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Researchers find variant cells in lungs of patients with idiopathic pulmonary fibrosis

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Houston | May 18, 2023 9:39:16 AM IST
A pair of internationally known stem cell cloning researchers from the University of Houston have reported their discovery of mutant cells in the lungs of patients with Idiopathic Pulmonary Fibrosis (IPF), which will most likely be crucial targets in any future treatment for the ailment.

IPF is a gradual, irreversible, and deadly lung disease in which the lungs scar and breathing becomes difficult. The disease's rapid development and fatal progression are caused by unknown mechanisms, but the most widely accepted theory is that IPF is caused by recurrent, subclinical lung injury that causes changes in epithelial and stromal cells, compromising lung repair and favouring fibrosis.

Frank McKeon, professor of biology and biochemistry and director of the Stem Cell Centre, and Wa Xian, research associate professor at the centre, used single cell cloning technologies to generate libraries of basal stem cells from the lungs of 16 patients with IPF and 10 patients without the disease to delve deeper into the cause of IPF.

Houston Methodist Lung Transplant Center provided the lung tissue from patients who underwent transplant for end-stage lung disease from which some of these basal cell clones were generated. The basal cells were used because consistently single-cell RNA sequencing studies have identified lung basal cells in IPF.

"We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts to pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts," reports Xian and McKeon in Science Translational Medicine.

"This study breaks new ground by showing lung fibrosis is driven by specific basal stem cell variants that become overly abundant in diseased lungs," said Howard J. Huang, M.D., Medical Director, Houston Methodist Lung Transplant Center. "Importantly, these variants are distinct from abnormal variants identified in other chronic lung diseases. These findings suggest therapies selectively targeting these pathogenic stem cell variants may ameliorate fibrotic lung disease progression."

The concept that IPF is associated with aberrant epithelial cell types is consistent with a recent clonogenic analysis of chronic obstructive pulmonary disease (COPD) conducted by Xian and McKeon. It linked the widespread lung disease to the emergence of three discrete and clonogenic epithelial distal airway stem cell variants that autonomously promote mucin hypersecretion, fibrosis and inflammation.

"In this study, we applied the same single cell cloning technology used to assess COPD to the lungs of patients with IPF. In contrast to the three pathogenic basal cell variants found to dominate the COPD lung, lungs with advanced IPF showed a major basal cell variant in addition to the normal distal airway stem cell," said Xian. "This IPF variant showed constitutive expression of proinflammatory and profibrotic genes and displayed the functional capacity to orchestrate the fibrotic state both in vitro and in vivo." (ANI)

 
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