Senescent cells survive by shedding fragments that leave cellular debris
Cells that have stopped dividing shed fragments containing damaged mitochondria, which helps them survive
On August 28, Developmental Cell published a study showing that, in cultured human cells, a senescent cell, meaning a cell that has stopped dividing, leaves a large fragment on a neighboring cell when contact between them breaks. The fragment contains damaged mitochondria, and the authors link its separation to the survival of the senescent cell. The fragment then breaks down, leaving deposits of cellular material nearby. The researchers observed similar fragments in mouse liver.
A senescent cell stops dividing but remains biologically active. Its effects on surrounding cells are usually attributed to the release of soluble signals. In this study, the authors used live-cell imaging to observe how cells change as they enter senescence.
In cultures of human fibroblasts, which are connective tissue cells, two neighboring cells made contact and then moved apart. Sometimes the connection between them did not break immediately. Instead, it stretched until a large fragment detached from one cell and remained on the other. These fragments did not form in low-density cultures, where the cells had no neighbors to contact.
Analysis showed that the fragments were enclosed by a membrane and contained cytoplasm and organelles, including damaged mitochondria. The researchers then reduced the activity of two proteins that form sites of cell adhesion. Fewer fragments formed, mitochondria and reactive oxygen species accumulated inside the senescent cells, and cell viability declined. The antioxidant N-acetylcysteine prevented cell loss after these proteins were suppressed. The authors proposed the following mechanism: fragmentation allows a cell to remove some of its damaged mitochondria.
The isolated fragments remained intact during the first day and then ruptured. After three days, large deposits of cellular material remained on the surfaces of neighboring cells. These deposits contained intracellular molecules that act as damage signals when released outside the cell. Adding the fragments to human fibroblasts increased their proliferation and migration. In a three-dimensional culture of liver cancer cells, the fragments increased cell growth and invasion into the gel.
The researchers also observed fragments in mouse liver, both in an experiment in which an oncogene induced cellular senescence and in old animals whose senescent cells had been genetically labeled. The study describes one physical route by which a senescent cell removes some damaged organelles while leaving their contents in the immediate cellular environment.