A pair of internationally renowned stem cell cloning experts at the University of Houston are reporting their findings about altered cells in the lungs of patients with idiopathic pulmonary fibrosis (IPF) that likely represent key targets in any future treatment of the condition.
IPF is a progressive, irreversible, and fatal lung disease in which the lungs become scarred and breathing becomes difficult. The rapid progression and lethal progression of the disease occurs through uncertain mechanisms, but the most widely held school of thought is that IPF arises from recurrent subclinical lung injury that imparts changes to epithelial and stromal cells, which in turn compromise and favor lung repair. fibrosis.
To delve deeper into the cause of IPF, Frank McKeon, professor of biology and biochemistry and director of the Stem Cell Center, and Wa Xian, research associate professor at the center, used single-cell cloning techniques to create libraries of basal stem cells from the lungs of 16 patients with IPF and 10 patients without the disease. .
The Lung Transplant Center at Houston Methodist provided lung tissue from patients who underwent transplants for end-stage lung disease from which some of these basophil clones were produced. Basophils were used because single-cell RNA-sequencing studies have consistently identified lung basophils in IPF.
“We identified a major type of stem cell that was distinguished from normal stem cells by its ability to convert normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts into xenografts,” Xian and McKeon report in Science Translational Medicine.
This study breaks new ground by showing lung fibrosis is driven by specific basal stem cell variants that become very abundant in diseased lungs. Importantly, these variants differ from abnormal variants identified in other chronic lung diseases. These findings suggest that therapies that selectively target disease-causing stem cell variants may improve the progression of fibrotic lung disease. “
Howard J. Huang, MD, medical director, Lung Transplant Center at Houston Methodist
The concept of an association of IPF with aberrant epithelial cell types is consistent with a recent clone analysis of chronic obstructive pulmonary disease (COPD) by Xian and McKeon. She has linked the spread of lung disease to the emergence of three separate, cloned distal airway stem cell variants that independently promote mucin overexpression, fibrosis, and inflammation.
“In this study, we applied the same single-cell cloning technique used to evaluate COPD in the lungs of COPD patients. In contrast to the three pathogenic basal cell variants found to dominate the lung, lungs with advanced IPF showed a major basal cell in addition to normal distal stem cells,” Xian said. “This IPF variant showed constitutive expression of proinflammatory and proinflammatory genes and demonstrated the functional ability to regulate the fibrotic state both in vitro and in vivo.”
Understanding how these secondary variables are differentially amplified in chronic obstructive pulmonary disease, chronic pulmonary fibrosis and possibly other lung conditions will refine specific risk factors for these diseases.
“On the contrary, deciphering why these variants control the lung could help our ability to treat these conditions,” McCune said.
Wang, S.; et al. (2023) Cloning of a type of profibrotic stem cell in idiopathic pulmonary fibrosis. Translational Medicine Sciences. doi.org/10.1126/scitranslmed.abp9528.