Activating <i>Igf2</i> restored liver regeneration in old mice

Activating Igf2 restored liver regeneration in old mice

On September 4, Cell Stem Cell published a study examining how the Hippo-IGF2 pathway controls liver growth. In mice with chronic liver injury, Hippo signaling weakened, allowing the Igf2 gene to become active again. This response was impaired in old animals, and restoring Igf2 expression restored liver regeneration.

The liver grows rapidly after birth and then maintains a stable size. The Hippo pathway regulates this transition by limiting the activity of YAP and TAZ, two proteins that control gene expression. When YAP and TAZ are active, they help activate Igf2. This gene encodes IGF2, a signal that stimulates cell division.

In an openly available early version of the study, the authors tested this causal pathway directly. In mice with artificially activated YAP and TAZ, deleting Igf2 reduced the liver-to-body weight ratio by approximately 70% and decreased the number of dividing cells. In 16-month-old mice, disabling several inhibitory proteins in the Hippo pathway increased IGF2 levels and was accompanied by liver enlargement.

This mechanism operates only in some liver cell types. In hepatocytes, the organ’s main cell type, the DNA regions that regulate Igf2 are accessible to YAP and TAZ. In bile duct cells, chemical modifications to the DNA and its packaging proteins prevent YAP and TAZ from accessing Igf2.

The authors also studied this pathway in a mouse model of hepatoblastoma, a childhood liver cancer. An IGF1R inhibitor reduced tumor burden. In healthy growing mice, the same inhibitor reduced both liver size and body weight.

Within this pathway, the same growth signal contributes both to the repair of an injured liver and to tumor growth. The outcome depends on the conditions, the cell type, and the timing of signal activation.