Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels

Melly, Ludovic F; Marsano, Anna; Frobert, Aurelien; Boccardo, Stefano; Helmrich, Uta; Heberer, Michael; Eckstein, Friedrich S; Carrel, Thierry P; Giraud, Marie-Noëlle; Tevaearai, Hendrik T; Banfi, Andrea (2012). Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels. Human gene therapy - methods, 23(5), pp. 346-56. New Rochelle, N.Y.: Mary Ann Liebert 10.1089/hgtb.2012.032

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Vascular endothelial growth factor (VEGF) can induce normal angiogenesis or the growth of angioma-like vascular tumors depending on the amount secreted by each producing cell because it remains localized in the microenvironment. In order to control the distribution of VEGF expression levels in vivo, we recently developed a high-throughput fluorescence-activated cell sorting (FACS)-based technique to rapidly purify transduced progenitors that homogeneously express a specific VEGF dose from a heterogeneous primary population. Here we tested the hypothesis that cell-based delivery of a controlled VEGF level could induce normal angiogenesis in the heart, while preventing the development of angiomas. Freshly isolated human adipose tissue-derived stem cells (ASC) were transduced with retroviral vectors expressing either rat VEGF linked to a FACS-quantifiable cell-surface marker (a truncated form of CD8) or CD8 alone as control (CTR). VEGF-expressing cells were FACS-purified to generate populations producing either a specific VEGF level (SPEC) or uncontrolled heterogeneous levels (ALL). Fifteen nude rats underwent intramyocardial injection of 10(7) cells. Histology was performed after 4 weeks. Both the SPEC and ALL cells produced a similar total amount of VEGF, and both cell types induced a 50%-60% increase in both total and perfused vessel density compared to CTR cells, despite very limited stable engraftment. However, homogeneous VEGF expression by SPEC cells induced only normal and stable angiogenesis. Conversely, heterogeneous expression of a similar total amount by the ALL cells caused the growth of numerous angioma-like structures. These results suggest that controlled VEGF delivery by FACS-purified ASC may be a promising strategy to achieve safe therapeutic angiogenesis in the heart.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiovascular Surgery

UniBE Contributor:

Carrel, Thierry; Giraud, Marie-Noelle and Tevaearai, Hendrik

ISSN:

1946-6536

Publisher:

Mary Ann Liebert

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:31

Last Modified:

17 Mar 2015 21:17

Publisher DOI:

10.1089/hgtb.2012.032

PubMed ID:

23075102

Web of Science ID:

000316107300006

URI:

https://boris.unibe.ch/id/eprint/11833 (FactScience: 218083)

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