Extracellular Vesicle-Derived microRNAs of Human Wharton’s Jelly Mesenchymal Stromal Cells May Activate Endogenous VEGF-A to Promote Angiogenesis

Abstract

Despite low levels of vascular endothelial growth factor (VEGF)-A, the secretome of human Wharton’s jelly (WJ) mesenchymal stromal cells (MSCs) effectively promoted proangiogenic responses in vitro, which were impaired upon the depletion of small (~140 nm) extracellular vesicles (EVs). The isolated EVs shared the low VEGF-A profile of the secretome and expressed five microRNAs, which were upregulated compared to fetal dermal MSC-derived EVs. These upregulated microRNAs exclusively targeted the VEGF-A gene within 54 Gene Ontology (GO) biological processes, 18 of which are associated with angiogenesis. Moreover, 15 microRNAs of WJ-MSC-derived EVs were highly expressed (Ct value ≤ 26) and exclusively targeted the thrombospondin 1 (THBS1) gene within 75 GO biological processes, 30 of which are associated with the regulation of tissue repair. The relationship between predicted microRNA target genes and WJ-MSC-derived EVs was shown by treating human umbilical-vein endothelial cells (HUVECs) with appropriate doses of EVs. The exposure of HUVECs to EVs for 72 h significantly enhanced the release of VEGF-A and THBS1 protein expression compared to untreated control cells. Finally, WJ-MSC-derived EVs stimulated in vitro tube formation along with the migration and proliferation of HUVECs. Our findings can contribute to a better understanding of the molecular mechanisms underlying the proangiogenic responses induced by human umbilical cord-derived MSCs, suggesting a key regulatory role for microRNAs delivered by EVs.

MicroRNA-Enriched Exosomes from Different Sources of Mesenchymal Stem Cells Can Differentially Modulate Functions of Immune Cells and Neurogenesis

“…We reported that exosomes from BM and WJ showed better angiogenic properties than AD. These results were in line with the previously published reports where WJ and BM have been shown to exhibit enhanced angiogenetic potential [ 55 , 58 ]. However, there are reports that AD-MSCs can promote angiogenesis by increasing endothelial cell differentiation and cell migration [ 59 ], while BM-MSCs express VEGF that promotes angiogenesis [ 60 ].…”

Intraperitoneally Delivered Mesenchymal Stem Cells Alleviate Experimental Colitis Through THBS1-Mediated Induction of IL-10-Competent Regulatory B Cells

“…THBS1 is a member of the matricellular protein family that is important in the control of extracellular matrix (ECM) remodelling and has also been reported to promote the proliferation and migration of mesenchymal cells through modulating TGFb activation or protecting the degradation of PDGF (66,67). There are many studies on the MSC-secreted THBS1 in regulating angiogenesis, but rarely on its immunoregulatory function in MSCs (68,69). Marie Maumus and colleagues reported that THBS1 secreted by adipose-derived MSCs may play a protective role in a collagen-induced osteoarthritis (CIOA) mouse model by chondroprotective effects and anti-inflammatory effects on T lymphocytes (70).…”

Angiogenic Potential of Human Adipose-Derived Mesenchymal Stromal Cells in Nanofibrillated Cellulose Hydrogel

“…The exact paracrine mechanism affecting HUVEC tube formation by hASCs, whether it be a secretory molecule or occurs via extracellular vesicle (EV) secretion, was not evaluated in this study and should be analyzed in more detail in the future. In a previous study by Cinnici et al [ 73 ], MSC-secreted EVs were studied and found to be a crucial part of releasing proangiogenic molecules, leading to increased vascularization. In addition to the culturing conditions, these paracrine properties can be affected by the transplantation mechanisms and better results have been shown with the local administration of mesenchymal stromal cells instead of systemic exposure [ 74 ].…”