Abstract
Macrophages play a critical role in regulating wound healing and tissue regeneration by changing their polarization state in response to local microenvironmental stimuli. The native roles of polarized macrophages encompass biomaterials and tissue remodeling needs, yet harnessing or directing the polarization response has been largely absent as a potential strategy to exploit in regenerative medicine to date. Recent data have revealed that specific alteration of cells’ resting potential (Vmem) is a powerful tool to direct proliferation and differentiation in a number of complex tissues, such as limb regeneration, craniofacial patterning and tumorigenesis. In this study, we explored the bioelectric modulation of macrophage polarization by targeting ATP sensitive potassium channels (KATP). Glibenclamide (KATP blocker) and pinacidil (KATP opener) treatment not only affect macrophage polarization, but also influence the phenotype of prepolarized macrophages. Furthermore, modulation of cell membrane electrical properties can fine-tune macrophage plasticity. Glibenclamide decreased the secretion and gene expression of selected M1 markers, while pinacidil augmented M1 markers. More interestingly, glibencalmide promoted macrophage alternative activation by enhancing certain M2 markers during M2 polarization. These findings suggest that control of bioelectric properties of macrophages could offer a promising approach to regulate macrophage phenotype as a useful tool in regenerative medicine.
Highlights
Macrophages play a critical role in regulating wound healing and tissue regeneration by changing their polarization state in response to local microenvironmental stimuli
We explored the bioelectric modulation of macrophage polarization by targeting ATP sensitive potassium channels (KATP)
Pinacidil caused cell hyperpolarization, except that a depolarizing effect was observed in M2 macrophages at 8 h. These results indicated that glibenclamide and pinacidil treatments effectively changed macrophage Vmem and Vmem in macrophages is a function of KATP channels
Summary
Macrophages play a critical role in regulating wound healing and tissue regeneration by changing their polarization state in response to local microenvironmental stimuli. Studies already demonstrated that human mesenchymal stem cells’ (hMSCs) and tissue level responses to changes in membrane potential significantly modulate cell functions, including differentiation, transdifferentiation and tissue regeneration[7,8]. The goal of this study was to determine whether bioelectric modulation of cell membrane properties would exert control over macrophage polarization. One approach to Vmem modulation is to target ion channels expressed on the cell surface with specific channel blocker or openers, which could potentially cause cell depolarization and hyperpolarization, respectively Immune cells regulate their intracellular Ca2+ signaling pathways for proliferation and/or differentiation by modulating the expression and activity of ion channels. The effect of modulation of cell membrane electric properties on macrophage phenotype was investigated using the human monocytic cell line THP-1
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