The hepatocyte growth factor-expressing character is required for mesenchymal stem cells to protect the lung injured by lipopolysaccharide in vivo

Abstract

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening condition in critically ill patients. Recently, we have found that mesenchymal stem cells (MSC) improved the permeability of human lung microvascular endothelial cells by secreting hepatocyte growth factor (HGF) in vitro. However, the properties and functions of MSC may change under complex circumstances in vivo. Here, we sought to determine the role of the HGF-expressing character of MSC in the therapeutic effects of MSC on ARDS in vivo.MethodsMSC with HGF gene knockdown (MSC-ShHGF) were constructed using lentiviral transduction. The HGF mRNA and protein levels in MSC-ShHGF were detected using quantitative real-time polymerase chain reaction and Western blotting analysis, respectively. HGF levels in the MSC culture medium were measured by enzyme-linked immunosorbent assay (ELISA). Rats with ARDS induced by lipopolysaccharide received MSC infusion via the tail vein. After 1, 6, and 24 h, rats were sacrificed. MSC retention in the lung was assessed by immunohistochemical assay. The lung wet weight to body weight ratio (LWW/BW) and Evans blue dye extravasation were obtained to reflect lung permeability. The VE-cadherin was detected with inmmunofluorescence, and the lung endothelial cell apoptosis was assessed by TUNEL assay. The severity of lung injury was evaluated using histopathology. The cytokines and HGF levels in the lung were measured by ELISA.ResultsMSC-ShHGF with markedly lower HGF expression were successfully constructed. Treatment with MSC or MSC carrying green fluorescent protein (MSC-GFP) maintained HGF expression at relatively high levels in the lung at 24 h. MSC or MSC-GFP decreased the LWW/BW and the Evans Blue Dye extravasation, protected adherens junction VE-cadherin, and reduced the lung endothelial cell apoptosis. Furthermore, MSC or MSC-GFP reduced the inflammation and alleviated lung injury based on histopathology. However, HGF gene knockdown significantly decreased the HGF levels without any changes in the MSC retention in the lung, and diminished the protective effects of MSC on the injured lung, indicating the therapeutic effects of MSC on ARDS were partly associated with the HGF-expressing character of MSC.ConclusionsMSC restores lung permeability and lung injury in part by maintaining HGF levels in the lung and the HGF-expressing character is required for MSC to protect the injured lung.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0320-5) contains supplementary material, which is available to authorized users.

Mesenchymal Stem Cells Modified with Heme Oxygenase-1 Have Enhanced Paracrine Function and Attenuate Lipopolysaccharide-Induced Inflammatory and Oxidative Damage in Pulmonary Microvascular Endothelial Cells

“…MSCs are capable of selfrenewal and can be obtained from multiple sources, including bone marrow, adipose tissue, umbilical cord blood, skin, tendon, muscle, and dental pulp [6,[12][13][14]. Their relative ease of isolation and enormous expansion potential in culture make them attractive therapeutic candidates [15].…”

“…Oxidative stress causes recruitment of inflammatory cells leading to inflammation, while inflammatory cells cause induction of oxidative stress [5]. Diffuse injury of pulmonary endothelial cells is characteristic of ALI/ARDS and leads to an increase in alveolar-capillary permeability and alveolar pulmonary edema [6]. Lipopolysaccharides (LPS), important components of the outer wall of Gram-negative bacteria, are highly proinflammatory molecules that cause pulmonary endothelial injury through induction of inflammatory and oxidative damage [7].…”

Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50–Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

“…Additionally, fibroblasts have emerged as regulators of inflammation resolution that act by producing proresolving peroxisome proliferator-activated receptor-g ligands (19), as well as COX-2 and PGD 2 (20). Recently, accumulating evidence has demonstrated that the growth factors secreted from fibroblasts can promote alveolar barrier function (21)(22)(23), alleviate pulmonary edema (21,24), and protect against lung injury from various stresses, such as LPS (25,26), ventilator (24) and ischemia/reperfusion-induced lung injury (27,28). Thus, lung fibroblasts have emerged as essential players in the resolution of ARDS.…”

Insights Into Signaling in Cell-Based Therapy for Heart Disease

“…176 As indicated earlier, HGF is a cellular growth factor that is produced by MSCs that play a major in angiogenesis. However, HGF treatment ameliorates GVHD, 178 and MSC with HGF gene knockout increases lung injury via lipopolysaccharides (LPS), 179 suggesting that HGF bears immunomodulatory properties as well. Furthermore, MSCs overexpressing HGF in a mouse MI model have shown to enhance cell survival and paracrine effects.…”