Researchers at Baylor College of Medicine, along with collaborators from various institutions, have identified a critical molecular element involved in lung repair and the development of pulmonary fibrosis. This condition is a severe class of adult lung diseases associated with respiratory failure.
Their study, published in Nature Communications, highlights the role of a small gene named let-7 as essential for maintaining lung health and facilitating healing processes. The absence of this gene in mice leads to improper lung repair following injury, resulting in pulmonary fibrosis characterized by scarring and inflammation. The research outlines molecular pathways through which let-7 operates, suggesting potential targets for new therapeutic interventions.
"Pulmonary fibrosis refers to a group of incurable interstitial lung diseases that usually affect people over 50 years old," stated Dr. Antony Rodríguez, associate professor at Baylor's section of immunology, allergy and rheumatology. "The lungs become stiff due to improper healing that makes it difficult to breathe."
While the lungs generally recover from injuries such as severe flu or COVID-19 infections, their regenerative capacity declines with age. According to Rodríguez, progenitor stem cells known as AT2 are crucial for lung repair. These cells activate upon injury but can become dysfunctional over time, leading instead to scar formation observed in pulmonary fibrosis.
Rodríguez and his team explored how let-7 influences the transformation of healthy AT2 into fibrotic cells. Previous studies had linked let-7 with tumor suppression across various cancers. Using advanced techniques on mouse models and human tissue samples, they investigated mechanisms promoting AT2 cell-induced scarring.
They found reduced expression of let-7 in both mouse models and human cases of pulmonary fibrosis. Eliminating the gene in mice led to spontaneous fibrosis development, indicating its pivotal role in preventing disease progression.
Further analysis revealed that let-7 inhibits genes associated with cancer and organ fibrosis from becoming active during cell reprogramming into scar-forming entities. "We showed that these cancer-associated genes become more active as the AT2 cells were being reprogrammed into fibrotic scar-forming cells," Rodríguez explained.
Additionally, their findings suggest that let-7 might modulate tumor-like pathways through epigenetic changes within histones or DNA-related proteins in these scar-forming cells.
Given its expression across multiple organs like kidneys, liver and heart – all susceptible to similar fibrotic conditions – researchers believe investigating this mechanism's relevance beyond lungs could prove valuable.
Contributors include Matthew J. Seasock among others affiliated with Baylor College of Medicine; Texas Children’s Hospital; Rice University; University Cambridge; St Jude Children's Research Hospital Memphis supported by grants from NHLBI (R01HL140398), NIGMS (T32 GM136554) CPRIT grants RP210227 & 829 RP200504 NIEHS P30 ES030285 & P42 ES027725).
