Stem cells are dispensable for lung homeostasis but restore airways after injury.
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ABSTRACT:
SUBMITTER: Giangreco A
PROVIDER: S-EPMC2687999 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:Cells demonstrate plasticity following injury, but the extent of this phenomenon and the cellular mechanisms involved remain underexplored. Using single-cell RNA sequencing (scRNA-seq) and lineage tracing, we uncover that myoepithelial cells (MECs) of the submucosal glands (SMGs) proliferate and migrate to repopulate the airway surface epithelium (SE) in multiple injury models. Specifically, SMG-derived cells display multipotency and contribute to basal and luminal cell types of the SMGs and SE. Ex vivo expanded MECs have the potential to repopulate and differentiate into SE cells when grafted onto denuded airway scaffolds. Significantly, we find that SMG-like cells appear on the SE of both extra- and intra-lobular airways of large animal lungs following severe injury. We find that the transcription factor SOX9 is necessary for MEC plasticity in airway regeneration. Because SMGs are abundant and present deep within airways, they may serve as a reserve cell source for enhancing human airway regeneration.
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Project description:Our previous study demonstrated that mesenchymal stem cell (MSC) microvesicles (MV) reduced lung inflammation, protein permeability, and pulmonary edema in endotoxin-induced acute lung injury in mice. However, the underlying mechanisms for restoring lung protein permeability were not fully understood. In this current study, we hypothesized that MSC MV would restore protein permeability across injured human lung microvascular endothelial cells (HLMVEC) in part through the transfer of angiopoietin-1 (Ang1) mRNA to the injured endothelium. A transwell coculture system was used to study the effect of MSC MV on protein permeability across HLMVECs injured by cytomix, a mixture of IL-1?, TNF-?, and IFN-? (50 ng/ml). Our result showed that cytomix significantly increased permeability to FITC-dextran (70 kDa) across HLMVECs over 24 hours. Administration of MSC MVs restored this permeability in a dose dependent manner, which was associated with an increase in Ang1 mRNA and protein secretion in the injured endothelium. This beneficial effect was diminished when MSC MV was pretreated with an anti-CD44 antibody, suggesting that internalization of MV into the HLMVEC was required for the therapeutic effect. Fluorescent microscopy showed that MSC MV largely prevented the reorganization of cytoskeleton protein F-actin into "actin stress fiber" and restored the location of the tight junction protein ZO-1 and adherens junction protein VE-cadherin in injured HLMVECs. Ang1 siRNA pretreatment of MSC MV prior to administration to injured HLMVECs eliminated the therapeutic effect of MV. In summary, MSC MVs restored protein permeability across HLMVEC in part by increasing Ang1 secretion by injured HLMVEC. Stem Cells Translational Medicine 2018;7:615-624.
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Project description:ObjectiveBronchopulmonary dysplasia (BPD) is a common chronic lung disease in preterm neonates and has no effective treatment. This study aimed to investigate the therapeutic effects of neonatal mouse lung resident mesenchymal stem cells (L-MSCs) on the hyperoxia-induced lung injury.MethodsL-MSCs were separated and identified according to the MSC criterions. Hyperoxia-Induced Lung Injury (HILI) of neonatal KM mice was induced with hyperoxia (FiO2?=?60%) and investigated with pathological methods. Neonatal KM mice were divided into 3 groups (hyperoxia?+?L-MSC group, hyperoxia?+?PBS group, and air control group). Mice in the hyperoxia?+?L-MSC group were treated with L-MSCs at 3, 7, and 14 days after birth. After hyperoxia exposure for 21 days, the lung pathology, Radial Alveolar Count (RAC), CD31 expression, and vascular endothelial growth factor (VEGF) expression were investigated.ResultsAfter hyperoxia exposure, the body weight, RAC, CD31 expression, and VEGF expression in the hyperoxia?+?L-MSC group were significantly better than those in the hyperoxia?+?PBS group but inferior to those in the air control group significantly. These indicate L-MSCs are partially protective on the lung injury of mice with hyperoxia-induced BPD.ConclusionL-MSCs are helpful for the prevention and treatment of BPD, and endogenous L-MSCs may play a role in the postinjury repair of the lung.
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Project description:Memory T cells respond rapidly to repeated antigen exposure and can maintain their population for extended periods through self-renewal. These characteristics of memory T cells have mainly been studied during viral infections, whereas their existence and functions in allergic diseases have been studied incompletely. Since allergic patients can suffer repeated relapses caused by intermittent allergen exposure, we hypothesized that allergen- specific memory Th2 cells are present and the factors necessary for the maintenance of these cells are provided by the lung and airways. Using a murine model of airway inflammation, we found that allergen-specific CD4 T cells survived longer than 70 days in the lung and airways in an IL-7 dependent fashion. These T cells showing homeostatic proliferation were largely found in the mediastinal lymph node (mLN), rather than the airways; however, cells residing in the lung and airways developed recall responses successfully. We also found that CD4 T cells exhibited differential phenotypes in the mLN and in the lung. Altogether, we believe that allergen-specific memory T cells reside and function in the lung and airways, while their numbers are replenished through homeostatic turnover in the mLNs. Furthermore, we determined that IL-7 signaling is important for the homeostasis of these cells.
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