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Transcriptomic characterization of human microglial cells upon therapy-induced senescence and treatment by a natural flavonoid dihydromyricetin

ABSTRACT: The central mechanisms underlying development of central nervous system (CNS) diseases remain unclear, limiting the development of effective therapeutic strategies. Cellular senescence, a biological phenomenon observed in cultured fibroblasts in vitro, has been reported to be a crucial intrinsic mechanism that influences homeostasis of the brain microenvironment and contributes to the onset and progression of CNS pathologies. Cellular senescence has been observed in disease models established in vitro and in vivo, and in bodily fluids or tissues from patients with CNS diseases. These findings raise senescent cells as a potential target for preventing, delaying and treating CNS diseases. Emerging therapies that target senescent cells have shown promising therapeutic effects in preclinical and clinical studies on aging and age-related diseases. Such innovative therapies can potentially avoid brain cell loss and functional changes, thus improving the prognosis of CNS disorders and providing alternative treatments for CNS patients. Microglia, a group of unique myeloid cells residing in mammalian brain parenchyma, represent the first line of immune defense within the central nervous system (CNS). In addition to their immune functions, microglial cells are actively implicated in other cerebral processes including regulation of synaptic architecture and neurogenesis. However, chronic microglial activation is usually detrimental, and is considered a pathogenic mechanism shared by several neurological disorders. To date, the expression pattern of senescent human microglial cells and their susceptibility to senolytic agents remain underexplored. The human microglial clone 3 cell line, HMC3, was established in 1995, through SV40-dependent immortalization of human embryonic microglial cells. In this study, we treated these cells with a chemotherapeutic agent bleomycin (BLEO), which induces therapy-induced senescence (TIS). We established the expression landscape of senescent microglial cells to characterize their senescence-associated expression pattern. Further, we treated senescent microglial cells with dihydromyricetin (DMY), a natural flavonoid that exhibits senolytic activity against certain types of stromal cells, and investigated their overall transcriptomic expression changes. The senotherapeutic effect of DMY can be partially reflected by the genome-wide expression of senescent microglial cells, which are abundant in the brain and can serve as a novel target for treatment of chronic neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275834 | GEO | 2026/01/13

REPOSITORIES: GEO

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Project description:Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found no predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the ABT263 or the combination of dasatinib and quercetin (D+Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-xL was significantly correlated to senescent cell killing by both ABT263 and D+Q, despite no significant changes in the gene or protein expression of BCL-xL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.

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Transcriptomic characterization of human microglial cells upon therapy-induced senescence and treatment by a natural flavonoid dihydromyricetin

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