期刊
STEM CELL RESEARCH & THERAPY
卷 11, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13287-019-1492-6
关键词
ALI; ARDS; Mesenchymal stem cells; Liraglutide; Combination therapy
资金
- National Natural Science Foundation of China [81770075, 81630001, 81490533, 81570028, 81770039]
- State Key Basic Research Program (973) project [2015CB553404]
- National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program', China [2018ZX09201002-006]
- Shanghai Top-Priority Clinical Key Disciplines Construction Project (Respiratory Medicine)
- Shanghai Jiao Tong University Medical Cross Project [YG2017MS64]
- Shanghai Natural Science Foundation [18ZR1424000]
- Shanghai Shenkang Hospital Development Center Clinical Science and Technology Innovation Project [SHDC12018102]
- National Innovative Research Team of High-level Local Universities in Shanghai
BackgroundALI/ARDS is the major cause of acute respiratory failure in critically ill patients. As human chorionic villi-derived MSCs (hCMSCs) could attenuate ALI in the airway injury model, and liraglutide, glucagon-like peptide 1 (GLP-1) agonist, possesses anti-inflammatory and proliferation promotion functions, we proposed to probe the potential combinatory effect of hCMSCs and liraglutide on ALI.MethodsWe examined the time- and dose-dependent manner of GLP-1R, SPC, Ang-1, and FGF-10 with LPS via western blot and qRT-PCR. Western blot and chromatin immunoprecipitation assay detected the effects of liraglutide on GLP-1R, SPC, Ang-1, and FGF-10 through PKAc/beta -catenin pathway and cAMP pathway. In the ALI animal model, we detected the effects of MSC and liraglutide combination on ALI symptoms by H&E staining, western blot, ELISA assays, calculating wet-to-dry ratio of the lung tissue, and counting neutrophils, leukocytes, and macrophages in mouse bronchoalveolar lavage fluid (BALF).ResultsThe data demonstrated that LPS reduced hCMSC proliferation and GLP-1R, SPC, Ang-1, and FGF-10 levels in a dose- and time-dependent manner. Liraglutide significantly dampened the reduction of GLP-1R, SPC, Ang-1, and FGF-10 and reversed the effect of LPS on hCMSCs, which could be regulated by GLP-1R and its downstream cAMP/PKAc/beta -catenin-TCF4 signaling. Combination of hCMSCs with liraglutide showed more therapeutic efficacy than liraglutide alone in reducing LPS-induced ALI in the animal model.ConclusionsThese results reveal that the combination of hCMSCs and liraglutide might be an effective strategy for ALI treatment.
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