New Study Uncovers Mechanism Behind Lung Stem Cell Differentiation in IPF

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by scarring, resulting from the improper differentiation of lung stem cells into bronchial epithelial cells instead of alveolar type 1 (AT1) cells, which are essential for gas exchange.

A group of researchers at the Mayo Clinic conducted a study to prove that healthy lungs sustain their stem cells through tonic Hippo and β-catenin signaling, leading to the degradation of Yap/Taz and low levels of the Wnt target gene Myc.

Stijn P. De Langhe, Ph.D.

The reason for the study was simple, according to lead author Stijn P. De Langhe, Ph.D., a professor of biochemistry and molecular biology at the Mayo Clinic. “We want to cure IPF,” he told Managed Healthcare Executive.

The results of the research were published in Nature on Dec. 5, 2024.

De Langhe noted the study revealed that when the Hippo pathway’s activators are inactivated in lung stem cells, β-catenin signaling and Myc expression are reduced, pushing the cells toward differentiation into AT1 cells. Conversely, higher Myc levels, in conjunction with Yap, promote differentiation into basal and myoepithelial-like lineages, allowing these cells to invade lung tissue similarly to submucosal gland development.

“Therefore, the research concludes that stem cells with the highest Myc expression become dominant in driving lung remodeling while those with lower Myc levels differentiate into AT1 cells,” he said.

The experimental study involved the breeding and maintenance of various genetically modified mouse strains in a pathogen-free environment with controlled lighting, temperature and access to food and water. Both male and female mice were utilized in experiments. Specific strains included Sox2CreERT2, Krt5CreERT2, Scgb1a1CreERT, and others, many of which have established identifiers from Jackson Laboratory.

For the bleomycin injury model, 8- to 12-week-old adult mice received intratracheal doses of bleomycin based on specific conditions. Additionally, mice were infected intranasally with a sublethal dose of H1N1 influenza virus, with varying viral titers tailored for each strain.

De Langhe explained tamoxifen induction was conducted using tamoxifen-containing chow for tthree weeks, followed by intraperitoneal injections for specific strains. After a three-week washout period, mice were subjected to bleomycin or H1N1 treatments. Mice containing the LSL-rtTA3 construct were placed on doxycycline chow on the day of bleomycin administration. Other strains began tamoxifen chow two weeks post-injury. All procedures were approved by the Mayo Clinic Institutional Animal Care and Use Committee.

De Langhe shared the mouse models used accurately reflect the complexities of human IPF, particularly regarding the dynamics of stem cell competition and differentiation.

“We compared it to human disease and there are quite a number of papers now on the role of aberrant basaloid cells in pulmonary fibrosis,” he said.

Based on the findings, De Langhe believes one could try to target Myc and reduce the competitiveness of the basal cells and force them to differentiate into AT1 cells, though he cautions that Myc has been found difficult to target.