In brain cell cultures, astrocytes and microglia transmitted signs of senescence to neighboring cells through different pathways
In brain cell cultures, astrocytes and microglia transmitted signs of senescence to neighboring cells through different pathways
On August 15, Aging Cell published a study in which researchers transferred culture medium among five types of human brain cells and measured which recipient cells developed signs of senescence. Astrocytes and microglia triggered this response more often than the other cell types, while interventions targeting individual signaling pathways worked only for certain cell pairs.
Cellular senescence is a state in which a cell stops dividing after stress and changes how it functions. The cell releases SASP, a mixture of proteins and other molecules, into its surroundings. These substances can alter the state of neighboring cells. The authors tested which cells sent this signal and which cells responded to it.
The authors used five immortalized human cell lines, which are cultures that can continue dividing in the laboratory for long periods. These comprised astrocytes, vascular endothelial cells, microglia, which are the immune cells of the brain, oligodendrocytes, which form insulation around nerve fibers, and neuron-like cells. The cultures were treated for seven days with BrdU, a substance that induced signs of senescence in this model. The medium in which each cell type had grown was then transferred to the other cell types. Medium from control cells and fresh medium allowed the researchers to distinguish the effects of substances released by the cells from the properties of the culture medium itself.
Medium from BrdU-treated astrocytes and microglia increased the proportion of cells positive for SA-β-gal, an enzymatic marker of senescence, among astrocytes and vascular endothelial cells. Microglia also responded to medium from several other cell types. For cell pairs involving astrocytes and microglia, the authors examined additional markers of senescence, DNA damage, mitochondrial function, which supplies the cell with energy, and lysosomal function, through which the cell breaks down unwanted substances. The initial map, based on a single enzymatic assay, was therefore tested against several independent measures.
The choice of five cell types followed from a 2025 study by the same group, in which the researchers found that these cultures responded differently to DNA damage. The new experiment tested whether this difference affected signaling between cells. An analysis of molecules in the medium and receptors on the cells narrowed the search to four possible components of this communication: the signaling proteins CCL2 and MIF, the cell-surface receptor CXCR7, and the enzyme DPP4, which affects the availability of one of the signals.
Interventions targeting these components produced different patterns of responses. In the “astrocyte → astrocyte” pair, each of the four interventions reduced the proportion of cells positive for SA-β-gal. In the “microglia → astrocyte” direction, none of them worked. In this culture system, the same interventions therefore produced different results depending on the direction of transmission.