Epithelial stem cells at the intersection of tissue regeneration and pulmonary fibrosis
Stem cell proliferation and differentiation, carefully controlled re-activation of developmental pathways and finely regulated fibrogenesis all represent fundamental parts of the physiological regenerative processes following injury. When these overlapping processes are disrupted during the ensuing wound-healing response, this results in pathological fibrosis and organ dysfunction. IPF is the most progressive and fatal of all fibrotic conditions, and is hypothesised to be driven by epithelial stem cell dysfunction and a highly dysregulated epithelial–mesenchymal crosstalk in response to chronic epithelial injury in aged and genetically susceptible individuals. Dysregulated re-emergence of developmental pathways, genetic alterations, senescence and mechanical forces within the lung micro-environment drive transcriptional changes within existing stem cell populations, as well as the persistence of regenerative cell intermediates and the emergence of aberrant new cell populations. Dysfunctional epithelial stem cells and epithelial–mesenchymal crosstalk result in stem cell failure to effectively differentiate and repair, leading to fibrosis.
