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Pro-Angiogenic Actions of CMC-Derived Extracellular Vesicles Rely on Selective Packaging of Angiopoietin 1 and 2, but Not FGF-2 and VEGF

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Abstract

While the fundamental mechanism by which cardiac cell therapy mitigates ventricular dysfunction in the post ischemic heart remains poorly defined, donor cell paracrine signaling is presumed to be a chief contributor to the afforded benefits. Of the many bioactive molecules secreted by transplanted cells, extracellular vesicles (EVs) and their proteinaceous, nucleic acid, and lipid rich contents, comprise a heterogeneous assortment of prospective cardiotrophic factors-whose involvement in the activation of endogenous cardiac repair mechanism(s), including reducing fibrosis and promoting angiogenesis, have yet to be fully explained. In the current study we aimed to interrogate potential mechanisms by which cardiac mesenchymal stromal cell (CMC)-derived EVs contribute to the CMC pro-angiogenic paracrine signaling capacity in vitro. Vesicular transmission and biological activity of human CMC-derived EVs was evaluated in in vitro assays for human umbilical vein endothelial cell (HUVEC) function, including EV uptake, cell survival, migration, tube formation, and intracellular pathway activation. HUVECs incubated with EVs exhibited augmented cell migration, tube formation, and survival under peroxide exposure; findings which paralleled enhanced activation of the archetypal pro-survival/pro-angiogenic pathways, STAT3 and PI3K-AKT. Cytokine array analyses revealed preferential enrichment of a subset of prototypical angiogenic factors, Ang-1 and Ang-2, in CMC EVs. Interestingly, pharmacologic inhibition of Tie2 in HUVECs, the cognate receptors of angiopoietins, efficiently attenuated CMC-EV-induced HUVEC migration. Further, in additional assays a Tie2 kinase inhibitor exhibited specificity to inhibit Ang-1-, but not Ang-2-, induced HUVEC migration. Overall, these findings suggest that the pro-angiogenic activities of CMC EVs are principally mediated by Ang-1-Tie2 signaling.

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Acknowledgments

This work was supported by NIH Grants P20 GM103492, P01 HL078825 (to RB and MW), R01 HL141191 (to MW), UM1 HL113530 (to RB), and R01 HL141081 (to JBM).

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Authors and Affiliations

  1. Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA

    Marcin Wysoczynski, Asif Pathan, Joseph B. Moore IV, Talha Farid, Jae Kim, Marjan Nasr, Yi Kang, Hong Li & Roberto Bolli

  2. University of Louisville, 580 South Preston St. – Rm 119F, Louisville, KY, 40202, USA

    Marcin Wysoczynski

  3. University of Louisville, 550 S Jackson St.- ACB, Third Floor, Louisville, KY, 40292, USA

    Roberto Bolli

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  1. Marcin Wysoczynski
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Supplementary Figure 1

Angiogenic protein array. CMC lysates, CMC-conditioned media (CM), and CMC-EVs (EVs) were evaluated for expression of pro- and anti-angiogenic factors with cytokine array membranes (Proteome Profiler Human Angiogenic Array Kit; R&D Systems, Minneapolis, MN). Proteome cytokine array heat map illustrating densitometric quantification or relative pixel density for each cytokine (A). Cytokine array membranes detected using enhanced chemiluminescence (B). (PPTX 81 kb)

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Wysoczynski, M., Pathan, A., Moore, J.B. et al. Pro-Angiogenic Actions of CMC-Derived Extracellular Vesicles Rely on Selective Packaging of Angiopoietin 1 and 2, but Not FGF-2 and VEGF. Stem Cell Rev and Rep 15, 530–542 (2019). https://doi.org/10.1007/s12015-019-09891-6

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