Organs in the adult body stay relatively the same size. For some organs, however, this stable size masks a dynamic turnover in cells. Most obvious is the skin, which constantly peels off dead cells that promptly replaced underneath. The pancreas, whose disturbance leads to diabetes and cancer, is another dynamic organ. In their latest study, CiRA Prof. Yoshiya Kawaguchi and his research team create a mutant mouse in which they show how the Pdx-1 gene is vital to maintaining the proper pancreas size.

Pdx-1 is a vital gene for insulin and other hormones that regulate glucose levels. Its importance in the development of the pancreas is also well established.

"We know a lot about Pdx-1 in pancreas organogenesis. Knockout of Pdx-1 results in pancreas agenesis and apoptosis. On the other hand, we know little about the significance of Pdx-1 in adult pancreas," says Kawaguchi.

To investigate, his team prepared mutant mice in which the Pdx-1 gene could be suppressed in half the acinar cells of the pancreas by administering a drug to the mice. Had this suppression occurred in the fetal stage, it would have led to mice with severe disabilities related to the pancreas.

"We previously showed that inactivation of Ptf1a, the other key transcription factor in embryonic pancreas formation, caused severe reduction in pancreatic size in adult organ," says Kawaguchi (see pressrelease).

However, the study shows that in adult mice, the pancreas was able to maintain its normal size.

However, when looked at microscopically, obvious differences between normal and mutated pancreas emerged. One was the constituency of the pancreas with acinar cells in which Pdx-1 was active and inactive.

"The cells that expressed Pdx-1 proliferated more, while the mutant cells stopped proliferating and were gradually removed from the organ," observes Kawaguchi.

The maintenance of a normal pancreas depends on cells duplicating. The suppression of Pdx-1 inhibited this duplication ability and caused the cells to become senescent. Senescent cells are normal throughout the body including the pancreas with age, which results in their elimination by the immune system.

"Senescence is a cellular response to stress and stops a cell from proliferating, and frequently triggers the senescent-associated secretory phenotype (SASP) thereby affecting the surrounding cells" notes Kawaguchi.

Interestingly, the findings suggest that the mutant cells communicated their senescence to the normal which responded by proliferating to maintain the pancreas size.

"Our findings indicate that stress triggered SASP to maintain pancreas homeostasis. The unknown SASP protein that triggers proliferation in other cells could have therapeutic benefits," says Kawaguchi.

• doi: 10.1002/1873-3468.13504