JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration
The mechanisms contributing to excessive fibronectin in preeclampsia, a pregnancy-related disorder, remain unknown. Herein, we investigated the role of JMJD6, an O2- and Fe2+-dependent enzyme, in mediating placental fibronectin processing and function. MALDI-TOF identified fibronectin as a novel tar...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.652607/full |
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| author | Sruthi Alahari Sruthi Alahari Abby Farrell Abby Farrell Leonardo Ermini Chanho Park Julien Sallais Julien Sallais Sarah Roberts Taylor Gillmore Taylor Gillmore Michael Litvack Martin Post Martin Post Martin Post Isabella Caniggia Isabella Caniggia Isabella Caniggia Isabella Caniggia |
| author_facet | Sruthi Alahari Sruthi Alahari Abby Farrell Abby Farrell Leonardo Ermini Chanho Park Julien Sallais Julien Sallais Sarah Roberts Taylor Gillmore Taylor Gillmore Michael Litvack Martin Post Martin Post Martin Post Isabella Caniggia Isabella Caniggia Isabella Caniggia Isabella Caniggia |
| author_sort | Sruthi Alahari |
| collection | DOAJ |
| description | The mechanisms contributing to excessive fibronectin in preeclampsia, a pregnancy-related disorder, remain unknown. Herein, we investigated the role of JMJD6, an O2- and Fe2+-dependent enzyme, in mediating placental fibronectin processing and function. MALDI-TOF identified fibronectin as a novel target of JMJD6-mediated lysyl hydroxylation, preceding fibronectin glycosylation, deposition, and degradation. In preeclamptic placentae, fibronectin accumulated primarily in lysosomes of the mesenchyme. Using primary placental mesenchymal cells (pMSCs), we found that fibronectin fibril formation and turnover were markedly impeded in preeclamptic pMSCs, partly due to impaired lysosomal degradation. JMJD6 knockdown in control pMSCs recapitulated the preeclamptic FN phenotype. Importantly, preeclamptic pMSCs had less total and labile Fe2+ and Hinokitiol treatment rescued fibronectin assembly and promoted lysosomal degradation. Time-lapse imaging demonstrated that defective ECM deposition by preeclamptic pMSCs impeded HTR-8/SVneo cell migration, which was rescued upon Hinokitiol exposure. Our findings reveal new Fe2+-dependent mechanisms controlling fibronectin homeostasis/function in the placenta that go awry in preeclampsia. |
| first_indexed | 2024-12-22T01:01:53Z |
| format | Article |
| id | doaj.art-5e0a1521e14747388abe0a71afe80bbd |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-22T01:01:53Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-5e0a1521e14747388abe0a71afe80bbd2022-12-21T18:44:10ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-05-01910.3389/fcell.2021.652607652607JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast MigrationSruthi Alahari0Sruthi Alahari1Abby Farrell2Abby Farrell3Leonardo Ermini4Chanho Park5Julien Sallais6Julien Sallais7Sarah Roberts8Taylor Gillmore9Taylor Gillmore10Michael Litvack11Martin Post12Martin Post13Martin Post14Isabella Caniggia15Isabella Caniggia16Isabella Caniggia17Isabella Caniggia18Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaDepartment of Physiology, University of Toronto, Toronto, ON, CanadaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaProgram in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON, CanadaDepartment of Physiology, University of Toronto, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaProgram in Translational Medicine, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON, CanadaLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaDepartment of Physiology, University of Toronto, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaDepartment of Obstetrics and Gynecology, University of Toronto, Toronto, ON, CanadaThe mechanisms contributing to excessive fibronectin in preeclampsia, a pregnancy-related disorder, remain unknown. Herein, we investigated the role of JMJD6, an O2- and Fe2+-dependent enzyme, in mediating placental fibronectin processing and function. MALDI-TOF identified fibronectin as a novel target of JMJD6-mediated lysyl hydroxylation, preceding fibronectin glycosylation, deposition, and degradation. In preeclamptic placentae, fibronectin accumulated primarily in lysosomes of the mesenchyme. Using primary placental mesenchymal cells (pMSCs), we found that fibronectin fibril formation and turnover were markedly impeded in preeclamptic pMSCs, partly due to impaired lysosomal degradation. JMJD6 knockdown in control pMSCs recapitulated the preeclamptic FN phenotype. Importantly, preeclamptic pMSCs had less total and labile Fe2+ and Hinokitiol treatment rescued fibronectin assembly and promoted lysosomal degradation. Time-lapse imaging demonstrated that defective ECM deposition by preeclamptic pMSCs impeded HTR-8/SVneo cell migration, which was rescued upon Hinokitiol exposure. Our findings reveal new Fe2+-dependent mechanisms controlling fibronectin homeostasis/function in the placenta that go awry in preeclampsia.https://www.frontiersin.org/articles/10.3389/fcell.2021.652607/fullfibronectinironJMJD6pMSCspreeclampsiatrophoblast migration |
| spellingShingle | Sruthi Alahari Sruthi Alahari Abby Farrell Abby Farrell Leonardo Ermini Chanho Park Julien Sallais Julien Sallais Sarah Roberts Taylor Gillmore Taylor Gillmore Michael Litvack Martin Post Martin Post Martin Post Isabella Caniggia Isabella Caniggia Isabella Caniggia Isabella Caniggia JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration Frontiers in Cell and Developmental Biology fibronectin iron JMJD6 pMSCs preeclampsia trophoblast migration |
| title | JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration |
| title_full | JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration |
| title_fullStr | JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration |
| title_full_unstemmed | JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration |
| title_short | JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration |
| title_sort | jmjd6 dysfunction due to iron deficiency in preeclampsia disrupts fibronectin homeostasis resulting in diminished trophoblast migration |
| topic | fibronectin iron JMJD6 pMSCs preeclampsia trophoblast migration |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.652607/full |
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