Bone marrow-derived mesenchymal stem cells (BMSCs) repair acute necrotized pancreatitis by secreting microRNA-9 to target the NF-\u03baB1/p50 gene in rats

Daohai Qian,Jian Li,Jian Gong,Zhigang He,Hongbo Meng,Jie Hua,Ge Wei,Hongfei Teng,Qili Hu,Zhenshun Song,Chenglei Xu,Shengping Lin,Bo Zhou

doi:10.1038/s41598-017-00629-3

Abstract

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-α↓, IL-1β↓, IL-6↓, HMGB1↓, MPO↓, CD68↓, IL-4↑, IL-10↑, and TGF-β↑) and enhanced regeneration of damaged pancreas (Reg4↑, PTF1↑, and PDX1↑) 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-κB1/p50 gene and inhibit the NF-κB signaling pathway (p-P65↓, NF-κB1/p50↓, IκBα↑, IκBβ↑). Taken together, these results show that miR-9 is a key paracrine factor of BMSCs attenuating SAP targeting the NF-κB1/p50 gene and suppressing the NF-κB signaling pathway.

Highlights

Acute pancreatitis (AP) is a frequently occurring abdominal disease, of which the annual incidence ranges from 13 to 45 cases per 100,000 individuals with a gradual increasing trend, in younger populations[1]
The results showed that the scores of pancreatic edema, infiltration, hemorrhage and necrosis along with the levels of serum amylase, lipase and pro-inflammatory cytokines in severe AP (SAP) or phosphate buffer saline (PBS) treatment (SAP+PBS) group were significantly higher than that in Normal Control (NC) or Sham group
We explored the possible mechanism of Bone marrow-derived mesenchymal stem cells (BMSCs) in repairing SAP by over-expressing or antagonizing (TuD-BMSCs) the expression of miR-9 and the results suggested that the damaged pancreatic tissues were repaired by pri-miR-9-BMSCs and miR-9 agomir

Summary

Introduction

Acute pancreatitis (AP) is a frequently occurring abdominal disease, of which the annual incidence ranges from 13 to 45 cases per 100,000 individuals with a gradual increasing trend, in younger populations[1]. Recent studies have found that the pro-inflammatory mediators released by the injured PACs, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6, etc, induce a feed-forward inflammatory response, leading to the exacerbation of AP These molecules, such as TNF-α, IL-1β, IL-6, etc[2,3,4], form a cascade amplifying inflammatory response termed damage associated molecular patterns (DAMPs), which have multiple biological functions during the progression of AP5–8. We propose that miR-9 may be a small RNA molecule involved in the occurrence and progression of AP, and infused MSCs deliver miR-9 to the pancreas so as to inhibit the inflammatory response and repair the necrotized pancreatic tissues. To test the above hypothesis, we conduct this study to investigate the relationship between miR-9 and SAP and to reveal the possible mechanism of MSCs promoting the repair and regeneration of necrotized pancreatic tissues

Methods

Results

Conclusion