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Investigating the effects of hypoxia on macrophages and their interactions with cardiomyocytes

Creative Commons 'BY' version 4.0 license

Macrophages are versatile cells that polarize into a continuum spectrum of functional phenotypes depending on the microenvironment physiological and pathological cues. As a major immune regulator, macrophages are of interest especially with the current global COVID-19 pandemic. COVID-19 caused by the SARS-CoV-2 virus negatively impact the health of patients through the respiratory system. However, notable cases of COVID-19 showed cardiac damages triggered by prolonged low oxygenation leading to hyperinflammatory responses within the heart. As cardiac tissues cannot regenerate once damaged, looking into the role of macrophages present in the heart during inflammation in response to hypoxia can provide insightful knowledge of the underlying mechanisms taken place. Before exploring macrophages and cardiomyocytes interactions upon in vitro hypoxic stimulation, an optimal culturing medium is required to ensure healthy growth and proliferation of both cell types in a controlled setting. Interestingly, the combination of M199, a standard cardiomyocytes culturing media, and M-CSF, a potent hematopoietic cytokine known for differentiating monocytes into macrophages, leads to normal culture of macrophages. To assess the effect of direct and indirect hypoxia on macrophages functions, macrophages cultured in M199 with M-CSF media or neonatal rat ventricular myocytes (NRVMs) media treated with varying degrees and durations of hypoxia were stimulated. Cytokine secretion levels were used as indicators of inflammatory and healing activation. Short term hypoxia is found to modulate the release of TNF-α leading to increased inflammatory responses. In contrast, long term hypoxia regulates the polarization of macrophages to be more M2 or pro-healing-like. These findings function as the framework for developing an experimental system aimed at understanding the interactions between macrophages and cardiomyocytes.

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