Bone marrow-derived mesenchymal stem cells (BMSCs) repair acute necrotized pancreatitis by secreting microRNA-9 to target the NF-κB1/p50 gene in rats

Acute pancreatitis (AP) is a common acute abdominal disease, 10-20% of which can evolve into severe AP ( SAP) causing significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential of repairing SAP, but the detailed mechanism remains unknown. We demonstrate here that microRNA-9 (miR-9) modified BMSCs (pri-miR-9-BMSCs) can significantly reduce the pancreatic edema, infiltration, hemorrhage, necrosis, the release of amylase and lipase. Meanwhile, decreased local/systemic inflammatory response (TNF-alpha down arrow, IL- 1 beta down arrow, IL- 6 down arrow, HMGB1 down arrow, MPO down arrow, CD68 down arrow, IL4 up arrow, IL- 10 up arrow, and TGF-beta up arrow) and enhanced regeneration of damaged pancreas ( Reg4 up arrow, PTF1 up arrow, and PDX1 up arrow) are also promoted. But these effects diminish or disappear after antagonizing miR-9 (TuD). Besides, we find that miR-9 is negatively correlated with AP and miR-9 agomir which can mimic the effects of pri-miR-9-BMSCs and protect injured pancreas. Furthermore, we investigate that BMSCs deliver miR-9 to the injured pancreas or peripheral blood mononuclear cell (PBMC), which can target the NF-kappa B1/p50 gene and inhibit the N-F kappa B signaling pathway (p-P65 down arrow, NF-kappa B1/p50 down arrow, I kappa Ba., I kappa B up arrow). Taken together, these results show that miR-9 is a key paracrine factor of BMSCs attenuating SAP targeting the NF kappa B1/p50 gene and suppressing the NF-kappa B signaling pathway.