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Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice.

ABSTRACT: Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ALI mice, a human AT2R expressing lentiviral vector and a lentivirus vector carrying AT2R shRNA were constructed and introduced into human bone marrow MSCs. A mouse model of lipopolysaccharide-induced ALI was used to investigate the migration of AT2R-regulated MSCs and the therapeutic potential in vivo. Overexpression of AT2R dramatically increased Ang II-enhanced human bone marrow MSC migration in vitro. Moreover, MSC-AT2R accumulated in the damaged lung tissue at significantly higher levels than control MSCs 24 and 72 hours after systematic MSC transplantation in ALI mice. Furthermore, MSC-AT2R-injected ALI mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti-inflammatory effects. In contrast, there were less lung retention in MSC-ShAT2R-injected ALI mice compared with MSC-Shcontrol after transplantation. Thus, MSC-ShAT2R-injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. Our results demonstrate that overexpression of AT2R enhance the migration of MSCs in ALI mice and may provide a new therapeutic strategy for ALI. Stem Cells Translational Medicine 2018;7:721-730.

SUBMITTER: Xu XP

PROVIDER: S-EPMC6186265 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice.

Xu Xiu-Ping XP Huang Li-Li LL Hu Shu-Ling SL Han Ji-Bin JB He Hong-Li HL Xu Jing-Yuan JY Xie Jian-Feng JF Liu Ai-Ran AR Liu Song-Qiao SQ Liu Ling L Huang Ying-Zi YZ Guo Feng-Mei FM Yang Yi Y Qiu Hai-Bo HB

Stem cells translational medicine 20180821 10

Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ...[more]

PMID: 30133167

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Project description:BackgroundLow differentiation rates of mesenchymal stem cells (MSCs) limit their therapeutic effects on patients in clinical studies. Our previous study demonstrated that overexpressing p130 or E2F4 affected the multipotential differentiation of MSCs, and the underlying mechanism was attributed to the regulation of the G1 phase. Improving the efficiency of MSC differentiation into epithelial cells is considered to be a new method. Therefore, this study was conducted to evaluate the effects of overexpressing p130 or E2F4 in MSCs on improving re-epithelization in lipopolysaccharide (LPS)-induced ARDS animals.MethodsMouse MSCs (mMSCs) stably transfected with p130 and E2F4 were transplanted intratracheally into LPS-induced ARDS mice. After 7 and 14 days, the mice were sacrificed, and the histopathology of the lungs was assessed by haematoxylin-eosin staining and lung injury scoring. Homing and differentiation of mMSCs were analysed by labelling and tracking mMSCs with NIR815 dye and immunofluorescent staining. Surfactant proteins A and C and occludin in the lungs were assessed by western blot. Permeability was evaluated by analysing the protein concentration of BALF using ELISA. Alveolar fluid clearance was assessed by absorbance measurements of BALF. Lung fibrosis was assessed by Masson's trichrome staining and Ashcroft scoring.ResultsThe engraftment of mMSCs overexpressing p130 or E2F4 led to attenuated histopathological impairment of the lung tissue, and the lung injury scores of the LPS+mBM-MSC-p130 and LPS+mBM-MSC-E2F4 groups were also decreased (p < 0.05). Overexpression of p130 or E2F4 also increased the retention of mMSCs in the lung (p < 0.05), increased differentiation into type II alveolar epithelial cells (p < 0.05), and improved alveolar epithelial permeability (p < 0.05). Additionally, mMSCs overexpressing p130 or E2F4 inhibited lung fibrosis according to the deposition of collagen and the fibrosis score in the lungs (p < 0.05).ConclusionOverexpressing p130 or E2F4 in mMSCs could further improve the injured structure and function of epithelial cells in the lungs of ARDS mice as a result of improved differentiation of mMSCs into epithelial cells.

Project description:BackgroundThe acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. ALI is characterized by disruption of the lung alveolar-capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudate. Current specific treatment strategies for ALI/ARDS are lacking. We hypothesized that mesenchymal stem cells (MSCs), with or without transfection with the vasculoprotective gene angiopoietin 1 (ANGPT1) would have beneficial effects in experimental ALI in mice.Methods and findingsSyngeneic MSCs with or without transfection with plasmid containing the human ANGPT1 gene (pANGPT1) were delivered through the right jugular vein of mice 30 min after intratracheal instillation of lipopolysaccharide (LPS) to induce lung injury. Administration of MSCs significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts in bronchoalveolar lavage (BAL) fluid (53%, 95% confidence interval [CI] 7%-101%; and 60%, CI 4%-116%, respectively) as well as reducing levels of proinflammatory cytokines in both BAL fluid and lung parenchymal homogenates. Furthermore, administration of MSCs transfected with pANGPT1 resulted in nearly complete reversal of LPS-induced increases in lung permeability as assessed by reductions in IgM and albumin levels in BAL (96%, CI 6%-185%; and 74%, CI 23%-126%, respectively). Fluorescently tagged MSCs were detected in the lung tissues by confocal microscopy and flow cytometry in both naïve and LPS-injured animals up to 3 d.ConclusionsTreatment with MSCs alone significantly reduced LPS-induced acute pulmonary inflammation in mice, while administration of pANGPT1-transfected MSCs resulted in a further improvement in both alveolar inflammation and permeability. These results suggest a potential role for cell-based ANGPT1 gene therapy to treat clinical ALI/ARDS.

Dataset Information

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice.

Publications

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice.

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