Phoenix Children’s Researchers Identify Fibrotic Pericytes and FOXF1 as a Potential Target in Pulmonary Fibrosis

November 12, 2026

Key Takeaways

Researchers identified a group of pericytes – support cells that wrap around the lung’s small blood vessels – that appear in fibrotic lungs but not in healthy ones. The same cells appeared in mice with lung fibrosis.
FOXF1, a protein that switches genes on and off and keeps pericytes working normally, was sharply reduced in these cells in both patients and mice.
In mice with lung scarring, raising FOXF1 in pericytes reduced collagen in the lungs and improved oxygen levels. The work is preclinical and does not prove benefit in patients yet.
In children, pulmonary fibrosis most commonly follows lung injury from cancer therapy, particularly hematopoietic cell transplantation (HCT).

A Cellular Target Beyond Slowing Decline

Nintedanib, pirfenidone and, more recently, nerandomilast slow the loss of lung function in patients with pulmonary fibrosis, but none has been shown to restore lung architecture. For eligible patients, lung transplantation remains the only option that changes the course of the disease. Most research into new treatments has focused on two cell types: the epithelial cells that line the air sacs, called alveoli, and the fibroblasts that lay down scar tissue. A study published in Nature Communications adds a new cell type critical for the disease. Researchers identified a population of pericytes that appear in fibrotic lungs but not in healthy ones, along with FOXF1, the transcription factor that keeps the pericytes from turning fibrotic.

Tatiana Kalin, MD, PhD, and Vlad Kalinichenko, MD, PhD, of Phoenix Children’s co-authored the study with Wen Gao, et al. Dr. Kalin was senior author.

“We identified a pathogenic pericyte subset that does not exist in healthy lungs but is present in disease,” said Dr. Kalin. “That gives us a specific cell and pathway to target, rather than a broad anti-scarring effect.”

What the Study Found

Pericytes wrap around the lung’s capillaries and help keep those vessels stable. In fibrotic lungs, the team found pericytes that had started to lose that role and act more like scar-forming cells (myofibroblasts).

Two kinds of pericytes: Using single-cell RNA sequencing, which measures gene activity one cell at a time, the team found normal pericytes (Peri1) in both healthy and diseased lungs. A second group (Peri2) appeared only in fibrotic lungs. Peri2 cells had turned down the genes that mark normal pericytes and turned up collagen and other scar-related genes. Computer data modeling suggested that normal pericytes become Peri2 cells as fibrosis develops.
Human data first: Peri2 and reduced FOXF1 were found in a public single-cell dataset of 49 donor lungs and 67 pulmonary fibrosis lungs, confirmed with tissue staining. Peri2 also appeared in mice with lung injury. Removing FOXF1 from pericytes worsened fibrosis in three mouse models: a drug-induced lung injury (bleomycin), silica exposure and thin slices of mouse lung kept alive in the lab.

Removing FOXF1 made it worse: Mice without FOXF1 in their pericytes had lower survival, worse lung function, more weight loss and more fibrotic
Raising FOXF1 helped: Higher FOXF1 levels in pericytes reduced fibrosis, reversed fibrotic changes and improved survival. Even when FOXF1 was raised after scarring had set in (8–12 days after the injury), the mice had less collagen in their lungs, less scarring under the microscope, less weight loss and better oxygen levels.

Pericytes Help Direct Fibroblasts

Fibroblasts lay down scar tissue, and pericytes appear to steer them. Healthy pericytes release ANGPT1, which provides a signal that stabilizes blood vessels. Fibrotic pericytes switch to signals that push fibroblasts toward scarring. In lab experiments, fibroblasts exposed to substances released by human pericytes lacking FOXF1 moved and multiplied more and turned on scar-related genes. FOXF1 turns on two genes, ID3 and APLP2, and turns off a third, ACVRL1. Restoring ID3 lowered two pro-fibrotic signals the pericytes released, IL-8 and CXCL1.

“Fibroblasts therefore do not act alone,” said Dr. Kalin. “A pericyte signaling network helps direct them.”

Slowing Decline vs. Reversal

The mouse data suggest “fibrotic remodeling is not a one-way street when a key regulator is restored,” said Dr. Kalin. FOXF1 itself is hard to target with a drug, but the genes it controls are not. Possible approaches include boosting ID3 or APLP2 or blocking ACVRL1. In patients, the team could show only that lower FOXF1 goes along with more severe disease. The cause-and-effect experiments were done in mice and in human pericytes grown in the lab.

The findings are preclinical and do not show that this approach would reverse disease in patients.

Next steps include finding which of these genes is the best drug target; testing it in patient lung tissue and in more animal models, including older ones; finding a way to deliver treatment to pericytes specifically; and checking safety, since FOXF1 also works in other cell types. “Only then can clinical trials begin,” said Dr. Kalin. Reaching patients will take several years.

Clinical Implications for Your Practice

The best-described fibrotic complication after pediatric HCT is pleuroparenchymal fibroelastosis (PPFE). It occurs in about 4% of pediatric HCT recipients (allogeneic or autologous), typically appears several years after transplant and is often fatal. It is strongly associated with pneumonia after transplant (hazard ratio 10.78).
PPFE and other fibrotic interstitial changes are also reported after autologous HCT for high-risk neuroblastoma, with a median of about nine years from diagnosis to pulmonary referral. Conditioning-regimen toxicity (for example, busulfan) and chronic graft-versus-host disease can each cause chronic interstitial pneumonia with fibrosis on their own.
Post-HCT lung problems are the leading cause of non-relapse mortality in pediatric HCT. The FOXF1 findings do not yet prove benefit in patients, and future clinical trials must support this research direction.

How to Refer

To refer a patient, call the Division of Pulmonology at Phoenix Children’s at 602-933-KIDS (5437) or submit a referral online.

Vladimir Kalinichenko, MD, PhD

About the Authors

Tatiana Kalin, MD, PhD
Vice Chair of Translational Research, Center for Cancer & Blood Disorders, Phoenix Children’s

Dr. Kalin joined the Phoenix Children’s Research Institute at the University of Arizona College of Medicine – Phoenix in 2023. She is vice chair of translational research for the Phoenix Children’s Center for Cancer & Blood Disorders and a professor of Child Health at the University of Arizona College of Medicine – Phoenix. At Cincinnati Children’s, she founded and directed the Kalin Research Lab, which focuses on therapies for metastatic lung cancers and chronic lung diseases. She earned her medical degree from Pirogov National Research Medical University, USSR, and completed postdoctoral training in molecular biology and immunology at the University of Illinois Chicago.

Vlad Kalinichenko, MD, PhD
Director, Phoenix Children’s Research Institute at the University of Arizona College of Medicine – Phoenix

Dr. Kalinichenko’s research focuses on pediatric genomics and lung regenerative medicine, including stem-cell-derived bioengineered lung tissue and treatments for conditions such as acute respiratory distress syndrome. He previously led the Center for Lung Regenerative Medicine at Cincinnati Children’s. He earned his medical degree and a doctorate in immunology from Pirogov National Research Medical University, USSR, and completed postdoctoral work in molecular immunology, developmental biology and molecular genetics at the University of Illinois College of Medicine in Chicago. He serves on several editorial and research advisory boards and has published more than 160 peer-reviewed articles.

Sources

Gao W, et al. Emergence of fibrotic pericytes and their transcriptional regulation in pulmonary fibrosis. Nature Communications. 2026;17:8121. PubMed ID 42373667.