Synthetic microparticles conjugated with VEGF165 improve the survival of endothelial progenitor cells via microRNA-17 inhibition

Sezin Aday; Janet Zoldan; Marie Besnier; Laura Carreto; Jaimy Saif; Rui Fernandes; Tiago Santos; Liliana Bernardino; Robert Langer; Costanza Emanueli; Lino Ferreira

doi:10.1038/s41467-017-00746-7

Synthetic microparticles conjugated with VEGF165 improve the survival of endothelial progenitor cells via microRNA-17 inhibition

Sezin Aday
, Janet Zoldan
, Marie Besnier
, Laura Carreto
, Jaimy Saif
, Rui Fernandes
, Tiago Santos
, Liliana Bernardino
, Robert Langer
, Costanza Emanueli
, Lino Ferreira

Aston Medical School

Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, BS2 8HW, UK.
Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, 78712, USA.
University of Aveiro, 3810-193, Aveiro, Portugal.
HEMS-Histology and Electron Microscopy Service, IBMC/I3S, Universidade do Porto, 4200-135, Porto, Portugal.
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6201-506, Covilhã, Portugal.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
National Heart and Lung Institute, Hammersmith Campus, Imperial College of London, London, SW7 2AZ, UK. [email protected].
Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal. [email protected].

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

106 Downloads (Pure)

Abstract

Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases. Poor survival and vascular engraftment rates of transplanted cells force them to work mainly via time-limited paracrine actions. Although several approaches, including the use of soluble vascular endothelial growth factor (sVEGF)-VEGF165, have been developed in the last 10 years to enhance cell survival, they showed limited efficacy. Here, we report a pro-survival approach based on VEGF-immobilized microparticles (VEGF-MPs). VEGF-MPs prolong VEGFR-2 and Akt phosphorylation in cord blood-derived late outgrowth endothelial progenitor cells (OEPCs). In vivo, OEPC aggregates containing VEGF-MPs show higher survival than those treated with sVEGF. Additionally, VEGF-MPs decrease miR-17 expression in OEPCs, thus increasing the expression of its target genes CDKN1A and ZNF652. The therapeutic effect of OEPCs is improved in vivo by inhibiting miR-17. Overall, our data show an experimental approach to improve therapeutic efficacy of proangiogenic cells for the treatment of ischemic diseases.Soluble vascular endothelial growth factor (VEGF) enhances vascular engraftment of transplanted cells but the efficacy is low. Here, the authors show that VEGF-immobilized microparticles prolong survival of endothelial progenitors in vitro and in vivo by downregulating miR17 and upregulating CDKN1A and ZNF652.

Original language	English
Article number	747
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00746-7
Publication status	Published - 29 Sept 2017

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Keywords

Cell Survival
Cell- and Tissue-Based Therapy
Cell-Derived Microparticles
Cyclin-Dependent Kinase Inhibitor p21/genetics
DNA-Binding Proteins/genetics
Endothelial Progenitor Cells/cytology
Fetal Blood/cytology
Gene Expression Regulation
Human Umbilical Vein Endothelial Cells
Humans
Ischemia/metabolism
MicroRNAs/metabolism
Neovascularization, Physiologic
Phosphorylation
Proto-Oncogene Proteins c-akt/metabolism
Vascular Endothelial Growth Factor A/metabolism
Vascular Endothelial Growth Factor Receptor-2/metabolism

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Synthetic microparticles conjugated with VEGFFinal published version, 2.07 MBLicence: CC BY 3.0

Cite this

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title = "Synthetic microparticles conjugated with VEGF165 improve the survival of endothelial progenitor cells via microRNA-17 inhibition",

abstract = "Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases. Poor survival and vascular engraftment rates of transplanted cells force them to work mainly via time-limited paracrine actions. Although several approaches, including the use of soluble vascular endothelial growth factor (sVEGF)-VEGF165, have been developed in the last 10 years to enhance cell survival, they showed limited efficacy. Here, we report a pro-survival approach based on VEGF-immobilized microparticles (VEGF-MPs). VEGF-MPs prolong VEGFR-2 and Akt phosphorylation in cord blood-derived late outgrowth endothelial progenitor cells (OEPCs). In vivo, OEPC aggregates containing VEGF-MPs show higher survival than those treated with sVEGF. Additionally, VEGF-MPs decrease miR-17 expression in OEPCs, thus increasing the expression of its target genes CDKN1A and ZNF652. The therapeutic effect of OEPCs is improved in vivo by inhibiting miR-17. Overall, our data show an experimental approach to improve therapeutic efficacy of proangiogenic cells for the treatment of ischemic diseases.Soluble vascular endothelial growth factor (VEGF) enhances vascular engraftment of transplanted cells but the efficacy is low. Here, the authors show that VEGF-immobilized microparticles prolong survival of endothelial progenitors in vitro and in vivo by downregulating miR17 and upregulating CDKN1A and ZNF652.",

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author = "Sezin Aday and Janet Zoldan and Marie Besnier and Laura Carreto and Jaimy Saif and Rui Fernandes and Tiago Santos and Liliana Bernardino and Robert Langer and Costanza Emanueli and Lino Ferreira",

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AU - Besnier, Marie

AU - Carreto, Laura

AU - Saif, Jaimy

AU - Fernandes, Rui

AU - Santos, Tiago

AU - Bernardino, Liliana

AU - Langer, Robert

AU - Emanueli, Costanza

AU - Ferreira, Lino

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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N2 - Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases. Poor survival and vascular engraftment rates of transplanted cells force them to work mainly via time-limited paracrine actions. Although several approaches, including the use of soluble vascular endothelial growth factor (sVEGF)-VEGF165, have been developed in the last 10 years to enhance cell survival, they showed limited efficacy. Here, we report a pro-survival approach based on VEGF-immobilized microparticles (VEGF-MPs). VEGF-MPs prolong VEGFR-2 and Akt phosphorylation in cord blood-derived late outgrowth endothelial progenitor cells (OEPCs). In vivo, OEPC aggregates containing VEGF-MPs show higher survival than those treated with sVEGF. Additionally, VEGF-MPs decrease miR-17 expression in OEPCs, thus increasing the expression of its target genes CDKN1A and ZNF652. The therapeutic effect of OEPCs is improved in vivo by inhibiting miR-17. Overall, our data show an experimental approach to improve therapeutic efficacy of proangiogenic cells for the treatment of ischemic diseases.Soluble vascular endothelial growth factor (VEGF) enhances vascular engraftment of transplanted cells but the efficacy is low. Here, the authors show that VEGF-immobilized microparticles prolong survival of endothelial progenitors in vitro and in vivo by downregulating miR17 and upregulating CDKN1A and ZNF652.

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Synthetic microparticles conjugated with VEGF165 improve the survival of endothelial progenitor cells via microRNA-17 inhibition

Abstract

Bibliographical note

Keywords

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