Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca2+ reporter, Salsa6f, reveal that Ca2+ influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses.
Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.
The extracellular matrix (ECM) is a complex and dynamic structural scaffold for cells within tissues and plays an important role in regulating cell function. Recently it has become appreciated that the ECM contains bioactive motifs that can directly modulate immune responses. This review describes strategies for engineering immunomodulatory biomaterials that utilize natural ECM‐derived molecules and have the potential to harness the immune system for applications ranging from tissue regeneration to drug delivery. A top‐down approach utilizes full‐length ECM proteins, including collagen, fibrin, or hyaluronic acid‐based materials, as well as matrices derived from decellularized tissue. These materials have the benefit of maintaining natural conformation and structure but are often heterogeneous and encumber precise control. By contrast, a bottom‐up approach leverages immunomodulatory domains, such as Arg–Gly–Asp (RGD), matrix metalloproteinase (MMP)‐sensitive peptides, or leukocyte‐associated immunoglobulin‐like receptor‐1(LAIR‐1) ligands, by incorporating them into synthetic materials. These materials have tunable control over immune cell functions and allow for combinatorial approaches. However, the synthetic approach lacks the full natural context of the original ECM protein. These two approaches provide a broad range of engineering techniques for immunomodulation through material interactions and hold the potential for the development of future therapeutic applications.
This project focuses on the surface modification of silica‐coated superparamagnetic iron oxide NPs to achieve tissue specific drug delivery to pancreatic tumors. The treatment of pancreatic cancer remains a challenge in the biomedical community. Over half of cases are diagnosed after the cancer has spread to other tissues, and in these cases the 5‐year survival rate is 2%. The non‐specific nature of currently available chemotherapies has spurred interest in developing vehicles to deliver potent therapies specifically to tumors. Nanoparticles (NPs) present an ideal vehicle due to their high surface area, small size, and low toxicity. Recent work explored the conjugation of NPs to a targeting moiety: monoclonal antibody CHO 31.1, which recognizes gpA33, a membrane glycoprotein overexpressed in 50% of pancreatic cancers and 95% of colorectal cancers. Building on existing methods, the antibody was attached to the silica surface of the NPs via a polyethylene glycol (PEG) linker. In vitro techniques were also developed to quantify NP detection using magnetic resonance imaging (MRI). Attachment of multiple moieties was explored using orthogonal surface chemistries. Cellular internalization was determined using confocal microscopy. Moving forward these novel nanoparticles will be further characterized for morphology, size and zeta potential, and for their utility as contrast agents for tracking in vivo.
Grant Funding Source: Supported by NIH grant #1R15CA156393‐01A1
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