Study links new cell type to lung scarring in pulmonary fibrosis patients
Findings point to promising targets for future PF therapies
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A new type of pericyte called Peri2 is linked to scar tissue formation in the lungs of people with pulmonary fibrosis (PF), according to a study.
Pericytes are cells that surround blood vessels.
A gene called FOXF1 was also shown to help control whether these cells stay healthy or switch into a damaging, fibrosis-driving state. Boosting this gene’s activity in lung pericytes from a mouse model of PF reduced lung scarring.
“Further investigation into the precise molecular pathways downstream of FOXF1 could unveil promising therapeutic targets for the treatment of pulmonary fibrosis,” researchers wrote.
The study, “Emergence of fibrotic pericytes and their transcriptional regulation in pulmonary fibrosis,” was published in Nature Communications.
In PF, pericytes detach from blood vessels, contribute to fibrosis
PF is marked by excessive tissue scarring and hardening, or fibrosis, that makes it increasingly difficult to breathe and leads to symptoms such as shortness of breath, dry cough, and fatigue. In idiopathic PF (IPF), the most common disease type, the underlying cause is unknown.
Pericytes are cells that are found in the outer rims of small blood vessels and are part of their proper structure. In PF, however, pericytes detach from blood vessels and contribute to fibrosis and abnormal blood vessel permeability. In this study, researchers in the U.S. sought to understand how this transition occurs.
“Given the multifaceted role of pericytes in mediating tissue repair and shaping fibrotic microenvironment, elucidating the mechanisms by which pericytes contribute to fibrosis is essential and holds great promise for uncovering novel therapeutic targets and improving outcomes for patients with pulmonary fibrosis,” the scientists wrote.
FOXF1 protein levels were reduced in lung pericytes from PF patients
By analyzing lung tissue from IPF patients and healthy individuals, the researchers identified a previously unknown group of pericytes, called Peri2, found only in fibrotic lungs. These cells had lower levels of pericyte-specific markers and increased activity of genes linked to scar tissue formation, including COL1A1, COL3A1, and ACTA2.
Similar Peri2 cells were also found in mouse models of PF, suggesting that this cell population is conserved across species.
An approach called lineage tracing supported the observation that these lung cells switch to fibrosis-driving Peri2 cells during disease progression. Comparing human and mouse data sets also identified four genes — FOXF1, ID1, TBX3, and HEYL — whose activity was consistently reduced in fibrotic Peri2 pericytes.
Among them, FOXF1 stood out because mutations in this gene are linked to a rare inherited lung disorder associated with fibrosis. FOXF1 protein levels were markedly reduced in lung pericytes from people with PF.
While about 60% of pericytes in healthy lungs had FOXF1, this protein was found in only 10% of pericytes of PF lungs. A similar difference was observed in mice with PF-like disease.
Altogether, these findings demonstrate that FOXF1 directly regulates a network of pericyte genes critical to the progression of pulmonary fibrosis and transition of pericytes to the fibrotic state.
To test FOXF1’s role in lung fibrosis, the researchers removed the gene from lung pericytes in mice. Compared to controls with preserved FOXF1 gene, these animals developed more severe fibrosis, poorer breathing, greater weight loss, and higher levels of pro-fibrotic genes.
In contrast, boosting FOXF1 gene activity in pericytes improved blood oxygen levels, lowered the accumulation of collagen (the main component of fibrotic tissue), and limited the transition of pericytes into the fibrosis-driving state.
Further analysis showed that FOXF1 controls a network of genes involved in fibrosis, including the TGF-beta signaling pathway. FOXF1 directly activated genes such as ID3 and APLP2 while suppressing ACVRL1, helping maintain healthy pericyte behavior.
When FOXF1 protein levels dropped, this gene network shifted toward a fibrotic state. Restoring key FOXF1-regulated genes reduced the activation of fibroblasts, the cells responsible for producing scar tissue.
“Altogether, these findings demonstrate that FOXF1 directly regulates a network of pericyte genes critical to the progression of pulmonary fibrosis and transition of pericytes to the fibrotic state,” the researchers wrote.
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