Understanding the Role of Macrophage Phenotype in Biomaterial-Mediated Tissue Regeneration
Tuesday, January 9, 2018
11:15 AM-1:15 PM
BIOMED PhD Thesis Defense
Title:
Understanding the Role of Macrophage Phenotype in Biomaterial-Mediated Tissue Regeneration
Speaker:
Pamela L. Graney, PhD Candidate, School of Biomedical Engineering, Science and Health Systems, Drexel University
Advisor:
Kara L. Spiller, PhD, Assistant Professor, School of Biomedical Engineering, Science and Health Systems, Drexel University
Abstract:
The underlying goal of tissue engineering is to functionally repair and regenerate complex tissues and organs. One of the major challenges in engineering viable tissues is forming functional and stable blood vessel networks (angiogenesis) within the tissue, which supply oxygen and nutrients to the cells. Following implantation, these networks must subsequently connect with the body’s existing vasculature (anastomosis) for continued survival. Currently, there is no known way to control anastomosis, preventing the translation of many potentially useful biomaterials for tissue engineering applications. Macrophages, the primary cells of the inflammatory response, are major contributors to vascularization and regulate the response to implanted biomaterials; however, macrophages are highly plastic cells that alter their behavior in response to local stimuli, and the contributions of macrophage phenotype to these processes are poorly understood. Therefore, the overarching goals of this work were to (1) understand how regenerative biomaterials modulate macrophage behavior and (2) delineate the impact of changing macrophage phenotype on biomaterial vascularization.
First, the in vitro response of primary human macrophages to biomaterials proven to enhance tissue regeneration in animal models was evaluated. Interestingly, biomaterials more successful in promoting tissue repair induced a phenotypic shift in macrophage behavior toward an anti-inflammatory “M2” state. The modulatory effects of these scaffolds were predominantly due to direct cell-scaffold interactions, as only modest changes in macrophage gene expression were observed by soluble factors derived from the scaffolds. Importantly, these findings provide evidence that regenerative biomaterials modulate macrophage behavior. Then, to elucidate the effects of changing macrophage phenotype on biomaterial vascularization, crosstalk between macrophages and vascular endothelial cells (ECs) was assessed via transwell co-culture. Interestingly, the angiogenic behavior of ECs was differentially influenced by macrophage phenotype; specifically, macrophages stimulated toward M1 and M2c activation induced EC up-regulation of genes related to vessel sprouting, while M2a and M2f macrophages altered genes related to vessel branching and extracellular matrix disassembly, respectively. Finally, the functional consequences of changing macrophage phenotype on biomaterial vascularization were ascertained through development of a 3D in vitro model of vascular growth. Self-assembly of ECs and support cells into vascular structures was achieved by co-culture on commercially available Gelfoam® scaffolds, to which macrophages were seeded at different stages of vessel development. Consistent with the previous study, M1 and, to a lesser extent, M2, macrophages increased vessel sprouting and the number of connected vessels relative to vascular networks without macrophages. Preliminary studies also demonstrated the potential for temporal control over macrophage activation to enhance vascularization.
Collectively, these findings can be used to inform the design of biomaterials that harness the inflammatory response to promote vascularization and improve healing outcomes. This work also has important implications for treating diseases characterized by extensive blood vessel growth, such as cancer and autoimmune conditions, whereby vascularization of the tissue facilitates disease progression.
Contact Information
Ken Barbee
215-895-1335
barbee@drexel.edu