Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss
Iron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron di...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/7836 |
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| author | Fengrun Sun Liyuan Cui Jinfeng Qian Mengdie Li Lanting Chen Chunqin Chen Dajin Li Songcun Wang Meirong Du |
| author_facet | Fengrun Sun Liyuan Cui Jinfeng Qian Mengdie Li Lanting Chen Chunqin Chen Dajin Li Songcun Wang Meirong Du |
| author_sort | Fengrun Sun |
| collection | DOAJ |
| description | Iron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron diet (LID) also showed iron deposition in the decidua and adverse pregnancy outcomes. Decreased ferroportin (cellular iron exporter) expression that inhibited the iron export from decidual stromal cells (DSCs) might be the reason for local iron deposition in DSCs from low-serum-iron RPL patients and LID-fed mice. Iron supplementation reduced iron deposition in the decidua of spontaneous abortion models and improved pregnancy outcomes. Local iron overload caused ferroptosis of DSCs by downregulating glutathione (GSH) and glutathione peroxidase 4 levels. Both GSH and cystine (for the synthesis of GSH) supplementation reduced iron-induced lipid reactive oxygen species (ROS) and cell death in DSCs. Ferroptosis inhibitor, cysteine, and GSH supplementation all effectively attenuated DSC ferroptosis and reversed embryo loss in the spontaneous abortion model and LPS-induced abortion model, making ferroptosis mitigation a potential therapeutic target for RPL patients. Further study that improves our understanding of low-serum-iron-induced DSC ferroptosis is needed to inform further clinical evaluations of the safety and efficacy of iron supplementation in women during pregnancy. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:17:17Z |
| publishDate | 2023-04-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-98e3561266414413beab76af0cd976862023-11-17T23:01:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01249783610.3390/ijms24097836Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy LossFengrun Sun0Liyuan Cui1Jinfeng Qian2Mengdie Li3Lanting Chen4Chunqin Chen5Dajin Li6Songcun Wang7Meirong Du8Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaLaboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, ChinaIron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron diet (LID) also showed iron deposition in the decidua and adverse pregnancy outcomes. Decreased ferroportin (cellular iron exporter) expression that inhibited the iron export from decidual stromal cells (DSCs) might be the reason for local iron deposition in DSCs from low-serum-iron RPL patients and LID-fed mice. Iron supplementation reduced iron deposition in the decidua of spontaneous abortion models and improved pregnancy outcomes. Local iron overload caused ferroptosis of DSCs by downregulating glutathione (GSH) and glutathione peroxidase 4 levels. Both GSH and cystine (for the synthesis of GSH) supplementation reduced iron-induced lipid reactive oxygen species (ROS) and cell death in DSCs. Ferroptosis inhibitor, cysteine, and GSH supplementation all effectively attenuated DSC ferroptosis and reversed embryo loss in the spontaneous abortion model and LPS-induced abortion model, making ferroptosis mitigation a potential therapeutic target for RPL patients. Further study that improves our understanding of low-serum-iron-induced DSC ferroptosis is needed to inform further clinical evaluations of the safety and efficacy of iron supplementation in women during pregnancy.https://www.mdpi.com/1422-0067/24/9/7836decidual stromal cellsrecurrent pregnancy lossironferroptosis |
| spellingShingle | Fengrun Sun Liyuan Cui Jinfeng Qian Mengdie Li Lanting Chen Chunqin Chen Dajin Li Songcun Wang Meirong Du Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss International Journal of Molecular Sciences decidual stromal cells recurrent pregnancy loss iron ferroptosis |
| title | Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss |
| title_full | Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss |
| title_fullStr | Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss |
| title_full_unstemmed | Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss |
| title_short | Decidual Stromal Cell Ferroptosis Associated with Abnormal Iron Metabolism Is Implicated in the Pathogenesis of Recurrent Pregnancy Loss |
| title_sort | decidual stromal cell ferroptosis associated with abnormal iron metabolism is implicated in the pathogenesis of recurrent pregnancy loss |
| topic | decidual stromal cells recurrent pregnancy loss iron ferroptosis |
| url | https://www.mdpi.com/1422-0067/24/9/7836 |
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