Abstract
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.
Highlights
The glycoprotein fibronectin (FN) is a fundamental component of the extracellular matrix (ECM), actively mediating a variety of cellular events including differentiation, migration, invasion, and wound healing (Wierzbicka-Patynowski and Schwarzbauer, 2003)
IF analysis of 1st-trimester placental villous tissue revealed a strong positive FN signal within the villous core, within mesenchymal stromal cells as indicated by vimentin (VIM)-positive staining; while no FN signal was detected in cytokeratin-7 (CK7)-positive trophoblasts (Figure 1C)
Fluorescenceactivated cell sorting (FACS) analyses confirmed the predominant expression of mesenchymal stromal cell surface markers CD29, CD73, CD90, and CD105 and lack of hematopoietic markers, CD34 and CD45, in representative 7-week and PE placental mesenchymal cells (pMSCs) (Supplementary Figure 1C)
Summary
The glycoprotein fibronectin (FN) is a fundamental component of the extracellular matrix (ECM), actively mediating a variety of cellular events including differentiation, migration, invasion, and wound healing (Wierzbicka-Patynowski and Schwarzbauer, 2003). Soluble FN, produced in Regulation of Fibronectin in Preeclampsia the endoplasmic reticulum (ER), is initially synthesized as monomers that are post-translationally modified and dimerize as they traffic to the Golgi apparatus In this cellular compartment, dimers are folded into a compact conformation and secreted into the extracellular space (Johnson et al, 1999), where they serve as ligands for the FN high-affinity transmembrane receptor, α5β1 integrin. Dimers are folded into a compact conformation and secreted into the extracellular space (Johnson et al, 1999), where they serve as ligands for the FN high-affinity transmembrane receptor, α5β1 integrin This interaction initiates a complex signaling cascade whereby short FN fibrils are eventually transformed into a dense, insoluble fibrillar network, forming functional links to other ECM proteins (Wierzbicka-Patynowski and Schwarzbauer, 2003)
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