Skip to main content
SpringerLink
Log in

Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis

Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Severe acute pancreatitis (SAP), a common necroinflammatory disease initiated by the premature activation of digestive enzymes within the pancreatic acinar cells, is associated with significant morbidity and mortality. In this study, we investigated whether human bone marrow-derived clonal mesenchymal stem cells (hcMSCs), isolated from human bone marrow aspirate according to our newly established isolation protocol, have potential therapeutic effects in SAP. SAP was induced by three intraperitoneal (i.p.) injections of cerulein (100 μg/kg) and sequential LPS (10 mg/kg) in Sprague-Dawley (SD) rats. hcMSCs (1 × 106/head) were infused on 24 h after LPS injection via the tail vein. The rats were sacrificed 3 days after infusion of hcMSCs. We observed that infused hcMSCs reduced the levels of serum amylase and lipase. Infused hcMSCs ameliorated acinar cell necrosis, pancreatic edema, and inflammatory infiltration. Also, infused hcMSCs decreased the level of malondialdehyde, and increased the levels of glutathione peroxidase and superoxide dismutase. The number of TUNEL positive acinar cells was reduced after hcMSCs infusion. In addition, hcMSCs reduced the expression levels of pro-inflammation mediators and cytokines, and increased the expression of SOX9 in SAP. Taken together, hcMSCs could effectively relieve injury of pancreatitis as a promising therapeutics for SAP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  • Al-Mufti, R.A., R.C. Williamson, and R.T. Mathie. 1998. Increased nitric oxide activity in a rat model of acute pancreatitis. Gut 43: 564–570.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Berezina, T.L., S.B. Zaets, D.J. Mole, Z. Spolarics, E.A. Deitch, and G.W. Machiedo. 2005. Mesenteric lymph duct ligation decreases red blood cell alterations caused by acute pancreatitis. American Journal of Surgery 190: 800–804.

    Article  PubMed  Google Scholar 

  • Bhatia, M. 2009. Acute pancreatitis as a model of SIRS. Frontiers in Bioscience (Landmark Ed) 14: 2042–2050.

    Article  CAS  Google Scholar 

  • Bhatia, M., F.L. Wong, Y. Cao, H.Y. Lau, J. Huang, P. Puneet, and L. Chevali. 2005. Pathophysiology of acute pancreatitis. Pancreatology 5: 132–144.

    Article  PubMed  Google Scholar 

  • Cassatella, M.A., F. Mosna, A. Micheletti, V. Lisi, N. Tamassia, C. Cont, F. Calzetti, M. Pelletier, G. Pizzolo, and M. Krampera. 2011. Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells 29: 1001–1011.

    Article  CAS  PubMed  Google Scholar 

  • Chan, Y.C., and P.S. Leung. 2007. Acute pancreatitis: animal models and recent advances in basic research. Pancreas 34: 1–14.

    Article  PubMed  Google Scholar 

  • Cheung, M., M.C. Chaboissier, A. Mynett, E. Hirst, A. Schedl, and J. Briscoe. 2005. The transcriptional control of trunk neural crest induction, survival, and delamination. Developmental Cell 8: 179–192.

    Article  CAS  PubMed  Google Scholar 

  • Daisuke, I., A. Haruhiko, S. Akira, N. Takashi, N. Toru, Y. Hideki, and T. Noriyuki. 2011. Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development 138: 1507–1519.

    Article  Google Scholar 

  • De Waal, Malefyt R., J. Abrams, B. Bennett, C.G. Figdor, and J.E. De Vries. 1991. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. Journal of Experimental Medicine 174: 1209–1220.

    Article  Google Scholar 

  • Dominguez Rojas, R. 1950. [Amebiasis of infants and children]. Revista Colombiana de Pediatria y Puericultura 10: 5–47.

    CAS  PubMed  Google Scholar 

  • Friedenstein, A.J., R.K. Chailakhyan, and U.V. Gerasimov. 1987. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell and Tissue Kinetics 20: 263–272.

    CAS  PubMed  Google Scholar 

  • Frossard, J.L., M.L. Steer, and C.M. Pastor. 2008. Acute pancreatitis. Lancet 371: 143–152.

    Article  PubMed  Google Scholar 

  • Genovese, T., E. Mazzon, R. Di Paola, C. Muia, C. Crisafulli, G. Malleo, E. Esposito, and S. Cuzzocrea. 2006. Role of peroxisome proliferator-activated receptor-alpha in acute pancreatitis induced by cerulein. Immunology 118: 559–570.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gong, J., H.B. Meng, J. Hua, Z.S. Song, Z.G. He, B. Zhou, and M.P. Qian. 2014. The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis. Molecular Medicine Reports 9(5): 1575–1582.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Humphreys, B.D., and J.V. Bonventre. 2008. Mesenchymal stem cells in acute kidney injury. Annual Review of Medicine 59: 311–325.

    Article  CAS  PubMed  Google Scholar 

  • Ishida, Y., T. Kondo, T. Ohshima, H. Fujiwara, Y. Iwakura, and N. Mukaida. 2002. A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury. FASEB Journal 16: 1227–1236.

    Article  CAS  PubMed  Google Scholar 

  • Jung, K.H., H.P. Shin, S. Lee, Y.J. Lim, S.H. Hwang, H. Han, H.K. Park, J.H. Chung, and S.V. Yim. 2009. Effect of human umbilical cord blood-derived mesenchymal stem cells in a cirrhotic rat model. Liver International 29: 898–909.

    Article  CAS  PubMed  Google Scholar 

  • Jung, K.H., S.U. Song, T. Yi, M.S. Jeon, S.W. Hong, H.M. Zheng, H.S. Lee, M.J. Choi, D.H. Lee, and S.S. Hong. 2011. Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats. Gastroenterology 140: 998–1008.

    Article  CAS  PubMed  Google Scholar 

  • Kopp, J.L., G. von Figura, E. Mayes, F.F. Liu, C.L. Dubois, J.P. Morris 4th, F.C. Pan, H. Akiyama, C.E. Wright, K. Jensen, M. Hebrok, and M. Sander. 2013. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22: 1–14.

    Google Scholar 

  • Kawaguchi, Y. 2013. Sox9 and programming of liver and pancreatic progenitors. Journal of Clinical Investigation 123: 1881–1886.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kolettas, E., H.I. Muir, J.C. Barrett, and T.E. Hardingham. 2001. Chondrocyte phenotype and cell survival are regulated by culture conditions and by specific cytokines through the expression of Sox-9 transcription factor. Rheumatology (Oxford) 40(10): 1146–1156.

    Article  CAS  Google Scholar 

  • Lanza, C., S. Morando, A. Voci, L. Canesi, M.C. Principato, L.D. Serpero, G. Mancardi, A. Uccelli, and L. Vergani. 2009. Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. Journal of Neurochemistry 110: 1674–1684.

    Article  CAS  PubMed  Google Scholar 

  • Lau, H.Y., F.L. Wong, and M. Bhatia. 2005. A key role of neurokinin 1 receptors in acute pancreatitis and associated lung injury. Biochemical and Biophysical Research Communication 327: 509–515.

    Article  CAS  Google Scholar 

  • Laurila, J.P., L. Laatikainen, M.D. Castellone, P. Trivedi, J. Heikkila, A. Hinkkanen, P. Hematti, and M.O. Laukkanen. 2009. Human embryonic stem cell-derived mesenchymal stromal cell transplantation in a rat hind limb injury model. Cytotherapy 11: 726–737.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Z.H., J.S. Peng, C.J. Li, Z.L. Yang, J. Xiang, H. Song, X.B. Wu, J.R. Chen, and D.C. Diao. 2009. A simple taurocholate-induced model of severe acute pancreatitis in rats. World Journal of Gastroenterology 15: 5732–5739.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Meng, H.B., J. Gong, B. Zhou, J. Hua, L. Yao, and Z.S. Song. 2013. Therapeutic effect of human umbilical cord-derived mesenchymal stem cells in rat severe acute pancreatitis. International Journal of Clinical and Experimental Pathology 6: 2703–2712.

    PubMed Central  PubMed  Google Scholar 

  • Moodley, Y., D. Atienza, U. Manuelpillai, C.S. Samuel, J. Tchongue, S. Ilancheran, R. Boyd, and A. Trounson. 2009. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. American Journal of Pathology 175: 303–313.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murakami, S., V. Lefebvre, and B. de Crombrugghe. 2000. Potent inhibition of the master chondrogenic factor Sox9 gene by interleukin-1 and tumor necrosis factor-alpha. Journal of Biological Chemistry 275(5): 3687–3692.

    Article  CAS  PubMed  Google Scholar 

  • Najar, M., R. Rouas, G. Raicevic, H.I. Boufker, P. Lewalle, N. Meuleman, D. Bron, M. Toungouz, P. Martiat, and L. Lagneaux. 2009. Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy 11: 570–583.

    Article  CAS  PubMed  Google Scholar 

  • Niehaus Jr, W.G., and B. Samuelsson. 1968. Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. European Journal of Biochemistry 6: 126–130.

    Article  CAS  PubMed  Google Scholar 

  • Norman, J., M. Franz, J. Messina, A. Riker, P.J. Fabri, A.S. Rosemurgy, and W.R. Gower Jr. 1995. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery 117: 648–655.

    Article  CAS  PubMed  Google Scholar 

  • Pandol, S.J., A.K. Saluja, C.W. Imrie, and P.A. Banks. 2007. Acute pancreatitis: bench to the bedside. Gastroenterology 132: 1127–1151.

    Article  CAS  PubMed  Google Scholar 

  • Perera, P.M., E. Wypasek, S. Madhavan, B. Rath-Deschner, J. Liu, J. Nam, B. Rath, Y. Huang, J. Deschner, N. Piesco, C. Wu, and S. Agarwal. 2010. Mechanical signals control SOX-9, VEGF, and c-Myc expression and cell proliferation during inflammation via integrin-linked kinase, B-Raf, and ERK1/2-dependent signaling in articular chondrocytes. Arthritis Research and Therapy 12(3): R106.

    Article  PubMed Central  PubMed  Google Scholar 

  • Rosenzweig, A. 2006. Cardiac cell therapy–mixed results from mixed cells. New England Journal of Medicine 355: 1274–1277.

    Article  CAS  PubMed  Google Scholar 

  • Schaefer, J.F., M.L. Millham, B. de Crombrugghe, and L. Buckbinder. 2003. FGF signaling antagonizes cytokine-mediated repression of Sox9 in SW1353 chondrosarcoma cells. Osteoarthritis Cartilage 11(4): 233–241.

    Article  CAS  PubMed  Google Scholar 

  • Shah, A.U., A. Sarwar, A.I. Orabi, S. Gautam, W.M. Grant, A.J. Park, J. Liu, P.K. Mistry, D. Jain, and S.Z. Husain. 2009. Protease activation during in vivo pancreatitis is dependent on calcineurin activation. American Journal of Physiology. Gastrointestinal and Liver Physiology 297: G967–G973.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Song, S.U., C.S. Kim, S.P. Yoon, S.K. Kim, M.H. Lee, J.S. Kang, G.S. Choi, S.H. Moon, M.S. Choi, Y.K. Cho, and B.K. Son. 2008. Variations of clonal marrow stem cell lines established from human bone marrow in surface epitopes, differentiation potential, gene expression, and cytokine secretion. Stem Cells and Development 17: 451–461.

    Article  CAS  PubMed  Google Scholar 

  • Tagawa, Y., K. Sekikawa, and Y. Iwakura. 1997. Suppression of concanavalin A-induced hepatitis in IFN-gamma(-/-) mice, but not in TNF-alpha(-/-) mice: role for IFN-gamma in activating apoptosis of hepatocytes. J of Immunology 159: 1418–1428.

    CAS  Google Scholar 

  • Tu, X.H., J.X. Song, X.J. Xue, X.W. Guo, Y.X. Ma, Z.Y. Chen, Z.D. Zou, and L. Wang. 2012. Role of bone marrow-derived mesenchymal stem cells in a rat model of severe acute pancreatitis. World Journal of Gastroenterology 18: 2270–2279.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Uccelli, A., L. Moretta, and V. Pistoia. 2008. Mesenchymal stem cells in health and disease. Nature Reviews Immunology 8: 726–736.

    Article  CAS  PubMed  Google Scholar 

  • Van Laethem, J.L., A. Marchant, A. Delvaux, M. Goldman, P. Robberecht, T. Velu, and J. Deviere. 1995. Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. Gastroenterology 108: 1917–1922.

    Article  PubMed  Google Scholar 

  • Wang, Y., J. Wang, R. Liu, H. Qi, Y. Wen, F. Sun, and C. Yin. 2012. Severe acute pancreatitis is associated with upregulation of the ACE2-angiotensin-(1-7)-Mas axis and promotes increased circulating angiotensin-(1-7). Pancreatology 12: 451–457.

    Article  CAS  PubMed  Google Scholar 

  • Wildi, S., J. Kleeff, J. Mayerle, A. Zimmermann, E.P. Bottinger, L. Wakefield, M.W. Buchler, H. Friess, and M. Korc. 2007. Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations. Gut 56: 685–692.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Williams, A.R., and J.M. Hare. 2011. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circulation Research 109: 923–940.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xiong, J., J. Ni, G. Hu, J. Shen, Y. Zhao, L. Yang, G. Yin, C. Chen, G. Yu, Y. Hu, M. Xing, R. Wan, and X. Wang. 2013. Shikonin ameliorates cerulein-induced acute pancreatitis in mice. Journal of Ethnopharmacology 145: 573–580.

    Article  CAS  PubMed  Google Scholar 

  • Zyromski, N., and M.M. Murr. 2003. Evolving concepts in the pathophysiology of acute pancreatitis. Surgery 133: 235–237.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare, Korea (A120266).

Author information

Authors and Affiliations

  1. Department of Drug Development, Inha University School of Medicine, 7-241, 3-ga, Sinheung-dong, Jung-Gu, Incheon, 400-712, Korea

    Kyung Hee Jung, TacGhee Yi, Mi Kwon Son & Soon-Sun Hong

  2. Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon, Republic of Korea

    Kyung Hee Jung, TacGhee Yi, Mi Kwon Son, Sun U. Song & Soon-Sun Hong

Authors
  1. Kyung Hee Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. TacGhee Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mi Kwon Son
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sun U. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soon-Sun Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sun U. Song or Soon-Sun Hong.

Additional information

Kyung Hee Jung and TacGhee Yi contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, K.H., Yi, T., Son, M.K. et al. Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis. Arch. Pharm. Res. 38, 742–751 (2015). https://doi.org/10.1007/s12272-014-0465-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-014-0465-7

Keywords

search

Navigation