Transendothelial migration of human umbilical mesenchymal stem cells across uterine endothelial monolayers: junctional dynamics and putative mechanisms

Ebrahim, Neven A. and Leach, Lopa (2016) Transendothelial migration of human umbilical mesenchymal stem cells across uterine endothelial monolayers: junctional dynamics and putative mechanisms. Placenta . ISSN 1532-3102

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Introduction: During 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.

Methods: Mesenchymal 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.

Results: WJ-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.

Discussion: Fetal 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.

Item Type: Article
Additional Information: ©2016. This manuscript is made available under the CC-BY-NC-ND4.0 license.
Keywords: Human umbilical mesenchymal stem cells; Human uterine microvascular endothelial cells; Transendothelial migration; VE-cadherin; P-Tyr685; P-Tyr731
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
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Depositing User: Eprints, Support
Date Deposited: 24 Oct 2016 09:45
Last Modified: 04 May 2020 18:16

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