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Lats2-Underexpressing Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice.

ABSTRACT: The pathophysiology of the acute lung injury (ALI) is characterized by the damage of alveolar epithelial cells, which can be repaired by exogenous bone marrow-derived mesenchymal stem cells (BMSCs). However, the migration and differentiation abilities of BMSCs are not sufficient for the purpose, and a new approach that could strengthen the repair effects of BMSCs in ALI still needs to be clarified. We have previously proved that in vitro large tumor suppressor kinase 2- (Lats2-) underexpressing BMSCs may enhance their tissue repair effects in ALI; thus, in the present study, we tried to explore whether Lats2-underexpressing BMSCs could rescue lipopolysaccharide- (LPS-) induced ALI in vivo. BMSCs from C57BL/6 mice transfected with Lats2-interfering lentivirus vector or lentivirus blank controls were transplanted intratracheally into LPS-induced ALI mice. The retention and differentiation of BMSCs in the lung were evaluated by in vivo imaging, immunofluorescence staining, and Western blotting. The lung edema and permeability were assessed by lung wet weight/body weight ratio (LWW/BW) and measurements of proteins in bronchoalveolar lavage fluid (BALF) using ELISA. Acute lung inflammation was measured by the cytokines in the lung homogenate and BALF using RT-qPCR and ELISA, respectively. Lung injury was evaluated by HE staining and lung injury scoring. Pulmonary fibrosis was evaluated by Picrosirius red staining, immunohistochemistry for ?-SMA and TGF-?1, and hydroxyproline assay and RT-qPCR for Col1?1 and Col3?1. Lats2-mediated inhibition of the Hippo pathway increased the retention of BMSCs and their differentiation toward type II alveolar epithelial cells in the lung. Furthermore, Lats2-underexpressing BMSCs improved lung edema, permeability of the lung epithelium, and lung inflammation. Finally, Lats2-underexpressing BMSCs alleviated lung injury and early pulmonary fibrosis. Our studies suggest that underexpression of Lats2 could further enhance the repair effects of BMSCs against epithelial impair and the therapeutic potential of BMSCs in ALI mice.

SUBMITTER: Dong L

PROVIDER: S-EPMC6854183 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Lats2-Underexpressing Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice.

Dong Liang L Li Lang L

Mediators of inflammation 20191021

The pathophysiology of the acute lung injury (ALI) is characterized by the damage of alveolar epithelial cells, which can be repaired by exogenous bone marrow-derived mesenchymal stem cells (BMSCs). However, the migration and differentiation abilities of BMSCs are not sufficient for the purpose, and a new approach that could strengthen the repair effects of BMSCs in ALI still needs to be clarified. We have previously proved that <i>in vitro</i> large tumor suppressor kinase 2- (Lats2-) underexpr ...[more]

PMID: 31772503

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Project description:Chronic hyperglycemia causes a progressive decrease of ?-cell function and mass in type 2 diabetic patients. Growing evidence suggests that augment of autophagy may be an effective approach to protect ? cells against various extra-/intracellular stimuli. In this study, we thus investigated whether bone marrow-derived mesenchymal stem cells (BM-MSCs) could ameliorate chronic high glucose (HG)-induced ?-cell injury through modulation of autophagy. Prolonged exposure to HG decreased cell viability, increased cell apoptosis and impaired basal insulin secretion and glucose-stimulated insulin secretion of INS-1 cells, but BM-MSC treatment significantly alleviated these glucotoxic alternations. In addition, western blotting displayed upregulated expression of Beclin1 and LC3-II in INS-1 cells co-cultured with BM-MSCs. Results from immunofluorescence staining and transmission electronic microscope analysis also revealed that BM-MSCs promoted autophagosomes and autolysosomes formation in HG-treated INS-1 cells. However, it should be noted that inhibition of autophagy significantly diminished the protective effects of BM-MSCs on HG-treated INS-1 cells, suggesting that the improvement of ?-cell function and survival induced by BM-MSCs was mediated through autophagy. Furthermore, our results showed that BM-MSCs improved mitochondrial function and reduced reactive oxygen species production in HG-treated INS-1 cells, largely owing to autophagic clearance of impaired mitochondria. In vivo study was performed in rats with type 2 diabetes (T2D). BM-MSC infusion not only ameliorated hyperglycemia, but also promoted restoration of pancreatic ? cells in T2D rats. Meanwhile, BM-MSC infusion upregulated LAMP2 expression and enhanced formation of autophagosomes and autolysosomes, combined with reduced ?-cell apoptosis and increased number of insulin granules. These findings together indicated that BM-MSCs could protect ? cells against chronic HG-induced injury through modulation of autophagy in vitro and in vivo. This study unveiled novel evidence of BM-MSCs as an ideal strategy to enhance autophagy for treatment of T2D mellitus.

Project description:BackgroundSulfur mustard (SM) is a notorious chemical warfare agent that can cause severe acute lung injury (ALI), in addition to other lesions. Currently, effective medical countermeasures for SM are lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs) possess self-renewal and multipotent differentiation capacity. BMSCs can also migrate to inflammation and injury sites and exert anti-inflammatory and tissue repair functions. Here, we report the curative effect of BMSCs on SM-induced ALI in a mouse model.MethodsMice BMSCs were injected into mice via the tail vein 24 h after SM exposure. The distribution of BMSCs in mice was detected by fluorescence imaging. The therapeutic potential of BMSCs was evaluated by the calculating survival rate. The effects of BMSCs on lung tissue injury and repair assessment were examined by staining with H&E and measuring the lung wet/dry weight ratio, BALF protein level, and respiratory function. The effects of BMSCs on the infiltration and phenotypic alteration of inflammatory cells were analyzed by immunohistochemistry and flow cytometry. The levels of chemokines and inflammatory cytokines were examined using the Luminex Performance Assay and ELISA. RNA interference, western blotting, and ELISA were applied to explore the role of the TLR4 signaling pathway in the anti-inflammatory effects of BMSCs. The extent of tissue repair was analyzed by ELISA, western blotting, and immunohistochemistry.ResultsFluorescence imaging indicated that the lung is the major target organ of BMSCs after injection. The injection of BMSCs significantly improved the survival rate (p < 0.05), respiratory function, and related lung damage indexes (wet/dry weight ratio, total proteins in BALF, etc.) in mice. BMSC administration also reduced the level of pro-inflammatory cytokines, chemokines, and inflammatory cell infiltration, as well as affected the balances of M1/M2 and Th17/Treg. Furthermore, solid evidence regarding the effects of BMSCs on the increased secretion of various growth factors, the differentiation of alveolar epithelial cells, and the enhancement of cell barrier functions was also observed.ConclusionBMSCs displayed protective effects against SM-induced ALI by alleviating inflammation and promoting tissue repair. The present study provides a strong experimental basis in a mouse model and suggests possible application for future cell therapy.

Dataset Information

Lats2-Underexpressing Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice.

Publications

Lats2-Underexpressing Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate LPS-Induced Acute Lung Injury in Mice.

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