Bacteria‐Induced Ferroptosis of Bone Marrow Mesenchymal Stem Cells to Promote the Repair of Infected Bone Defects
The specific mechanisms underlying bacteria-triggered cell death and osteogenic dysfunction in host bone marrow mesenchymal stem cells (BMSCs) remain unclear, posing a significant challenge to the repair of infected bone defects. This study identifies ferroptosis as the predominant cause of BMSCs death in the infected bone microenvironment. Mechanistically, the bacteria-induced activation of the innate immune response in BMSCs leads to upregulation and phosphorylation of interferon regulatory factor 7 (IRF7), thus facilitating IRF7-dependent ferroptosis of BMSCs through the transcriptional upregulation of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4). Moreover, it is found that intervening in ferroptosis can partially rescue cell injuries and osteogenic dysfunction. Based on these findings, a hydrogel composite 3D-printed scaffold is designed with reactive oxygen species (ROS)-responsive release of antibacterial quaternized chitosan and sustained delivery of the ferroptosis inhibitor Ferrostatin-1 (Fer-1), capable of eradicating pathogens and promoting bone regeneration in a rat model of infected bone defects. Together, this study suggests that ferroptosis of BMSCs is a promising therapeutic target for infected bone defect repair.
Authors
- Yixuan Lin (ORCID: https://orcid.org/0000-0003-0567-0831)
- Yakun Liang
- Caiqi Cheng (ORCID: https://orcid.org/0009-0006-2865-4171)
- Fupeng Li (ORCID: https://orcid.org/0000-0002-3329-1989)
- Zhifeng Yu (ORCID: https://orcid.org/0000-0002-2224-8344)
- Yiqi Yang (ORCID: https://orcid.org/0000-0001-5797-9967)
- Kai Yuan (ORCID: https://orcid.org/0000-0002-4777-4076)
- Weiqing Kong (ORCID: https://orcid.org/0000-0002-3203-6919)
- Tianyou Kan
- Tingting Tang (ORCID: https://orcid.org/0000-0002-1670-7452)
- Hanjun Li (ORCID: https://orcid.org/0000-0002-7017-8782)
- Haiyong Ao (ORCID: https://orcid.org/0000-0002-7967-2648)
- Haishuang Chang
- Yihao Liu (ORCID: https://orcid.org/0000-0002-1818-160X)
- Kai Huang (ORCID: https://orcid.org/0000-0001-9198-9202)
- Jie Huang (ORCID: https://orcid.org/0000-0001-5815-190X)
- Feng Zhou (ORCID: https://orcid.org/0000-0001-7279-8451)
- Shengbing Yang
- Yao Wang (ORCID: https://orcid.org/0009-0001-3762-4015)
Institutions
- East China Jiaotong University (CN)
- Xuzhou Medical College (CN)
- Shanghai Jiao Tong University (CN)
- Renji Hospital (CN)
- Soochow University (CN)
- Shanghai Ninth People's Hospital (CN)
- Xuzhou Central Hospital (CN)
- First Affiliated Hospital of Soochow University (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1002/advs.202404453
- Citations
- 24
- Primary Topic
- Cancer-related molecular mechanisms research
- Type
- article
- Field-Weighted Citation Impact
- 6.84
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation