Abstract
Acute pancreatitis (AP), a common acute abdominal disease, 10%–20% of which can evolve into severe acute pancreatitis (SAP), is of significant morbidity and mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to have a potential therapeutic role on SAP, but the specific mechanism is unclear. Therefore, we conducted this experiment to shed light on the probable mechanism. We validated that SDF-1α significantly stimulated the expressions of VEGF, ANG-1, HGF, TGF-β, and CXCR4 in BMSCs, which were inhibited by its receptor agonist, AMD3100. The capacities of proliferation, migration, and repair of human umbilical vein endothelial cells were enhanced by BMSCs supernatant. Meanwhile, BMSCs supernatant could also promote angiogenesis, especially after the stimulation with SDF-1α. In vivo, the migration of BMSCs was regulated by SDF-1α/CXCR4 axis. Moreover, transplanted BMSCs could significantly alleviate SAP, reduce the systematic inflammation (TNF-α↓, IL-1β↓, IL-6↓, IL-4↑, IL-10↑, and TGF-β↑), and promote tissue repair and angiogenesis (VEGF↑, ANG-1↑, HGF↑, TGF-β↑, and CD31↑), compared with the SAP and anti-CXCR4 groups. Taken together, the results showed that BMSCs ameliorated SAP and the SDF-1α/CXCR4 axis was involved in the repair and regeneration process.
Highlights
Though acute pancreatitis (AP) is considered one of the commonest acute abdominal diseases, no effective treatment has yet been available
Ltd (Beijing City, China), Lipofectamine 2000, Dulbecco’s modified Eagle’s medium–low glucose (DMEM-LG), penicillin, streptomycin, fetal bovine serum (FBS), and the Histostain-Plus Kit (DAB, Broad Spectrum) were from Invitrogen (Carlsbad, California, USA), 0.25% trypsin was from Hyclone (Logan, Utah, USA), Transwell plates were from Corning (NY, USA), BCA protein concentration assay kit, RIPA lysis buffer, TRIzol Reagent, phenylmethanesulfonyl fluoride (PMSF, 100 mM), and the Prussian blue staining kit were from Beyotime Biotechnology Research Institute (Nantong City, Jiangsu Province, China), recombinant rat SDF-1α protein was from Peprotech (Rocky Hill, USA), Matrigel matrix was from Becton, Dickinson and Company (New Jersey, USA), Antibodies directed against CXCR4 were from Abcam (Cambridge, MA, USA), and vascular endothelial growth factor (VEGF), angiopoietin-1 (ANG-1), and GAPDH, and a fluorescent secondary antibody were from ProteinTech (Wuhan City, Hubei Province, China)
The expressions of VEGF, ANG-1, HGF, transforming growth factor β (TGF-β), and CXCR4 were detected with qRT-PCR or immunoblotting assays at 24 h and 48 h after recombinant SDF-1α protein was added to the Bone marrow-derived mesenchymal stem cells (BMSCs) culture medium
Summary
Though acute pancreatitis (AP) is considered one of the commonest acute abdominal diseases, no effective treatment has yet been available. The incidence of AP is rising continually with 10%–20% of patients progressing to severe acute pancreatitis (SAP) [1], which is associated with significant morbidity and mortality. It is well recognized that AP begins with pancreatic acinar injury, attributed to the premature activation of trypsin within the pancreatic acinar cells, after which exudation, edema, and a local inflammatory response are observed [3, 4]. Some AP patients can still progress to SAP with hemorrhage, necrosis, and a systematic inflammatory response, further leading to shock, multiple organ failure, and even death. The treatment of SAP focuses predominantly on inhibiting the synthesis and secretion of trypsin and averting the systemic inflammatory response. No satisfactory therapeutic effect has been discovered whichever method is adopted
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