MicroRNA-9 modified bone marrow-derived mesenchymal stem cells (BMSCs) repair severe acute pancreatitis (SAP) via inducing angiogenesis in rats

• Published in: Stem cell research & therapy 2018-10, Vol.9 (1), p.282-15
• Main Authors: Qian, Daohai, Song, Guodong, Ma, Zhilong, Wang, Guannan, Jin, Lei, Hu, Minghua, Song, Zhenshun, Wang, Xiaoming
• Format: Article
• Language: English
• Subjects: Angiopoietin-1 - genetics; Angiopoietin-1 - metabolism; Animals; beta Catenin - genetics; beta Catenin - metabolism; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cadherins - genetics; Cadherins - metabolism; Ceruletide - administration & dosage; Endothelial Cells - cytology; Endothelial Cells - metabolism; Gene Expression Regulation; Genetic aspects; Genetic Engineering - methods; Health aspects; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Neovascularization; Neovascularization, Physiologic - genetics; Pancreas - metabolism; Pancreas - pathology; Pancreatitis; Pancreatitis, Acute Necrotizing - chemically induced; Pancreatitis, Acute Necrotizing - genetics; Pancreatitis, Acute Necrotizing - pathology; Pancreatitis, Acute Necrotizing - therapy; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Platelet Endothelial Cell Adhesion Molecule-1 - genetics; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Receptor, TIE-2 - genetics; Receptor, TIE-2 - metabolism; Stem cells; Transfection
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-018-1022-y

Severe acute pancreatitis (SAP) is an acute abdominal disease characterized by pancreatic necrosis and systemic disease. In a previous study, we showed that bone marrow-derived mesenchymal stem cells (BMSCs) can reduce SAP by secreting microRNA (miR)-9; however, the underlying mechanism remains unclear. The present study investigated the mechanism underlying BMSC-induced pancreatic regeneration. BMSCs were isolated, and miR-9 modified/antagonized BMSCs (pri-miR-9-BMSCs/TuD-BMSCs) were generated and injected into SAP rats. The levels of inflammatory cytokines and histopathologic changes were examined using ELISA and H&E staining. Angiogenesis was analyzed by qRT-PCR, western blotting, and immunohistochemistry. Cell function tests, dual luciferase reporter assays, cell co-culture, western blotting, and cell tracing were used to explore the mechanisms underlying miR-9 induced angiogenesis. Pri-miR-9-BMSCs induced angiogenesis in SAP rats (Ang-1↑, TIE-2↑, and CD31↑) and repaired damaged vascular endothelial cells (VECs) in vitro, promoting angiogenesis (Ang-1↑, TIE-2↑, PI3K↑, AKT↑, p-AKT↑, CD31↑, and CD34↑). Pri-miR-9-BMSCs released miR-9 into VECs or injured pancreatic tissue, targeting the VE-cadherin gene and promoting PI3K/AKT signaling to treat SAP (VE-cadherin↓, β-catenin↓, PI3K↑, p-AKT↑), whereas antagonizing miR-9 in BMSCs did not alleviate or aggravated SAP. Pri-miR-9-BMSCs can repair injured pancreatic tissue by secreting miR-9 and promoting angiogenesis.