In mice, continuous activation of Yamanaka factors caused liver failure through oxidative stress; an antioxidant delayed death
In mice, continuous activation of Yamanaka factors caused liver failure through oxidative stress; an antioxidant delayed death
On August 2, a paper by Hee Ji Eom's team drew attention for explaining why continuous activation of Yamanaka factors rapidly kills mice. Reactive oxygen species accumulated in liver cells; N-acetylcysteine reduced this stress and prolonged the animals' survival while preserving signs of cellular plasticity.
The Yamanaka factors, Oct4, Sox2, Klf4, and c-Myc, collectively known as OSKM, can briefly shift a mature cell into a more plastic state. Researchers use this approach in an effort to initiate tissue regeneration. Prolonged activation of OSKM in a living organism is dangerous: a 2023 study linked the early death of these mice to liver and intestinal failure.
In the new paper, Eom and colleagues examined the liver component of this process. The mice received doxycycline, which activated OSKM throughout the body. Within four days, the animals lost weight and died. By the third day, hepatocytes, the cells that perform most of the liver's functions, had already lost markers of mature cells and acquired markers of progenitor cells.
At the same time, levels of reactive oxygen species increased in hepatocytes. When present in excess, these reactive molecules damage DNA and proteins. RNA analysis in individual cell nuclei showed that the cells activated oxidative stress programs and NRF2, a protein that initiates antioxidant defenses. These defenses were insufficient: DNA damage increased, hepatocytes died, and the mice developed acute liver failure. Females whose hepatocytes showed stronger activation of antioxidant genes had fewer reactive oxygen species and survived longer.
N-acetylcysteine allowed the researchers to test this causal chain. It reduced oxidative stress and DNA damage in the mice and delayed early death. At the same time, the authors used the Pou5f1, Sox2, and Sox9 markers to confirm OSKM activity and a change in cellular state. The antioxidant reduced the toxicity of continuous OSKM activation while preserving the measured signs of reprogramming.
In this mouse model, continuous OSKM signaling initiated a sequence of events in the liver: excess reactive oxygen species, DNA damage, cell death, and organ failure. This means that the activation schedule of the factors and protection of the specific organ must be incorporated into the design of partial reprogramming.