Understanding and Controlling Macrophage Behavior in Angiogenesis

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Project Summary At the heart of angiogenesis and biomaterial vascularization lies the inflammatory response, orchestrated primarily by macrophages, which dramatically shift phenotype over time in response to microenvironmental cues. In the normal response to injury, macrophages are initially pro-inflammatory (aka M1), and at later stages they are replaced by a mixed population referred to collectively as M2 that upregulate factors associated with resolution of the wound healing process. The extent of the diversity of this M2 population in particular is not known. At later stages of angiogenesis and biomaterial vascularization, M2 macrophages are generated 1) via transition from M1 macrophages, or 2) from direct differentiation of newly arriving monocytes. The differences between the M2 macrophages arising from each population have not been investigated. Preliminary data suggest that M1-derived M2 macrophages possess enhanced angiogenic functionality, and that biomaterials that transiently stimulate the initial M1 phase may enhance the subsequent response to M2-promoting biomaterials to achieve enhanced vascularization and healing. The overarching hypothesis of this project is that biomaterials that promote sequential M1 and M2 activation of the same population of macrophages will enhance vascularization. To test this hypothesis, this work has the following goals: 1) Determine the effects of M1 pre- polarization on the functional phenotype of M2 macrophages in crosstalk with blood vessels in vitro, using primary human macrophages, gene and protein expression profiling, and tissue-engineered models of angiogenesis. 2) Determine the effects of pro-inflammatory pre-treatment on the regenerative effects of IL4- releasing biomaterials in vivo, using biomaterials that temporally control the phenotype of host macrophages in a murine hindlimb ischemia model. 3) Determine the angiogenic effects in vivo of a biomaterial-mediated macrophage cell therapy strategy that intracellularly directs a single population of macrophages from M1 to M2. This latter strategy may result in particularly beneficial biomaterials for patients who suffer from impaired leukocyte trafficking, including patients with diabetes, autoimmune disease, or those undergoing chemotherapeutic treatment for cancer. This work will advance our understanding of how biomaterials can be designed to leverage both the inflammatory and regenerative functions of macrophages to enhance angiogenesis, which will allow us to develop new strategies to treat numerous diseases characterized by pathological angiogenesis, including heart and brain ischemia, atherosclerosis, and diabetes, among many others. In addition, this project proposes a novel approach to direct tissue revascularization by controlling the actions of both recruited and exogenously administered macrophages using biomaterials.