Plain-language summary
Pulmonary fibrosis is driven in part by the loss of cells that keep the lung's smallest blood vessels healthy. This study identifies a previously unrecognised population of endothelial progenitor cells in the lung capillaries that carry both c-KIT and FOXF1, which the authors call capEPCs. These cells were markedly depleted in lung tissue from people with pulmonary fibrosis and in mice injured with bleomycin, suggesting their disappearance contributes to the disease. When donor capEPCs were transplanted into injured mice, the animals survived longer, laid down less collagen and recovered better lung function, and the transplanted cells settled into the lung microcirculation. Single-cell sequencing pointed to interferon-induced transmembrane protein 3 (IFITM3) as one of the most enriched transcripts in capEPCs. In culture, IFITM3 boosted endothelial proliferation and new vessel formation while blocking TGF-beta1-driven fibroblast activation, and the protein was found packaged inside capEPC-derived exosomes. Treating mice with those IFITM3-carrying exosomes reproduced the benefits of transplanting the cells themselves: better endothelial function, quieter fibroblasts, higher survival and less fibrosis. The work positions IFITM3-enriched exosomes as a candidate approach for vascular repair in fibrotic lung disease.
Key findings
- Lung capillary endothelial progenitor cells co-expressing c-KIT and FOXF1 (capEPCs) are depleted in human pulmonary fibrosis and in bleomycin-injured mice.
- Transplanting donor capEPCs into injured mice reduced collagen deposition, restored lung function and improved survival, with the cells engrafting into the lung microcirculation.
- IFITM3 was the standout transcript in capEPCs; it promoted endothelial proliferation and angiogenesis while suppressing TGF-beta1-induced fibroblast activation in vitro.
- IFITM3-containing exosomes from capEPCs reproduced the therapeutic effects of cell transplantation, including less fibrosis and better survival.
Original abstract
Endothelial progenitor cells (EPCs) are critical for vascular regeneration after injury. However, their role in pulmonary fibrosis (PF) remains unclear. Here, we identified a previously unrecognized population of lung capillary EPCs coexpressing c-KIT and FOXF1 (capEPCs) in adult human and mouse lungs. capEPCs were significantly reduced in lungs from patients with PF and in bleomycin-injured mice, implicating loss of this regenerative endothelial population in disease pathogenesis. Transplantation of donor capEPCs attenuated experimental PF, improved survival, reduced collagen deposition, and restored lung function. Donor capEPCs engrafted into the lung microcirculation of bleomycin-injured mice. Single-cell RNA sequencing identified interferon-induced transmembrane protein 3 as a highly enriched transcript in capEPCs. Conditioned media from IFITM3-overexpressing EPCs or recombinant IFITM3 enhanced endothelial proliferation and angiogenesis while suppressing TGF-β1-induced fibroblast activation in vitro. IFITM3 was found in capEPC-derived exosomes. Treatment with IFITM3-containing exosomes recapitulated the therapeutic effects of capEPC transplantation by improving endothelial function, inhibiting fibroblast activation, increasing animal survival, reducing lung fibrosis, and restoring lung function. Together these findings identified capEPC deficiency as a feature of PF and demonstrated that IFITM3-containing exosomes promoted vascular repair. Restoration of capEPC regenerative function or delivery of IFITM3-enriched exosomes may represent a promising therapeutic strategy for human PF.
Frequently asked questions
What did this study find?
Pulmonary fibrosis is driven in part by the loss of cells that keep the lung's smallest blood vessels healthy. This study identifies a previously unrecognised population of endothelial progenitor cells in the lung capillaries that carry both c-KIT and FOXF1, which the authors call capEPCs. These cells were markedly depleted in lung tissue from people with pulmonary fibrosis and in mice injured with bleomycin, suggesting their disappearance contributes to the disease. When donor capEPCs were transplanted into injured mice, the animals survived longer, laid down less collagen and recovered better lung function, and the transplanted cells settled into the lung microcirculation. Single-cell sequencing pointed to interferon-induced transmembrane protein 3 (IFITM3) as one of the most enriched transcripts in capEPCs. In culture, IFITM3 boosted endothelial proliferation and new vessel formation while blocking TGF-beta1-driven fibroblast activation, and the protein was found packaged inside capEPC-derived exosomes. Treating mice with those IFITM3-carrying exosomes reproduced the benefits of transplanting the cells themselves: better endothelial function, quieter fibroblasts, higher survival and less fibrosis. The work positions IFITM3-enriched exosomes as a candidate approach for vascular repair in fibrotic lung disease.
Was this tested in humans or in the laboratory?
This is preclinical work — the findings come from laboratory models, not from human participants.
Where can I read the original paper?
The full text lives with the publisher: https://doi.org/10.1172/jci.insight.199743
How to cite this paper
Lan Ying-Wei, Do Jonathan, Gao Wen, Deng Zicheng, Xia Xiaomei, Li Enhong et al.. Transplantation of endothelial progenitor cells attenuates pulmonary fibrosis via IFITM3-containing exosomes.. JCI insight. 2026, 2026-10-08. DOI: 10.1172/jci.insight.199743
Source & verification
- Journal: JCI insight
- Published: 8 October 2026
- DOI: 10.1172/jci.insight.199743
- PubMed ID: 42847995
- Indexed via: pubmed
- MeSH terms: Animals, Humans, Mice, Endothelial Progenitor Cells, Exosomes, Pulmonary Fibrosis, Membrane Proteins, RNA-Binding Proteins, Bleomycin, Lung, Male, Forkhead Transcription Factors