The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion Process
Poor placentation is closely related with the etiology of preeclampsia and may impact fetal growth restriction. For placental developmental growth, we have demonstrated that dysregulation of autophagy, a key mechanism to maintain cellular homeostasis, in trophoblasts contributes to the pathophysiolo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Reproductive Medicine |
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| Online Access: | https://www.mdpi.com/2673-3897/3/2/10 |
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| author | Atsushi Furuta Tomoko Shima Mihoko Kawaguchi Akemi Yamaki-Ushijima Ippei Yasuda Sayaka Tsuda Satoshi Yoneda Kazuma Higashisaka Shi-Bin Cheng Kenji Matsumoto Yasuo Tsutsumi Surendra Sharma Shigeru Saito Akitoshi Nakashima |
| author_facet | Atsushi Furuta Tomoko Shima Mihoko Kawaguchi Akemi Yamaki-Ushijima Ippei Yasuda Sayaka Tsuda Satoshi Yoneda Kazuma Higashisaka Shi-Bin Cheng Kenji Matsumoto Yasuo Tsutsumi Surendra Sharma Shigeru Saito Akitoshi Nakashima |
| author_sort | Atsushi Furuta |
| collection | DOAJ |
| description | Poor placentation is closely related with the etiology of preeclampsia and may impact fetal growth restriction. For placental developmental growth, we have demonstrated that dysregulation of autophagy, a key mechanism to maintain cellular homeostasis, in trophoblasts contributes to the pathophysiology of preeclampsia, a severe pregnancy complication, associated with poor placentation. It remains, however, unknown whether autophagy inhibition affects trophoblast syncytialization. This study evaluated the effect of autophagy in an in vitro syncytialization method using BeWo cells and primary human trophoblasts (PHT). In this study, we observed that autophagic activity decreased in PHT and BeWo cells during syncytialization. This decreased activity was accompanied by downregulation of the transcription factor, TFEB. Next, bafilomycin A1, an inhibitor of autophagy via suppressing V-ATPase in lysosomes, inhibited hCG production, CYP11A1 expression (a marker of differentiation), p21 expression (a senescence marker), and cell fusion in BeWo cells and PHT cells. Finally, LLOMe, an agent inducing lysosomal damage, also inhibited syncytialization and led to TFEB downregulation. Taken together, the autophagy-lysosomal machinery plays an important role in cytotrophoblast fusion, resulting in syncytiotrophoblasts. As autophagy inhibition contributed to the failure of differentiation in cytotrophoblasts, this may result in the poor placentation observed in preeclampsia. |
| first_indexed | 2024-03-09T22:35:17Z |
| format | Article |
| id | doaj.art-e9db575df0fb4cbaa099ada2a3493146 |
| institution | Directory Open Access Journal |
| issn | 2673-3897 |
| language | English |
| last_indexed | 2024-03-09T22:35:17Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Reproductive Medicine |
| spelling | doaj.art-e9db575df0fb4cbaa099ada2a34931462023-11-23T18:49:43ZengMDPI AGReproductive Medicine2673-38972022-05-013211212610.3390/reprodmed3020010The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion ProcessAtsushi Furuta0Tomoko Shima1Mihoko Kawaguchi2Akemi Yamaki-Ushijima3Ippei Yasuda4Sayaka Tsuda5Satoshi Yoneda6Kazuma Higashisaka7Shi-Bin Cheng8Kenji Matsumoto9Yasuo Tsutsumi10Surendra Sharma11Shigeru Saito12Akitoshi Nakashima13Department of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanDepartment of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanDepartment of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanDepartment of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanDepartment of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanDepartment of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanDepartment of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanLaboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita 565-0871, JapanDepartments of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905, USADepartment of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, JapanLaboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita 565-0871, JapanDepartments of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905, USAUniversity of Toyama, Toyama 930-8555, JapanDepartment of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, Toyama 930-8555, JapanPoor placentation is closely related with the etiology of preeclampsia and may impact fetal growth restriction. For placental developmental growth, we have demonstrated that dysregulation of autophagy, a key mechanism to maintain cellular homeostasis, in trophoblasts contributes to the pathophysiology of preeclampsia, a severe pregnancy complication, associated with poor placentation. It remains, however, unknown whether autophagy inhibition affects trophoblast syncytialization. This study evaluated the effect of autophagy in an in vitro syncytialization method using BeWo cells and primary human trophoblasts (PHT). In this study, we observed that autophagic activity decreased in PHT and BeWo cells during syncytialization. This decreased activity was accompanied by downregulation of the transcription factor, TFEB. Next, bafilomycin A1, an inhibitor of autophagy via suppressing V-ATPase in lysosomes, inhibited hCG production, CYP11A1 expression (a marker of differentiation), p21 expression (a senescence marker), and cell fusion in BeWo cells and PHT cells. Finally, LLOMe, an agent inducing lysosomal damage, also inhibited syncytialization and led to TFEB downregulation. Taken together, the autophagy-lysosomal machinery plays an important role in cytotrophoblast fusion, resulting in syncytiotrophoblasts. As autophagy inhibition contributed to the failure of differentiation in cytotrophoblasts, this may result in the poor placentation observed in preeclampsia.https://www.mdpi.com/2673-3897/3/2/10autophagybafilomycin A1BeWofusionhuman chorionic gonadotropinpreeclampsia |
| spellingShingle | Atsushi Furuta Tomoko Shima Mihoko Kawaguchi Akemi Yamaki-Ushijima Ippei Yasuda Sayaka Tsuda Satoshi Yoneda Kazuma Higashisaka Shi-Bin Cheng Kenji Matsumoto Yasuo Tsutsumi Surendra Sharma Shigeru Saito Akitoshi Nakashima The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion Process Reproductive Medicine autophagy bafilomycin A1 BeWo fusion human chorionic gonadotropin preeclampsia |
| title | The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion Process |
| title_full | The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion Process |
| title_fullStr | The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion Process |
| title_full_unstemmed | The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion Process |
| title_short | The Autophagy-Lysosomal Machinery Enhances Cytotrophoblast–Syncytiotrophoblast Fusion Process |
| title_sort | autophagy lysosomal machinery enhances cytotrophoblast syncytiotrophoblast fusion process |
| topic | autophagy bafilomycin A1 BeWo fusion human chorionic gonadotropin preeclampsia |
| url | https://www.mdpi.com/2673-3897/3/2/10 |
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