title: The role of macrophage phenotype in vascularization of tissue engineering scaffolds.
abstract: Angiogenesis is crucial for the success of most tissue engineering strategies. The natural inflammatory response is a major regulator of vascularization, through the activity of different types of macrophages and the cytokines they secrete. Macrophages exist on a spectrum of diverse phenotypes, from "classically activated" M1 to "alternatively activated" M2 macrophages. M2 macrophages, including the subsets M2a and M2c, are typically considered to promote angiogenesis and tissue regeneration, while M1 macrophages are considered to be anti-angiogenic, although these classifications are controversial. Here we show that in contrast to this traditional paradigm, primary human M1 macrophages secrete the highest levels of potent angiogenic stimulators including VEGF; M2a macrophages secrete the highest levels of PDGF-BB, a chemoattractant for stabilizing pericytes, and also promote anastomosis of sprouting endothelial cells in vitro; and M2c macrophages secrete the highest levels of MMP9, an important protease involved in vascular remodeling. In a murine subcutaneous implantation model, porous collagen scaffolds were surrounded by a fibrous capsule, coincident with high expression of M2 macrophage markers, while scaffolds coated with the bacterial lipopolysaccharide were degraded by inflammatory macrophages, and glutaraldehyde-crosslinked scaffolds were infiltrated by substantial numbers of blood vessels, accompanied by high levels of M1 and M2 macrophages. These results suggest that coordinated efforts by both M1 and M2 macrophages are required for angiogenesis and scaffold vascularization, which may explain some of the controversy over which phenotype is the angiogenic phenotype.
authors.affiliation: Department of Biomedical Engineering, Columbia University, 622 West 168th Street, New York, NY 10032, USA; School of Biomedical Engineering, Science, and Health Systems, Drexel University, 3141 Chestnut St., Philadelphia, PA 19104, USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Spiller
authors.affiliation: Department of Biomedical Engineering, Columbia University, 622 West 168th Street, New York, NY 10032, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Anfang
authors.affiliation: Department of Pathology, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Krista J
authors.initials: KJ
authors.lastname: Spiller
authors.affiliation: Department of Biomedical Engineering, Columbia University, 622 West 168th Street, New York, NY 10032, USA.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Ng
authors.affiliation: Department of Biomedical Engineering, Columbia University, 622 West 168th Street, New York, NY 10032, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Nakazawa
authors.affiliation: Lincoln Laboratory, Massachusetts Institute of Technology, 244 Wood Street, Lexington, MA 02420, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Daulton
authors.affiliation: Department of Biomedical Engineering, Columbia University, 622 West 168th Street, New York, NY 10032, USA. Electronic address: gv2131@columbia.edu.
authors.forename: Gordana
authors.initials: G
authors.lastname: Vunjak-Novakovic
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin
keywords: Angiogenesis; Collagen; Foreign body response; Inflammation; Macrophage