Researchers at Baylor College of Medicine and collaborating institutions have uncovered a key molecular player that is involved in lung repair and in the development of pulmonary fibrosis, a common and severe class of adult lung diseases linked to respiratory failure.
Published in Nature Communications , the study shows that a small gene named let-7 functions as a guardian of the lungs' health and healing processes. When the gene is absent in mice, injured lungs are not able to repair themselves properly – they develop pulmonary fibrosis, or scarring and severe inflammation. The researchers uncovered molecular pathways by which let-7 fulfills its functions, which can provide opportunities for new drugs and interventions to prevent or slow the progression of this devastating disease.
"Pulmonary fibrosis refers to a group of incurable interstitial lung diseases that usually affect people over 50 years old," said corresponding author Dr. Antony Rodríguez , associate professor of medicine , section of immunology, allergy and rheumatology at Baylor. "The lungs of affected individuals become stiff due to improper healing that makes it difficult to breathe. In our lab we focus on lung injury and regeneration and the healing processes that go wrong in pulmonary fibrosis."
The lungs are very resilient. During a person's life, the lungs can heal after repeated injuries, such as severe flu or COVID-19 infections. But as people age, the healing capacity of the lung declines. "Progenitor stem cells called AT2 are in charge of lung repair and healing," Rodriguez said. "Lung injuries activate AT2 stem cells, which then orchestrate the healing process by producing AT1 cells. As people age, AT2 cells become dysfunctional – instead of repairing the lungs, they create scars, which is what we see in pulmonary fibrosis."
To better understand the process that transforms healthy AT2 into fibrosis-promoting AT2 cells, Rodríguez and his colleagues investigated the involvement of the let-7 gene, whose expression is reduced in human pulmonary fibrosis. Previous studies showed that let-7 is a tumor suppressor gene involved in malignancy, cell growth and metastasis of epithelial cells in various cancers.
"Using a combination of molecular, biochemistry and microscopy techniques in mouse models, 3D lung organoids and tissue samples of pulmonary fibrosis, we examined the molecular mechanisms that promote the formation of AT2 cells that lead to scarring and inflammation in the lung," Rodríguez said.
They discovered that let-7 is downregulated in mouse models of the condition. When the researchers knocked out the gene in mice, the animals spontaneously developed fibrosis, strongly suggesting that let-7 is key to maintaining the lungs healthy and keeping fibrosis in check. But, how does it do it?
Digging deeper into the mechanism revealed that let-7 prevents the inappropriate expression of genes associated with cancer and organ fibrosis.
"We showed that these cancer-associated genes become more active as the AT2 cells were being reprogrammed into fibrotic scar-forming cells," Rodríguez said. "Probing further showed that let-7 also plays an integral role in modulating tumor-like pathways epigenetically via modifications in histones or DNA-associated proteins, in scar-forming AT2 cells."
Organ fibrosis is common in all different organs, including kidneys, liver and heart. "Let-7 is expressed in all the organs. Our findings support exploring whether the mechanism we have discovered also plays a role other organ fibrosis," Rodríguez said.
Other contributors to this work include Matthew J. Seasock, Md Shafiquzzaman, Maria E. Ruiz-Echartea, Rupa S. Kanchi, Brandon T. Tran, Lukas M. Simon, Matthew D. Meyer, Phillip A. Erice, Shivani L. Lotlikar, Stephanie C. Wenlock, Scott A. Ochsner, Anton Enright, Alex F. Carisey, Freddy Romero, Ivan O. Rosas, Katherine Y. King, Neil J. McKenna and Cristian Coarfa. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children's Hospital, Rice University, University of Cambridge and St. Jude Children's Research Hospital in Memphis.
This work was supported by grants from the NHLBI (R01HL140398, HL167814, HL155672, F31 HL164287), and NIGMS (grant T32 GM136554). Partial support was provided by the Cancer Prevention Institute of Texas (CPRIT grants RP210227 and 829 RP200504) and NIEHS grants (P30 ES030285 and P42 ES027725).
