Dual delivery of placental growth factor and vascular endothelial growth factor from poly(hydroxyethyl methacrylate-co-methyl methacrylate) microcapsules containing doubly transfected luciferase-expressing L929 cells.
Placental growth factor (PlGF) combined with vascular endothelial growth factor (VEGF(164)) did not result in greater luciferase expression of a microencapsulated genetically transfected mouse fibroblast cell line (L929 cells) implanted subcutaneously in nominally syngeneic C3H/HeJ mice than in a control without growth factors. The intent had been to increase the maturity status of VEGF-generated vessels in the implant site by co-delivery of PlGF and thereby to effect an improvement in the persistence of luciferase expression, a marker of encapsulated cell viability. L929 cells were doubly transfected with luciferase and PlGF or luciferase and VEGF. Two hundred microcapsules containing a 1:1 mixture of the two transfected cells were implanted minimally invasively in Matrigel on one side of the mouse; the other side contained 200 microcapsules containing cells expressing luciferase only. Luciferase expression, reflective of encapsulated cell number, peaked at day 21 in both groups at about three times the value at day 1. In contrast with the immature vessels produced with VEGF alone (as reported earlier), the vessels produced here were more mature at day 14, and there were more such vessels than in the control group, although by day 21, there was a mixture of mature and immature vessels with PlGF, consistent with the premise that the maturity status of new vessels is PlGF dose dependent. Furthermore, anti-L929 antibodies (according to flow cytometry) and CD3-positive cells (according to histology) were detected in mice receiving unencapsulated cells, suggesting that there may be minor MHC (major histocompatibility complex) alloantigens and an adaptive immune response in this animal model. Thus successful modulation of the host response to microencapsulated cells may require enhanced vascularization and manipulation of the immune response, even with nominally syngeneic cells.
Cheng
Dangxiao
D
Institute of Biomaterials and Biomedical Engineering, University of Toronto , Toronto, Ontario, Canada.
Sefton
Michael V
MV
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002214:Capsules; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D016503:Drug Delivery Systems; D015870:Gene Expression / Q000187:drug effects; D020007:Implants, Experimental; D007797:Laminin / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism*; D008768:Methylmethacrylates / Q000737:chemistry*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D000072483:Placenta Growth Factor; D011102:Polyhydroxyethyl Methacrylate / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry*; D011257:Pregnancy Proteins / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D014019:Tissue Donors; D017186:Titrimetry; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D051598:Whole Body Imaging
D000906:Antibodies; D017252:CD3 Complex; D002214:Capsules; D004338:Drug Combinations; D007797:Laminin; D008768:Methylmethacrylates; C000608037:Pgf protein, mouse; D011109:Polymethacrylic Acids; D011257:Pregnancy Proteins; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D000072483:Placenta Growth Factor; D011102:Polyhydroxyethyl Methacrylate; C040206:HTR composite; D003094:Collagen; D008156:Luciferases