Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) can be used to enhance lung repair in acute respiratory distress syndrome (ARDS); however, the repairing effect is limited by poor homing and retention of BMSCs. The purpose of this study was to investigate whether Lats1 and Lats2-mediated alteration of Hippo signaling pathway could promote the differentiation, proliferation, and migration of BMSCs. BMSCs were transduced by lentiviral vectors for high and low expression of Lats1 and Lats2. The expression levels of Lats1, Lats2, YAP, and 14-3-3, respectively, were assessed to clarify the regulatory effects of Lats1 and Lats2 on Hippo signaling. Osteogenic (Runx2 and OSX) and adipogenic (C/EBPα and PPAR-γ) transcription factors were determined to clarify the effects of Hippo signaling on BMSCs differentiation. The effects of Hippo signaling on BMSCs proliferation and horizontal and vertical migration were also measured by CCK-8, scratch assay, and Transwell migration assay, respectively. Lentiviral transduction efficiency could reach 93.11%–97.14%. High and low expression of Lats1 and Lats2 could activate and inhibit the Hippo signaling pathway, respectively. High and low expression of Lats1 and Lats2 could inhibit and promote BMSCs differentiation into osteoblasts and adipocytes. High and low expression of Lats1 and Lats2 could inhibit and promote BMSCs proliferation and horizontal and vertical migration, respectively. Our studies suggest that Lats1/2-meidiated inhibition of Hippo signaling in BMSCs may optimize their effects of tissue repair in ARDS, suggesting a novel strategy for enhancing disease therapeutics.
Highlights
Acute respiratory distress syndrome (ARDS) constitutes the acute noncardiogenic refractory respiratory failure resulting from injured alveolar epithelial cells [1]
The results indicated that the cell proliferation of the MSCLats1 and mesenchymal stem cells (MSCs)-large tumour suppressor 2 (Lats2) group were significantly lower than that of the MSC-green fluorescent protein (GFP) group, with the effect being most obvious from days 2 to 7 (Figure 5(a))
The results showed that the number of cells that migrated to the compartment below the Transwell membrane of the MSC-large tumour suppressor 1 (Lats1) or MSC-Lats2 group was significantly lower than that of the MSC-GFP group
Summary
Acute respiratory distress syndrome (ARDS) constitutes the acute noncardiogenic refractory respiratory failure resulting from injured alveolar epithelial cells [1]. Recent studies have shown that mesenchymal stem cells (MSCs) can be used as seed cells for lung repair in ARDS, as they can differentiate into alveolar epithelium, alleviating lung inflammation and improving survival in animal models of ARDS [3, 4]. Difficulties such as low percentages of MSCs homing to ARDS lung tissues and short MSCs retention remain to be addressed. The Hippo signaling pathway is able to regulate the differentiation, proliferation, and migration of many cell types; its role in MSC regulation remains to be elucidated [7, 8]
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