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Transendothelial migration of human umbilical mesenchymal stem cells across uterine endothelial monolayers: Junctional dynamics and putative mechanisms |
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| Institution: | 1. Department of Biology, University of Virginia, Charlottesville, VA, USA;2. Dompé Farmaceutici SpA, Via Campo di Pile, 67100 L''Aquila, Italy;3. Paolo Procacci Foundation, Via Tacito 7, 00193 Rome, Italy;4. Institute of Translational Pharmacology (IFT) – National Council of Research (CNR), 67100 L’Aquila, Italy;5. Department of MESVA, University of L’Aquila, 67100 L’Aquila, Italy;1. Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt;2. Biochemistry Department, Faculty of Science, King Abdulaziz University (KAU), Jeddah, Saudi Arabia;3. Clinical Pathology specialist, Ministry of Health, Egypt;4. Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Uttoxeter Road, Derby DE22 3DT, UK;1. Dept. of Biochemistry, Capital Institute of Pediatrics, Beijing 100020, China;2. Dept. of Biochemistry, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China;3. Graduate School, Chinese Academy of Medical Science, Beijing 100730, China;1. Laboratorio de Biología de la Reproducción (LABIR), Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina;2. Laboratorio de Medicina Experimental y Traduccional (LME&T), Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina;3. Laboratorio de Cronobiología (LABCRON), Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina;4. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis (IMIBIO-SL), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina;1. Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;2. Department of Cardiothoracic Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;3. Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;4. Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands |
| Abstract: | IntroductionDuring pregnancy, fetal stem cells can transfer to the maternal circulation and participate in tissue repair. How they transmigrate across maternal endothelial barriers and whether they can subsequently influence maternal endothelial integrity is not known.MethodsMesenchymal stem cells (WJ-MSC) were isolated from Wharton's jelly and their interactions with human uterine microvascular endothelial cell (HUtMEC) monolayers, junctional occupancy and expression/phosphorylation of vascular endothelial (VE)- cadherin and vascular endothelial growth factor (VEGF-A) secretion was studied over 48h by real time, confocal microscopy, immunoblotting and ELISA.ResultsWJ-MSC displayed exploratory behaviour with interrogation of paracellular openings and spreading into the resultant increased gaps followed by closing of the endothelium over the WJ-MSC. 62% of added cells crossed within 22h to sub-endothelial niches. There was a concomitant loss of junctional VE-cadherin in HUtMEC followed by a full return and increased VE-cadherin expression after 22h. During early hours, VE-cadherin showed a transient phosphorylation at Tyrosine (Tyr)-685 when VEGF-A secretion were high. From 16 to 22h, there was increased de-phosphorylation of Tyr-731. Anti-VEGF-A blocked Tyr-685 phosphorylation but not the decrease in P-Tyr731; this partially inhibited WJ-MSC transmigration.DiscussionFetal WJ-MSC can traverse uterine endothelial monolayers by mediating a non-destructive paracellular pathway. They can promote junctional stability of uterine endothelium from the sub-endothelial niche. Mechanistically, WJ-MSC induces VEGF-dependent phosphorylation events linked with paracellular permeability and VEGF-independent de-phosphorylation events associated with leukocyte extravasation. Our data also allows consideration of a possible role of fetal MSC in mature functioning of the uterine vasculature needed for optimal utero-placental perfusion. |
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