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The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis.

Gong J, Meng HB, Hua J, Song ZS, He ZG, Zhou B, Qian MP - Mol Med Rep (2014)

Bottom Line: Our results demonstrated that the expression of SDF-1 was significantly increased in the injured pancreas, and that these levels peaked on days 5-7 and began to decrease on day 10.This effect was inhibited by the anti-CXCR4 antibody.Taken together, these results indicate that the interaction of locally produced SDF-1 with CXCR4 on BMSCs, has an important regulatory role in the migration of BMSCs towards the injured pancreas in AP.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, P.R. China.

ABSTRACT
Stromal cell-derived factor-1 (SDF-1) and its receptor, CXC chemokine receptor-4 (CXCR4), are important regulators in the migration of bone marrow mesenchymal stem cells (BMSCs). However, the mechanisms underlying this effect in acute pancreatitis (AP) have not been investigated. In this study, BMSCs were identified by specific cell surface markers and differentiation potentials, and labeled with chloromethylbenzamido-1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (CM-Dil) for in vivo cell tracking. AP was induced by retrograde infusion of sodium taurocholate into the common bile duct in rats. The expression of SDF-1 in the injured pancreas was determined by immunohistochemistry and western blot analysis. BMSCs were incubated with or without anti-CXCR4 antibody and the contribution of SDF-1 to the migration of BMSCs was investigated. Our results demonstrated that the expression of SDF-1 was significantly increased in the injured pancreas, and that these levels peaked on days 5-7 and began to decrease on day 10. SDF-1 induced a dose-dependent migration of BMSCs in an in vitro transwell migration assay, which was almost completely blocked by AMD3100 (CXCR4-specific antagonist) or anti-CXCR4 antibody. In addition, by encouraging the migration of CM-Dil-labeled BMSCs, the SDF-1/CXCR4 axis facilitated the repair of the injured pancreas. This effect was inhibited by the anti-CXCR4 antibody. Taken together, these results indicate that the interaction of locally produced SDF-1 with CXCR4 on BMSCs, has an important regulatory role in the migration of BMSCs towards the injured pancreas in AP.

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Pancreatic histology and serum amylase activity. (A) Pathology of pancreatic tissues (magnification, ×200), edema and inflammation were significantly improved in the BMSCs group as compared with the control group on days 1 and 7 (P<0.01) and necrosis attenuated on day 7 (P<0.01). Edema and inflammation were improved in the BMSCs group as compared with the anti-CXCR4 group on day 1 (P<0.05) but not on day 7 (P>0.05). Necrosis was more severe in the anti-CXCR4 group than in the BMSCs group on day 7 (P<0.05). A large number of tubular complexes were observed in the BMSCs and anti-CXCR4 groups (as indicated by the arrow). (B) Serum amylase activity: serum amylase activity was significantly higher in the AP group than that in the control group on day 1 (P<0.001), and serum amylase activity was significantly lower in the BMSCs group compared with that in the AP and anti-CXCR4 group (P<0.001). *P<0.05; **P<0.01; and ***P<0.001; NS, not significant; d, day; AP, acute pancreatitis; BMSC, bone marrow mesenchymal stem cells; CXCR4, CXC-chemokine receptor 4.
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f5-mmr-09-05-1575: Pancreatic histology and serum amylase activity. (A) Pathology of pancreatic tissues (magnification, ×200), edema and inflammation were significantly improved in the BMSCs group as compared with the control group on days 1 and 7 (P<0.01) and necrosis attenuated on day 7 (P<0.01). Edema and inflammation were improved in the BMSCs group as compared with the anti-CXCR4 group on day 1 (P<0.05) but not on day 7 (P>0.05). Necrosis was more severe in the anti-CXCR4 group than in the BMSCs group on day 7 (P<0.05). A large number of tubular complexes were observed in the BMSCs and anti-CXCR4 groups (as indicated by the arrow). (B) Serum amylase activity: serum amylase activity was significantly higher in the AP group than that in the control group on day 1 (P<0.001), and serum amylase activity was significantly lower in the BMSCs group compared with that in the AP and anti-CXCR4 group (P<0.001). *P<0.05; **P<0.01; and ***P<0.001; NS, not significant; d, day; AP, acute pancreatitis; BMSC, bone marrow mesenchymal stem cells; CXCR4, CXC-chemokine receptor 4.

Mentions: Serum amylase analysis revealed that the amylase activity in the AP group was significantly higher compared with the control group on day 1 (P<0.001). Amylase activity appeared to decrease after BMSCs were transplanted and was significantly decreased as compared with the AP group (P<0.001). Concurrently, serum amylase activity in the anti-CXCR4 group was markedly higher than that in the BMSC group (P<0.001; Fig. 5B). The results of HE staining were consistent with the change in serum amylase activity, and revealed that the BMSCs could reduce pancreatic edema, hemorrhage and necrosis. This effect was compromised following pre-treatment with the anti-CXCR4 antibody. Furthermore, a large number of tubular complexes were observed during pancreatic repair in the BMSC group (Fig. 5A).


The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis.

Gong J, Meng HB, Hua J, Song ZS, He ZG, Zhou B, Qian MP - Mol Med Rep (2014)

Pancreatic histology and serum amylase activity. (A) Pathology of pancreatic tissues (magnification, ×200), edema and inflammation were significantly improved in the BMSCs group as compared with the control group on days 1 and 7 (P<0.01) and necrosis attenuated on day 7 (P<0.01). Edema and inflammation were improved in the BMSCs group as compared with the anti-CXCR4 group on day 1 (P<0.05) but not on day 7 (P>0.05). Necrosis was more severe in the anti-CXCR4 group than in the BMSCs group on day 7 (P<0.05). A large number of tubular complexes were observed in the BMSCs and anti-CXCR4 groups (as indicated by the arrow). (B) Serum amylase activity: serum amylase activity was significantly higher in the AP group than that in the control group on day 1 (P<0.001), and serum amylase activity was significantly lower in the BMSCs group compared with that in the AP and anti-CXCR4 group (P<0.001). *P<0.05; **P<0.01; and ***P<0.001; NS, not significant; d, day; AP, acute pancreatitis; BMSC, bone marrow mesenchymal stem cells; CXCR4, CXC-chemokine receptor 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4020475&req=5

f5-mmr-09-05-1575: Pancreatic histology and serum amylase activity. (A) Pathology of pancreatic tissues (magnification, ×200), edema and inflammation were significantly improved in the BMSCs group as compared with the control group on days 1 and 7 (P<0.01) and necrosis attenuated on day 7 (P<0.01). Edema and inflammation were improved in the BMSCs group as compared with the anti-CXCR4 group on day 1 (P<0.05) but not on day 7 (P>0.05). Necrosis was more severe in the anti-CXCR4 group than in the BMSCs group on day 7 (P<0.05). A large number of tubular complexes were observed in the BMSCs and anti-CXCR4 groups (as indicated by the arrow). (B) Serum amylase activity: serum amylase activity was significantly higher in the AP group than that in the control group on day 1 (P<0.001), and serum amylase activity was significantly lower in the BMSCs group compared with that in the AP and anti-CXCR4 group (P<0.001). *P<0.05; **P<0.01; and ***P<0.001; NS, not significant; d, day; AP, acute pancreatitis; BMSC, bone marrow mesenchymal stem cells; CXCR4, CXC-chemokine receptor 4.
Mentions: Serum amylase analysis revealed that the amylase activity in the AP group was significantly higher compared with the control group on day 1 (P<0.001). Amylase activity appeared to decrease after BMSCs were transplanted and was significantly decreased as compared with the AP group (P<0.001). Concurrently, serum amylase activity in the anti-CXCR4 group was markedly higher than that in the BMSC group (P<0.001; Fig. 5B). The results of HE staining were consistent with the change in serum amylase activity, and revealed that the BMSCs could reduce pancreatic edema, hemorrhage and necrosis. This effect was compromised following pre-treatment with the anti-CXCR4 antibody. Furthermore, a large number of tubular complexes were observed during pancreatic repair in the BMSC group (Fig. 5A).

Bottom Line: Our results demonstrated that the expression of SDF-1 was significantly increased in the injured pancreas, and that these levels peaked on days 5-7 and began to decrease on day 10.This effect was inhibited by the anti-CXCR4 antibody.Taken together, these results indicate that the interaction of locally produced SDF-1 with CXCR4 on BMSCs, has an important regulatory role in the migration of BMSCs towards the injured pancreas in AP.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University of Medicine, Shanghai 200072, P.R. China.

ABSTRACT
Stromal cell-derived factor-1 (SDF-1) and its receptor, CXC chemokine receptor-4 (CXCR4), are important regulators in the migration of bone marrow mesenchymal stem cells (BMSCs). However, the mechanisms underlying this effect in acute pancreatitis (AP) have not been investigated. In this study, BMSCs were identified by specific cell surface markers and differentiation potentials, and labeled with chloromethylbenzamido-1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (CM-Dil) for in vivo cell tracking. AP was induced by retrograde infusion of sodium taurocholate into the common bile duct in rats. The expression of SDF-1 in the injured pancreas was determined by immunohistochemistry and western blot analysis. BMSCs were incubated with or without anti-CXCR4 antibody and the contribution of SDF-1 to the migration of BMSCs was investigated. Our results demonstrated that the expression of SDF-1 was significantly increased in the injured pancreas, and that these levels peaked on days 5-7 and began to decrease on day 10. SDF-1 induced a dose-dependent migration of BMSCs in an in vitro transwell migration assay, which was almost completely blocked by AMD3100 (CXCR4-specific antagonist) or anti-CXCR4 antibody. In addition, by encouraging the migration of CM-Dil-labeled BMSCs, the SDF-1/CXCR4 axis facilitated the repair of the injured pancreas. This effect was inhibited by the anti-CXCR4 antibody. Taken together, these results indicate that the interaction of locally produced SDF-1 with CXCR4 on BMSCs, has an important regulatory role in the migration of BMSCs towards the injured pancreas in AP.

Show MeSH
Related in: MedlinePlus