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Yale researchers identify potential therapeutic targets for pulmonary fibrosis

December 09, 2021
by Elisabeth Reitman

A Yale-led study provides new insights into the molecular and cellular development of idiopathic pulmonary fibrosis (IPF), a lethal lung disease that has been diagnosed with increased frequency.

The research, led by the Greif Lab in the Yale Cardiovascular Research Center, identified the role of the gene KLF4 in myofibroblast differentiation and fibrosis.

The findings help to further illuminate the complex mechanisms underlying the progression of fibrotic lung disease and suggest potential targets for future therapies, the researchers said.

First author Rachana R. Chandran, a postdoctoral associate at Yale School of Medicine, previously contributed to a paper from the lab of senior author Daniel M. Greif, MD, an associate professor at the Yale School of Medicine, that identified how smooth muscle cells develop at the molecular level. In this latest study, Chandran, Greif, and colleagues focused on specialized cells that regulate pulmonary fibrosis.

The incidence of idiopathic pulmonary fibrosis (IPF), a lung disease that causes scarring and impairs breathing, is growing. In the United States alone, IPF causes 40,000 deaths per year. The research study provides new insights into the development of this lethal disease at the cellular and molecular levels.

The disease pathology of IPF is complex. Although the median survival after initial diagnosis is a dismal three years, the course can be variable. Some patients live less than two years, while others live for several years. Pulmonary fibrosis is driven by exaggerated production of extracellular matrix (ECM) — thought to be integral for injury repair and wound healing.

The research team discovered that the gene Kruppel-like factor 4 or KLF4, a stem cell factor first identified in 1996, regulates pivotal cellular processes in the course of pulmonary fibrosis.

In a laboratory setting, Greif and his team identified lung cells expressing platelet-derived growth factor receptor (PDGFR)-beta as the main source of lung myofibroblasts using genetic fate mapping and single-cell RNA sequencing. They also discovered that these cells robustly replicate after lung damage.

“At the cellular level, KLF4 increases in lung cells expressing PDGFR-beta and their cellular lineage during disease pathogenesis. Importantly, reduction of KLF4 in this cellular lineage decreases the severity of fibrosis by reducing ECM levels in PDGFR cells,” said Greif.

With further study, the researchers hope to analyze the role of other factors important in stem cell biology in the pathogenesis of lung fibrosis.

The study was published Dec. 10 in Nature Communications.

Yale researchers Yi Xie, Eunate Gallardo-Vara, Taylor Adams, Rolando Garcia-Milian, Inamul Kabir, Abdul Sheikh, Naftali Kaminski, Kathleen Martin, and Erica Herzog also contributed to this study.

Submitted by Elisabeth Reitman on December 10, 2021