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

Int J Mol Sci. 2021 Feb 19;22(4):2045. doi: 10.3390/ijms22042045.


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.

Keywords: VEGF-A and THBS1 target genes; Wharton’s jelly; extracellular vesicles; in vitro angiogenesis; mesenchymal stromal cells; microRNAs.

MeSH terms

  • Cell Movement
  • Cell Proliferation
  • Cell Separation
  • Extracellular Vesicles / metabolism*
  • Fetus / cytology
  • Fluoresceins / metabolism
  • Gene Ontology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Immunophenotyping
  • Mesenchymal Stem Cells / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nanoparticles / chemistry
  • Neovascularization, Physiologic*
  • Reproducibility of Results
  • Skin / cytology
  • Succinimides / metabolism
  • Thrombospondin 1 / metabolism
  • Umbilical Cord / cytology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Wharton Jelly / cytology*


  • 5-(6)-carboxyfluorescein diacetate succinimidyl ester
  • Fluoresceins
  • MicroRNAs
  • Succinimides
  • Thrombospondin 1
  • Vascular Endothelial Growth Factor A