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Resident Endothelial Cells and Endothelial Progenitor Cells Restore Endothelial Barrier Function After Inflammatory Lung Injury.

ABSTRACT: Disruption of endothelial barrier integrity is a characteristic of many inflammatory conditions. However, the origin and function of endothelial cells (ECs) restoring endothelial barrier function remain unknown. This study defined the roles of resident ECs (RECs) and bone marrow-derived endothelial progenitor cells (BMDEPCs) in endothelial barrier restoration after endotoxemic lung injury.We generated mice that enable to quantify proliferating RECs or BMDEPCs and also to study the causal link between REC or BMDEPC proliferation and endothelial barrier restoration. Using these mouse models, we showed that endothelial barrier restoration was associated with increased REC and BMDEPC proliferation. RECs and BMDEPCs participate in barrier repair. Immunofluorescence staining demonstrated that RECs proliferate in situ on endothelial layer and that BMDEPCs are engrafted into endothelial layer of lung microvessels at the active barrier repair phase. In lungs, 8 weeks after lipopolysaccharide-induced injury, the number of REC-derived ECs (CD45(-)/CD31(+)/BrdU(+)/rtTA(+)) or BMDEPC-derived ECs (CD45(-)/CD31(+)/eNOS(+)/GFP(+)) increased by 22- or 121-fold, respectively. The suppression of REC or BMDEPC proliferation by blocking REC or BMDEPC intrinsic nuclear factor-?B at the barrier repair phase was associated with an augmented endothelial permeability and impeded endothelial barrier recovery. RECs and BMDEPCs contributed differently to endothelial barrier repair. In lungs, 8 weeks after lipopolysaccharide-induced injury, REC-derived ECs constituted 22%, but BMDEPC-derived ECs constituted only 3.7% of the total new ECs.REC is a major and BMDEPC is a complementary source of new ECs in endothelial barrier restoration. RECs and BMDEPCs play important roles in endothelial barrier restoration after inflammatory lung injury.

SUBMITTER: Mao SZ

PROVIDER: S-EPMC4483164 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Resident Endothelial Cells and Endothelial Progenitor Cells Restore Endothelial Barrier Function After Inflammatory Lung Injury.

Mao Sun-Zhong SZ Ye Xiaobing X Liu Gang G Song Dongmei D Liu Shu Fang SF

Arteriosclerosis, thrombosis, and vascular biology 20150514 7

<h4>Objective</h4>Disruption of endothelial barrier integrity is a characteristic of many inflammatory conditions. However, the origin and function of endothelial cells (ECs) restoring endothelial barrier function remain unknown. This study defined the roles of resident ECs (RECs) and bone marrow-derived endothelial progenitor cells (BMDEPCs) in endothelial barrier restoration after endotoxemic lung injury.<h4>Approach and results</h4>We generated mice that enable to quantify proliferating RECs ...[more]

PMID: 25977568

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Project description:BackgroundEndothelial dysfunction, characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD), is a clinically significant feature of heart failure (HF). Mesenchymal stem cells (MSCs), which have pro-angiogenic properties, have the potential to restore endothelial function. Accordingly, we tested the hypothesis that MSCs increase EPC function and restore flow-mediated vasodilation (FMD).MethodsIdiopathic dilated and ischemic cardiomyopathy patients were randomly assigned to receive autologous (n = 7) or allogeneic (n = 15) MSCs. We assessed EPC-colony forming units (EPC-CFUs), FMD, and circulating levels of vascular endothelial growth factor (VEGF) in patients before and three months after MSC transendocardial injection (n = 22) and in healthy controls (n = 10).FindingsEPC-colony forming units (CFUs) were markedly reduced in HF compared to healthy controls (4 ± 3 vs. 25 ± 16 CFUs, P < 0.0001). Similarly, FMD% was impaired in HF (5.6 ± 3.2% vs. 9.0 ± 3.3%, P = 0.01). Allogeneic, but not autologous, MSCs improved endothelial function three months after treatment (Δ10 ± 5 vs. Δ1 ± 3 CFUs, P = 0.0067; Δ3.7 ± 3% vs. Δ-0.46 ± 3% FMD, P = 0.005). Patients who received allogeneic MSCs had a reduction in serum VEGF levels three months after treatment, while patients who received autologous MSCs had an increase (P = 0.0012), and these changes correlated with the change in EPC-CFUs (P < 0.0001). Lastly, human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide synthase inhibition, were rescued by allogeneic MSC conditioned medium (P = 0.006).InterpretationThese findings reveal a novel mechanism whereby allogeneic, but not autologous, MSC administration results in the proliferation of functional EPCs and improvement in vascular reactivity, which in turn restores endothelial function towards normal in patients with HF. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction.

Dataset Information

Resident Endothelial Cells and Endothelial Progenitor Cells Restore Endothelial Barrier Function After Inflammatory Lung Injury.

Publications

Resident Endothelial Cells and Endothelial Progenitor Cells Restore Endothelial Barrier Function After Inflammatory Lung Injury.

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