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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2021)

Macrophages are mechanosensitive cells of the innate immune system that play a critical role in maintaining tissue homeostasis, pathogen defense, and response to injury. This diversity in macrophage function stems from their ability to respond to biochemical or mechanical cues within their microenvironment. The role of biochemical stimuli in influencing macrophage function have been well studied. However, despite their abundance in mechanically active tissues or the presence of altered tissue mechanics in various pathological conditions, such as in response to implanted materials or atherosclerosis, the role of mechanical stimuli and the associated molecular mechanisms responsible for changes in macrophage function are poorly understood. In this study, we found that the mechanosensitive and Ca2+ permeable ion channel Piezo1 plays a critical role in regulating macrophage response to inflammatory or healing agonists as well as oxidized lipoproteins. In addition, we also determined a role for the Piezo1 channel in sensing and transducing environmental stiffness or mechanical stretch.

First, we determined a role for Piezo1 in regulating macrophage activation in response to inflammatory or healing biochemical stimuli, the impact of stiffness in influencing this process, and the role of this mechanically gated channel in regulating the host response to implanted materials of varying stiffness. Additionally, we investigated the effects of mechanical stretch in regulating macrophage activation, while also exploring the role of Piezo1 in modulating stretch-mediated changes in cell function. Finally, we evaluated the role of Piezo1 and mechanics in regulating macrophage uptake of oxidized low-density lipoproteins, a key process involved in atherosclerotic plaque formation. These findings further elucidate the importance of mechanical stimuli in regulating macrophage function and identifies the Piezo1 ion channel as a critical molecule responsible for macrophage mechanosensation of stiffness and stretch. Together, this work provides novel insight into immune cell mechanobiology, while also improving our current knowledge of disease and potentially uncovering molecular targets to regulate macrophage function.

    Cover page: Piezo1-mediated mechanotransduction in inflammation and healing
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2023)
    Advances in biomaterial science have allowed for unprecedented insight into the ability of material cues to influence stem cell function. These material approaches better recapitulate the microenvironment, providing a more realistic ex vivo model of the cell niche. However, recent advances in our ability to measure and manipulate niche properties in vivo have led to novel mechanobiological studies in model organisms. Thus, in this review, we will discuss the importance of material cues within the cell niche, highlight the key mechanotransduction pathways involved, and conclude with recent evidence that material cues regulate tissue function in vivo.
      Cover page: Getting physical: Material mechanics is an intrinsic cell cue
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2019)
      Macrophages perform critical functions for homeostasis and immune defense in tissues throughout the body. These innate immune cells are capable of recognizing and clearing dead cells and pathogens, and orchestrating inflammatory and healing processes that occur in response to injury. In addition, macrophages are involved in the progression of many inflammatory diseases including cardiovascular disease, fibrosis, and cancer. Although it has long been known that macrophages respond dynamically to biochemical signals in their microenvironment, the role of biophysical cues has only recently emerged. Furthermore, many diseases that involve macrophages are also characterized by changes to the tissue biophysical environment. This review will discuss current knowledge about the effects of biophysical cues including matrix stiffness, material topography, and applied mechanical forces, on macrophage behavior. We will also describe the role of molecules that are known to be important for mechanotransduction, including adhesion molecules, ion channels, as well as nuclear mediators such as transcription factors, scaffolding proteins, and epigenetic regulators. Together, this review will illustrate a developing role of biophysical cues in macrophage biology, and also speculate upon molecular targets that may potentially be exploited therapeutically to treat disease.
        Cover page: Biophysical regulation of macrophages in health and disease
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2024)
        Macrophages in the vascular wall ingest and clear lipids, but abundant lipid accumulation leads to foam cell formation and atherosclerosis, a pathological condition often characterized by tissue stiffening. While the role of biochemical stimuli in the modulation of macrophage function is well studied, the role of biophysical cues and the molecules involved in mechanosensation are less well understood. Here, we use genetic and pharmacological tools to show extracellular oxidized low-density lipoproteins (oxLDLs) stimulate Ca2+ signaling through activation of the mechanically gated ion channel Piezo1. Moreover, macrophage Piezo1 expression is critical in the transduction of environmental stiffness and channel deletion suppresses, whereas a gain-of-function mutation exacerbates oxLDL uptake. Additionally, we find that depletion of myeloid Piezo1 protects from atherosclerotic plaque formation in vivo. Together, our study highlights an important role for Piezo1 and its respective mutations in macrophage mechanosensing, lipid uptake, and cardiovascular disease.
          Cover page: Piezo1-mediated mechanotransduction enhances macrophage oxidized low-density lipoprotein uptake and atherogenesis.
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2021)
          Macrophages are versatile cells of the innate immune system that perform diverse functions by responding to dynamic changes in their microenvironment. While the effects of soluble cues, including cytokines and chemokines, have been widely studied, the effects of physical cues, including mechanical stimuli, in regulating macrophage form and function are less well understood. In this study, we examined the effects of static and cyclic uniaxial stretch on macrophage inflammatory and healing activation. We found that cyclic stretch altered macrophage morphology and responses to IFNγ/LPS and IL4/IL13. Interestingly, we found that both static and cyclic stretch suppressed IFNγ/LPS induced inflammation. In contrast, IL4/IL13 mediated healing responses were suppressed with cyclic but enhanced with static stretch conditions. Mechanistically, both static and cyclic stretch increased expression of the integrin CD11b (αM integrin), decreased expression of the mechanosensitive ion channel Piezo1, and knock down of either CD11b or Piezo1 through siRNA abrogated stretch-mediated changes in inflammatory responses. Moreover, we found that knock down of CD11b enhanced the expression of Piezo1, and conversely knock down of Piezo1 enhanced CD11b expression, suggesting the potential for crosstalk between integrins and ion channels. Finally, stretch-mediated differences in macrophage activation were also dependent on actin, since pharmacological inhibition of actin polymerization abrogated the changes in activation with stretch. Together, this study demonstrates that the physical environment synergizes with biochemical cues to regulate macrophage morphology and function, and suggests a role for CD11b and Piezo1 crosstalk in mechanotransduction in macrophages.
            Cover page: Crosstalk Between CD11b and Piezo1 Mediates Macrophage Responses to Mechanical Cues
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2018)
            Mechanical cues including stretch, compression, and shear stress play a critical role in regulating the behavior of many cell types, particularly those that experience substantial mechanical stress within tissues. Devices that impart mechanical stimulation to cells in vitro have been instrumental in helping to develop a better understanding of how cells respond to mechanical forces. However, these devices often have constraints, such as cost and limited functional capabilities, that restrict their use in research or educational environments. Here, we describe a low-cost method to fabricate a uniaxial cell stretcher that would enable widespread use and facilitate engineering design and mechanobiology education for undergraduate students. The device is capable of producing consistent and reliable strain profiles through the use of a servomotor, gear, and gear rack system. The servomotor can be programmed to output various waveforms at specific frequencies and stretch amplitudes by controlling the degree of rotation, speed, and acceleration of the servogear. In addition, the stretchable membranes are easy to fabricate and can be customized, allowing for greater flexibility in culture well size. We used the custom-built stretching device to uniaxially strain macrophages and cardiomyocytes, and found that both cell types displayed functional and cell shape changes that were consistent with the previous studies using commercially available systems. Overall, this uniaxial cell stretcher provides a more cost-effective alternative to study the effects of mechanical stretch on cells, and can therefore, be widely used in research and educational environments to broaden the study and pedagogy of cell mechanobiology.
              Cover page: A Low-Cost Mechanical Stretching Device for Uniaxial Strain of Cells: A Platform for Pedagogy in Mechanobiology
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2021)
              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.
                Cover page: Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2020)
                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.
                  Cover page: YAP-mediated mechanotransduction tunes the macrophage inflammatory response
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