Transplantation of endothelial progenitor cells attenuates pulmonary fibrosis via IFITM3-containing exosomes
6 affiliations
- 1Phoenix Children’s Research Institute, Department of Child Health, University of Arizona College of Medicine–Phoenix, Phoenix, Arizona, USA.
- 2Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Dignity Health, Phoenix, Arizona, USA.
- 3Department of Internal Medicine, Division of Pulmonary Medicine, University of Arizona College of Medicine–Phoenix, Phoenix, Arizona, USA.
- 4Division of Bioinnovation and Genome Sciences, The Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA.
- 5Division of Neonatology and
- 6Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, Arizona, USA.
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.
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BibTeX
@article{lan2026transplantation,
title = {{Transplantation of endothelial progenitor cells attenuates pulmonary fibrosis via IFITM3-containing exosomes}},
author = {Ying-Wei Lan and Jonathan Do and Wen Gao and Zicheng Deng and Xiaomei Xia and Enhong Li and Jillian Kash and Gautam Verma and Angara Sureshbabu and Kenneth S. Knox and Ross M. Bremner and Nicholas E. Banovich and Vladimir V. Kalinichenko and Tanya V. Kalin},
journal = {JCI Insight},
year = {2026},
month = oct,
doi = {10.1172/jci.insight.199743},
url = {https://doi.org/10.1172/jci.insight.199743},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Transplantation of endothelial progenitor cells attenuates pulmonary fibrosis via IFITM3-containing exosomes
AU - Ying-Wei Lan
AU - Jonathan Do
AU - Wen Gao
AU - Zicheng Deng
AU - Xiaomei Xia
AU - Enhong Li
AU - Jillian Kash
AU - Gautam Verma
AU - Angara Sureshbabu
AU - Kenneth S. Knox
AU - Ross M. Bremner
AU - Nicholas E. Banovich
AU - Vladimir V. Kalinichenko
AU - Tanya V. Kalin
PY - 2026
DA - 2026/10/08
JO - JCI Insight
DO - 10.1172/jci.insight.199743
UR - https://doi.org/10.1172/jci.insight.199743
AB - 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.
SN - 2379-3708
ER -