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Induction of angiogenesis by implantation of encapsulated primary myoblasts expressing vascular endothelial growth factor
Author(s) -
Springer Matthew L.,
Hortelano Gonzalo,
Bouley Donna M.,
Wong Jason,
Kraft Peggy E.,
Blau Helen M.
Publication year - 2000
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/1521-2254(200007/08)2:4<279::aid-jgm114>3.0.co;2-8
Subject(s) - angiogenesis , myocyte , vascular endothelial growth factor , inflammation , vascular endothelial growth factor a , neovascularization , microbiology and biotechnology , chemistry , immunology , endocrinology , medicine , biology , vegf receptors
Background We previously demonstrated that intramuscular implantation of primary myoblasts engineered to express vascular endothelial growth factor (VEGF) constitutively resulted in hemangioma formation and the appearance of VEGF in the circulation. To investigate the potential for using allogeneic myoblasts and the effects of delivery of VEGF‐expressing myoblasts to non‐muscle sites, we have enclosed them in microcapsules that protect allogeneic cells from rejection, yet allow the secretion of proteins produced by the cells. Methods Encapsulated mouse primary myoblasts that constitutively expressed murine VEGF 164 , or encapsulated negative control cells, were implanted either subcutaneously or intraperitoneally into mice. Results Upon subcutaneous implantation, capsules containing VEGF‐expressing myoblasts gave rise to large tissue masses at the implantation site that continued to grow and were composed primarily of endothelial and smooth muscle cells directly surrounding the capsules, and macrophages and capillaries further away from the capsules. Similarly, when injected intraperitoneally, VEGF‐producing capsules caused significant localized inflammation and angiogenesis within the peritoneum, and ultimately led to fatal intraperitoneal hemorrhage. Notably, however, VEGF was not detected in the plasma of any mice. Conclusions We conclude that encapsulated primary myoblasts persist and continue to secrete VEGF subcutaneously and intraperitoneally, but that the heparin‐binding isoform VEGF 164 exerts localized effects at the site of production. VEGF secreted from the capsules attracts endothelial and smooth muscle cells in a macrophage‐independent manner. These results, along with our previous results, show that the mode and site of delivery of the same factor by the same engineered myoblasts can lead to markedly different outcomes. Moreover, the results confirm that constitutive delivery of high levels of VEGF is not desirable. In contrast, regulatable expression may lead to efficacious, safe, and localized VEGF delivery by encapsulated allogeneic primary myoblasts that can serve as universal donors. Copyright © 2000 John Wiley & Sons, Ltd.