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 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.

In vivo association of immunophenotyped macrophages expressing CD163 with PDGF-B in gingival overgrowth-induced by three different categories of medications

“…8,9 M2a macrophages secrete the highest levels of PDGF-B, a chemoattractant stabilizing pericytes, and also promote anastomosis of sprouting endothelial cells in vitro. 10,11 Although PDGF is synthesized, stored, and released by platelets upon activation, it is also produced by a plethora of other cells, including smooth muscle cells, activated macrophages such as alveolar macrophages, and vascular endothelial cells. 12 Macrophages of M2c type express high levels of cluster of differentiation 163 (CD163), which has been shown to be associated with tissue repair and remodeling of the wound and promoting cell proliferation in mice.…”

The Role of Myeloid Cell-Derived PDGF-B in Neotissue Formation in a Tissue-Engineered Vascular Graft

“…For example, some studies have demonstrated that macrophage and monocyte phenotype plays an important role in secretion of angiogenic molecules, and that their selective secretion at various time points may also be important. Spiller et al demonstrated that M1 or 'classically activated' macrophages secrete VEGF to recruit endothelial cells and initiate angiogenesis, whereas alternatively activated macrophages secrete PDGF, causing pericyte migration and vessel maintenance [19]. Our next experiments are therefore aimed at applying FACS-based approaches to elucidate the autocrine effect of PDGF-B on monocyte and macrophage phenotype at varying times during neotissue formation.…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…The in vitro polarisation of macrophages into either proinflammatory M1 or anti-inflammatory M2 that are also involved in tissue repair and angiogenesis, becomes possible via differentiation of peripheral blood monocytes utilising specific cytokines [143,144]. Importantly, it has been shown that both subsets together highly support the angiogenesis.…”