title: Endothelial FoxM1 mediates bone marrow progenitor cell-induced vascular repair and resolution of inflammation following inflammatory lung injury.
abstract: Adult stem cell treatment is a potential novel therapeutic approach for acute respiratory distress syndrome. Given the extremely low rate of cell engraftment, it is believed that these cells exert their beneficial effects via paracrine mechanisms. However, the endogenous mediator(s) in the pulmonary vasculature remains unclear. Using the mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO), here we show that endothelial expression of the reparative transcriptional factor FoxM1 is required for the protective effects of bone marrow progenitor cells (BMPC) against LPS-induced inflammatory lung injury and mortality. BMPC treatment resulted in rapid induction of FoxM1 expression in wild type (WT) but not FoxM1 CKO lungs. BMPC-induced inhibition of lung vascular injury, resolution of lung inflammation, and survival, as seen in WT mice, were abrogated in FoxM1 CKO mice following LPS challenge. Mechanistically, BMPC treatment failed to induce lung EC proliferation in FoxM1 CKO mice, which was associated with impaired expression of FoxM1 target genes essential for cell cycle progression. We also observed that BMPC treatment enhanced endothelial barrier function in WT but not in FoxM1-deficient EC monolayers. Restoration of β-catenin expression in FoxM1-deficient ECs normalized endothelial barrier enhancement in response to BMPC treatment. These data demonstrate the requisite role of endothelial FoxM1 in the mechanism of BMPC-induced vascular repair to restore vascular integrity and accelerate resolution of inflammation, thereby promoting survival following inflammatory lung injury.
authors.affiliation: Department of Pharmacology, The University of Illinois College of Medicine, Chicago, Illinois, USA; Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, Illinois, USA.
authors.forename: Yidan D
authors.initials: YD
authors.lastname: Zhao
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Huang
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Dai
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Qian
authors.forename: Chinnaswamy
authors.initials: C
authors.lastname: Tiruppathi
authors.forename: Khiem
authors.initials: K
authors.lastname: Tran
authors.forename: You-Yang
authors.initials: YY
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012038:Regeneration; D012128:Respiratory Distress Syndrome / Q000628:therapy*; D015533:Transcriptional Activation
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D008070:Lipopolysaccharides
keywords: Acute respiratory distress syndrome; Adult stem cells; FoxM1; Inflammation; Vascular integrity