Induction of angiogenesis by implantation of encapsulated primary myoblasts expressing vascular endothelial growth factor

Background We previously demonstrated that intramuscular implantation of pr imary myoblasts engineered to express vascular endothelial growth factor (V EGF) 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 nonmu scle sites, we have enclosed them in microcapsules that protect allogeneic cells from rejection, yet allow the secretion of proteins produced by the c ells. Methods Encapsulated mouse primary myoblasts that constitutively expressed murine VEGF(164), or encapsulated negative control cells, were implanted ei ther 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 c ontinued to grow and were composed primarily of endothelial and smooth musc le 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 ang iogenesis within the peritoneum, and ultimately led to fatal intraperitonea l hemorrhage. Notably, however, VEGF was not detected in the plasma of any mice. Conclusions We conclude that encapsulated primary myoblasts persist and con tinue to secrete VEGF subcutaneously and intraperitoneally, but that the he parin-binding isoform VEGF(164) exerts localized effects at the site of pro duction. VEGF secreted from the capsules attracts endothelial and smooth mu scle cells in a macrophage-independent manner. These results, along with ou r previous results, show that the mode and site of delivery of the same fac tor by the same engineered myoblasts can lead to markedly different outcome s. Moreover, the results confirm that constitutive delivery of high levels of VEGF is not desirable. In contrast, regulatable expression may lead to e fficacious, safe, and localized VEGF delivery by encapsulated allogeneic pr imary myoblasts that can serve as universal donors. Copyright (C) 2000 John Wiley & Sons, Ltd.