Macrophages and microglia represent the primary phagocytes and first line of defense in the peripheral and central immune systems. They activate and polarize into a spectrum of pro- and anti-inflammatory phenotypes in response to various stimuli. This activation is tightly regulated to balance the appropriate immune response with tissue repair and homeostasis. Disruption of this balance results in inflammatory disease states and tissue damage. Adipose stem cells (ASCs) have great therapeutic potential because of the potent immunomodulatory capabilities which induce the polarization of microglia and macrophages to the anti-inflammatory, M2, phenotype. In this study, we examined the effects of donor heterogeneity on ASC function. Specifically, we investigated the impact of donor obesity on ASC stemness and immunomodulatory abilities. Our findings revealed that ASCs from obese donors (ObASCs) exhibited reduced stem cell characteristics when compared to ASCs from lean donors (LnASCs). We also found that ObASCs promote a pro-inflammatory phenotype in murine macrophage and microglial cells, as indicated by the upregulated expression of pro-inflammatory genes, increased nitric oxide pathway activity, and impaired phagocytosis and migration. These findings highlight the importance of considering individual donor characteristics such as obesity when selecting donors and cells for use in ASC therapeutic applications and regenerative medicine.
Glioblastoma (GBM) is an aggressive primary central nervous system neoplasia with limited therapeutic options and poor prognosis. Following reports of cytomegalovirus (HCMV) in GBM tumors, the anti-viral drug Valganciclovir was administered and found to significantly increase the longevity of GBM patients. While these findings suggest a role for HCMV in GBM, the relationship between them is not clear and remains controversial. Treatment with anti-viral drugs may prove clinically useful; however, their results do not explain the underlying mechanism between HCMV infection and GBM progression. We hypothesized that HCMV infection would metabolically reprogram GBM cells and that these changes would allow for increased tumor progression. We infected LN-18 GBM cells and employed a Seahorse Bioanalyzer to characterize cellular metabolism. Increased mitochondrial respiration and glycolytic rates were observed following infection. These changes were accompanied by elevated production of reactive oxygen species and lactate. Due to lactate’s numerous tumor-promoting effects, we examined the impact of paracrine signaling of HCMV-infected GBM cells on uninfected stromal cells. Our results indicated that, independent of viral transmission, the secretome of HCMV-infected GBM cells was able to alter the expression of key metabolic proteins and epigenetic markers. This suggests a mechanism of action where reprogramming of GBM cells alters the surrounding tumor microenvironment to be permissive to tumor progression in a manner akin to the Reverse-Warburg Effect. Overall, this suggests a potential oncomodulatory role for HCMV in the context of GBM.
Glioblastoma (GBM) is an aggressive central nervous system neoplasia with an extremely poor prognosis. Despite intense research, 5‐year survival rates have not increased for the past 20 years, pointing to the need for alternative therapeutic strategies. Accumulating evidence has described a role for cytomegalovirus (CMV) in GBM, yet the mechanism of action is still unclear. We hypothesized that CMV may be metabolically reprogramming GBM cells and that these changes may alter the tumor microenvironment (TME) resulting in enhanced tumor progression. To test this hypothesis we infected GBM cells with CMV and employed the Seahorse Bioanalyzer and flow cytometry to examine their metabolic function. We witnessed increased glycolysis and oxidative phosphorylation relative to control cells. These changes were also accompanied by increases in lactate and reactive oxygen species (ROS) production. Since both lactate and ROS are capable of producing significant tumor promoting effects within the TME, we examined the impact that CMV‐infected cells had on their neighbors by employing an indirect co‐culture model. We found that, independent of viral transmission, the secretome of infected GBM cells was able to alter the levels of key metabolic proteins and epigenetic marks of their neighbors. These findings suggest the potential for major alterations within the TME following CMV infection or reactivation. They point to an oncomodulatory role for CMV in the context of GBM and may underlie the enhanced disease progression seen in CMV positive patients. Further research into these findings may yield new therapeutic targets which could be exploited to treat GBM more effectively.
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