Mechanochemical Regulation of Macrophages by the Adhesive Microenvironment

Oral, Wendy Liu, presentation 040
Publication date: 25th July 2016

Macrophages are essential regulators of the innate immune system, and play an important role in advancing and resolving inflammation during wound healing.  To perform their functionally diverse roles, these cells can rapidly change their function in response to cues in their surrounding microenvironment.  For example, inflammatory stimuli such as interferon-gamma and toll like receptor ligands lead to macrophage polarization toward a classically activated phenotype and production of cytokines and reactive species to promote inflammatory signaling.  However, exposure to Th2 cytokines including IL-4 in a wound healing environment causes the same cells to polarize toward an alternatively activated phenotype, which promotes tissue healing and regeneration.  While much is known about how soluble cues in the environment regulate macrophage phenotype, less is understood about how physical cues modulate their behavior.  In particular, the effects of changes in adhesive environment caused by matrix remodeling during wound healing have not been clearly elucidated.  Our laboratory recently showed that the geometry of cell adhesion plays an important role in macrophage polarization; specifically cell elongation induced by micropatterned substrates promotes the expression of markers associated with an alternatively activated, pro-healing phenotype.  In current work, we investigate how adhesion in three-dimensional fibrillar matrices regulate macrophage cell shape and function.  We developed three-dimensional matrices composed of natural biopolymers including collagen and fibrin, which are present at varying concentrations and proportions during the wound healing process.  Fibril dimensions were characterized by second harmonic and backscattering imaging techniques, which revealed that the addition of fibrin reduced the fiber length and thickness.  In addition, while macrophages remained mostly rounded when seeded on three-dimensional matrices, the presence of fibrin enhanced cell spreading and the formation of cell protrusions into the matrix.  Current work is focused on examining how adhesion within engineered fibrillar matrices impacts the inflammatory versus wound healing behavior of macrophages.  A better understanding of how physical and adhesive cues regulate macrophage behavior will ultimately aid in the design of biopolymer scaffolds for tissue engineering and regeneration.

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