Bone marrow-derived mesenchymal stem cells repair severe acute pancreatitis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling |
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| Institution: | 1. Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China;2. Shanghai Key Laboratory of Molecular Mycology, Department of Dermatology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China;3. Department of Anesthesiology, Fuzhou General Hospital of Nanjing Military Region, Fuzhou 350025, Fujian Province, China;1. Department of General Surgery, Shanghai Tenth People''s Hospital, Tongji University School of Medicine, Shanghai, China;2. Clinical Medical College of Nanjing Medical University, Nanjing, China;3. Shanghai Clinical Medical College of Anhui Medical University, Hefei, China;4. Department of Hepatobiliary Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, China;1. Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China;2. Medical Research Center, Southwestern Hospital, The Third Military Medical University, Chongqing 400038, China |
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| Abstract: | BackgroundSevere acute pancreatitis (SAP) is associated with high morbidity and mortality. Bone marrow mesenchymal stem cells (BMSCs) have shown obvious protective effect on SAP. However, little is known about the underlying mechanism. The objective of this study is to unravel the role and regulatory mechanism of miR-181a-5p in BMSCs-mediated pancreatic repair.MethodsBMSCs were isolated from Sprague-Dawley rats and characterized by flow cytometry and Oil Red O staining. Sodium taurocholate- and caerulein-induced models were used as SAP models in vivo and in vitro, respectively. Pancreatic injury were evaluated by H&E and histopathological analysis, as well as by measuring levels of amylase, lipase and cytokines. qRT-PCR and western blotting were performed to detect the level of miR-181a-5p and the protein levels of PTEN/Akt, respectively. ELISA was conducted to detect the levels of TNF-α, IL-1β, IL-6, angiopoietin, IL-4, IL-10 and TGF-β1. The apoptotic rate of AR42 J cells was quantitated by concurrent staining with Annexin-V-FITC and PI.ResultsBMSCs significantly attenuated pancreatic injury in SAP rats by reducing inflammatory infiltration and necrosis, and this effect was abolished by CXCR4 agonist AMD3100. ADM3100 exhibited more severe pancreatic injury and decreased miR-181a-5p levels in the pancreas and serum compared to SAP group. Overexpression of miR-181a-5p in BMSCs (BMSCs-miR-181a-5p) markedly potentiated the protective effect of BMSCs by reducing histological damage and levels of amylase and lipase. Moreover, BMSCs-miR-181a-5p dramatically reduced levels of angiopoietin, TNF-α, IL-1β and IL-6, but induced the levels of IL-4 and IL-10. In caerulein-treated AR42 J cells, co-culturing of BMSCs-miR-181a-5p alleviated caerulein-induced increase of amylase and lipase, and apoptosis via PTEN/Akt/TGF-β1 signaling.ConclusionBMSCs alleviate SAP and reduce inflammatory responses and apoptosis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling. Hence, BMSCs-miR-181a-5p could serve as potential therapeutic target for SAP. |
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| Keywords: | Severe acute pancreatitis Bone marrow mesenchymal stem cells miR-181a-5p PTEN Akt TGF-β1 |
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