Fuelling repair: metabolic regulation of alveolar type 2 cell fate in lung regeneration and disease

ABSTRACT

There is growing scientific interest in uncovering the mechanisms of lung regeneration, aiming to inform the development of innovative therapies for irreversible lung damage associated with chronic diseases. Cellular metabolism and its associated metabolites are increasingly recognised as active regulators of stem cell behaviour and tissue repair in other organs, yet little is known about how metabolic programmes and metabolite-mediated processes influence lung progenitor cell fate decisions. This Review explores current knowledge of how cellular metabolism directs the stem cell functions of alveolar type 2 (AT2) cells, the main epithelial progenitor cells of the distal lungs. Recent studies suggest that AT2 cell regenerative functions are linked to shifts in glycolytic and oxidative metabolism and require tight regulation of mitochondrial function and lipid metabolism for effective repair. Dysregulation of AT2 cell metabolism, as observed in chronic lung diseases, such as pulmonary fibrosis and chronic obstructive pulmonary disease, is emerging as a mechanism of regenerative failure and associated with respiratory disease progression. Improving our understanding of how AT2 cell metabolism ‘fails to fuel’ and starts ‘fuelling to fail’ lung repair is paramount for the development of innovative therapies that may slow or reverse the progression of chronic lung diseases.