An antibody restored an age-weakened signal between lung cells and replenished the pool of cells that repair the lung air sacs in old mice
An antibody restored an age-weakened signal between lung cells and replenished the pool of cells that repair the lung air sacs in old mice
On August 19, bioRxiv published a preprint on lung repair in old mice. The authors linked the loss of AT2 cells, which help repair the alveoli, the lung air sacs where blood takes up oxygen, to reduced secretion of the chemical signal Wnt2 by neighboring fibroblasts, which are connective tissue cells. An antibody activated Fzd5, the receptor through which AT2 cells receive this signal, and increased the pool of these cells.
After injury, AT2 cells divide, and some of them subsequently become AT1 cells, which form the thin surface required for gas exchange. For the lung to recover, the cells must first proliferate and then transition to the AT1 state.
A 2018 study in mice pointed to Wnt2 as a possible cause. It showed that some AT2 cells are located next to fibroblasts that secrete Wnt, a chemical signal that maintains a pool of cells capable of dividing. The authors of the new preprint tested whether this local support weakens with age.
Old mice had fewer AT2 cells in their lungs, and neighboring fibroblasts produced less Wnt2. After acute injury, Wnt signaling in AT2 cells began later and remained weaker. The cells proliferated more slowly, were more likely to remain in an intermediate state, and were less likely to become AT1 cells.
The authors then tried to replenish the reserve by acting directly on AT2 cells. Fzd5 is a receptor on their surface through which the cells receive Wnt signals. Over eight weeks, an antibody that activates Fzd5 increased the number of AT2 cells in old mice to the levels seen in young animals. In another experiment, old mice received the antibody for four weeks before their lungs were injured with bleomycin. On day seven, treated animals had more dividing AT2 cells and less early lung injury.
The later stage of repair produced a different result. On days 21 and 35, the area of fibrosis, which is scar tissue in the lung, was the same in antibody-treated animals and controls. Genetic labeling used to track the fate of AT2 cells also provided no evidence that more of them became AT1 cells. The study therefore separated two stages of lung repair. The antibody replenished the cell pool available for the early response to injury, but did not change the cells' transition into the thin alveolar lining.