Why lung epithelial cells divide only after injury

Why lung epithelial cells divide only after injury

Tissues are not all created equal in their ability to regenerate. Skin and blood cells are continually turning over, making entirely new populations of cells every few days. At the other end of the spectrum, heart and brain cells regenerate slowly, if at all, after injury.

Between these two extremes are tissues such as the lung and liver, which have little cellular turnover in normal adults, but can regenerate extensively after injury. Such tissues, overall, are thought to be quiescent.

This inactive state was previously thought to be the default mode of many tissues, including the lung, in the absence of a proliferative stimulus such as injury. However, it has remained unclear how quiescence is maintained in organs such as the lung that display a low level of cell turnover.

"We demonstrated that quiescence in the adult lung in an animal model is an actively maintained state and is regulated by hedgehog signaling," said the senior author of the Nature publication.

First, they deleted the gene sonic hedgehog in airway epithelial cells of the adult lung. The protein made from sonic hedgehog is secreted from airway epithelial cells and acts on the adjoining cells surrounding the airways called mesenchymal cells.

The team observed that after the loss of sonic hedgehog expression, mesenchymal cells began to spontaneously proliferate. This also occurred when they directly inactivated hedgehog signaling in mesenchymal cells themselves.

To determine what occurred after lung injury, the researchers performed multiple different injuries to lung tissue and found that in contrast to previous reports, hedgehog signaling decreased. This decline correlated with the loss of the cells that normally express the sonic hedgehog gene, which were destroyed as a result of the injury.

They also showed that hedgehog signaling in mesenchymal cells also regulates epithelial quiescence and loss of this regulation leads to abnormal epithelial regeneration after injury. Loss of hedgehog in the adult lung leads to too many epithelial cells lining the airways after injury whereas increased hedgehog signaling blocks regeneration of the airway epithelium.

Such results suggest that increased hedgehog signaling causes a breakdown of the normal regenerative properties of the lung airways, leading to degenerative disease states.