In mice, disabling genes that transmit tension to the nuclei of connective tissue cells improved lung repair after injury
In mice, disabling genes that transmit tension to the nuclei of connective tissue cells improved lung repair after injury
On August 18, the authors published a bioRxiv preprint on lung injury in mice. When they genetically disabled two genes in fibroblasts, this group had less scarring and severely damaged tissue by day 28.
Alveoli are air sacs through whose walls oxygen enters the blood. After injury, their surface is restored by AT2 cells, a type of alveolar epithelial cell. Alveolar fibroblasts, which are connective tissue cells, are located nearby and send the epithelium signals needed for repair. After severe injury, tissue stretch can alter fibroblast function for an extended period.
To separate the effects of stretch from those of toxic injury, the authors partially removed a lung, which increased the stretch experienced by the remaining tissue. In another experiment, they ligated the bronchus supplying one lobe, which reduced stretch in that lobe. Under increased stretch, fibroblasts temporarily lost features of their normal alveolar state. When stretch was reduced, they retained those features. A 2024 study by the same group had already shown that communication between fibroblasts and the epithelium after injury can lead to pathological tissue remodeling. The authors have now tested how a physical signal maintains this altered state.
The LINC protein complex transmits tension from intracellular fibers to the nucleus and includes Sun1 and Sun2. The authors genetically disabled these genes only in fibroblasts from adult mice. In uninjured lungs, the fibroblasts persisted for at least six months, and their nuclear size did not differ from that of controls. By day 28 after bleomycin injury, the set of active genes in cells lacking Sun1 and Sun2 was closer to the uninjured state than it was in control mice.
The change in fibroblast state was followed by tissue repair. On day 14, AT2 cells divided more actively, and by day 28, the lungs had less scarring, fewer severely damaged regions, and less pathological epithelial remodeling. The authors propose that this effect may result from the restoration of Wnt2 and Fgf7, signals through which fibroblasts support the epithelium. In this mouse model, tissue stretch reaches the fibroblast nucleus and helps maintain the cell in an injury associated state. Disabling Sun1 and Sun2 changes how the alveoli recover.