Abstract
BackgroundSevere 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.MethodsBMSCs 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.ResultsPri-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.ConclusionsPri-miR-9-BMSCs can repair injured pancreatic tissue by secreting miR-9 and promoting angiogenesis.
Highlights
Severe acute pancreatitis (SAP) is an acute abdominal disease characterized by pancreatic necrosis and systemic disease
Data are shown as the mean ± SD for at least 3 separate experiments. *p < 0.05, **p < 0.01 and ***p < 0.001, compared with NC, ++p < 0.01 and +++p < 0.001, compared with SAP, $p < 0.05 and $$p < 0.01, compared with SAP+PBS, #p < 0.01, ##p < 0.001, compared with bone marrow-derived mesenchymal stem cells (BMSCs), &p < 0.05,&&p < 0.01, compared with EV-BMSCs, @p < 0.05,@@p < 0.01, compared with tough decoy (TuD)-BMSCs. b The results of IHC showed that the CD31 and CD34 were significantly upregulated by pri-miR-9-BMSCs
Data are shown as the mean ± SD. ***p < 0.001, compared with liver, ###p < 0.001, compared with spleen, @@@p < 0.001, compared with lung by using two-tailed t test pancreatic tissues showed that miR-9 levels were lower in the SAP group and higher in the BMSC group. miR-9 modified/antagonized BMSCs and empty virus BMSCs (EV-BMSCs) were injected into SAP rats as previously described [4, 15, 17]
Summary
Severe acute pancreatitis (SAP) is an acute abdominal disease characterized by pancreatic necrosis and systemic disease. The injured pancreas can be repaired in the presence of an adequate blood supply to support the self-renewal of pancreatic cells [4]. The PI3K/AKT signaling pathway, which can promote the proliferation and migration of VECs to trigger angiogenesis, has been investigated extensively [8,9,10]. Cellular growth factors play an important role in inducing angiogenesis by acting on their receptors to start downstream signal transduction and promote the proliferation and migration of VECs [4]. Angiopoietin-1 (ang-1), which is related to endothelial cell survival, proliferation, and migration, can reduce endothelial permeability and promote the maturation and stability of newly formed blood vessels by interacting with the tyrosine kinase TIE-2 receptor [6, 14]
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