Therapeutic Use of Adipose-Derived Stromal Cells in a Murine Model of Acute Pancreatitis

  • Alexandra M. Roch
  • Thomas K. Maatman
  • Todd G. Cook
  • Howard H. Wu
  • Stephanie Merfeld-Clauss
  • Dmitry O. Traktuev
  • Keith L. March
  • Nicholas J. ZyromskiEmail author
2019 SSAT Plenary Presentation



No specific therapy exists for acute pancreatitis (AP), and current treatment remains entirely supportive. Adipose stem cells (ASCs) have significant immunomodulatory and regenerative activities. We hypothesized that systemic administration of ASCs would mitigate inflammation in AP.


AP was induced in mice by 6 hourly intraperitoneal injections of cerulein. Twenty-four hours after AP induction, mice were randomized into four systemic treatment groups: sham group (no acute pancreatitis), vehicle, human ASCs, and human ASC–conditioned media. Mice were sacrificed at 48 h, and blood and organs were collected and analyzed. Pancreatic injury was quantified histologically using a published score (edema, inflammation, and necrosis). Pancreatic inflammation was also studied by immunohistochemistry and PCR.


When using IV infusion of Hoechst-labeled ASCs, ASCs were found to localize to inflamed tissues: lungs and pancreas. Mice treated with ASCs had less severe AP, as shown by a significantly decreased histopathology score (edema, inflammation, and necrosis) (p = 0.001). ASCs infusion polarized pancreatic macrophages toward an anti-inflammatory M2 phenotype. ASC-conditioned media reduced pancreatic inflammation similarly to ASCs only, highlighting the importance of ASCs secreted factors in modulating inflammation.


Intravenous delivery of human ASCs markedly reduces pancreatic inflammation in a murine model of AP ASCs which represent an effective therapy for AP.


Acute pancreatitis Murine model Treatment Adipose stem cells 


Funding Information

This work was supported by the 2016–2017 International Hepato-Pancreato-Biliary Association (IHPBA) Kenneth Warren Fellowship.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Fagenholz PJ, Fernandez-del Castillo C, Harris NS et al. Increasing United States hospital admissions for acute pancreatitis, 1988-2003. Annals of epidemiology 2007;17:491–7.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Fagenholz PJ, Fernandez-del Castillo C, Harris NS et al. Direct medical costs of acute pancreatitis hospitalizations in the United States. Pancreas 2007;35:302–7.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Steinberg W, Tenner S. Medical progress: acute pancreatitis. New Engl J Med 1994;330:1198–210.PubMedCrossRefGoogle Scholar
  4. 4.
    Banks PA, Bollen TL, Dervenis et al. Classification of acute pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62:102–11.CrossRefGoogle Scholar
  5. 5.
    Frossard JL, Steer ML and Pastor CM. Acute pancreatitis. Lancet 2008;371:143–52.PubMedCrossRefGoogle Scholar
  6. 6.
    Demols A, Lemoine O, Desalie F et al. CD4(+ )T cells play an important role in acute experimental pancreatitis in mice. Gastroenterology 2000;118:582–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Norman JG, Fink GW, Messina J et al. Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis. Surgery 1996;120:515–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Yang J, Denham W, Carter G, et al. Macrophage pacification reduces rodent pancreatitis-induced hepatocellular injury through down-regulation of hepatic tumor necrosis factor alpha and interleukin-1beta. Hepatology 1998;28:1282–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Mayer J, Rau B, Gansauge F and Beger HG. Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications. Gut 2000;47:546–52.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Sakai Y, Masamune A, Satoh A et al. Macrophage migration inhibitory factor is a critical mediator of severe acute pancreatitis. Gastroenterology 2003;124:725–36.PubMedCrossRefGoogle Scholar
  11. 11.
    Denham W, Yang J, Fink G et al. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis. Gastroenterology 1997;113:1741–6.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Tanaka N, Murata A, Uda K et al. Interleukin-1 receptor antagonist modifies the changes in vital organs induced by acute necrotizing pancreatitis in a rat experimental model. Critical care medicine 1995;23:901–8.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Frossard JL, Kwak B, Chanson M et al. Cd40 ligand-deficient mice are protected against cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. Gastroenterology 2001:12;184–94.CrossRefGoogle Scholar
  14. 14.
    Bhatia M, Ramnath RD, Chevali L and Guglielmotti A. Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis. American journal of physiology. Gastrointestinal and liver physiology 2005;288:1259–65.CrossRefGoogle Scholar
  15. 15.
    Gerard C, Frossard JL, Bhatia M et al. Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury. The Journal of clinical investigation 1997;100:2022–27.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006;101:2379–400.PubMedCrossRefGoogle Scholar
  17. 17.
    Van Santvoort HC, Besselink MG, Bakker OJ. A step up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med 2010; 362:1491–502.PubMedCrossRefGoogle Scholar
  18. 18.
    Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Domici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytottherapy 2006;8:315–7.CrossRefGoogle Scholar
  20. 20.
    Le Blanc K, Rasmussion I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004;363;1439–41.CrossRefGoogle Scholar
  21. 21.
    Chen S, Liu Z, Tian N et al. Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. J Invasive Cardiol 2006;18:552–556.PubMedGoogle Scholar
  22. 22.
    Neuhuber B, Timothy Himes B, Shumsky JS, Gallo G, Fischer I. Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res. 2005;1035:73–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Jung KH, Song SU, Yi T et al. Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats. Gastroenterology 2011;140:998–1008.PubMedCrossRefGoogle Scholar
  24. 24.
    Zuk PA, Zhu M, Mizuno H et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7:211–28.PubMedCrossRefGoogle Scholar
  25. 25.
    Strem BM, Hicick KC, Zhu M. et al. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med 2005;54:132–41 .PubMedCrossRefGoogle Scholar
  26. 26.
    Bura A, Planat-Benard V, Bourin P et al. Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia. Cytotherapy 2014;16:245–57.PubMedCrossRefGoogle Scholar
  27. 27.
    Yagi H, Soto-Gutierrez A, Parekkadan B et al. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. ML Cell Transplant. 2010; 19(6):667–79.PubMedCrossRefGoogle Scholar
  28. 28.
    Sanz-Baro R, García-Arranz M, Guadalajara H et al. First-in-human case study: pregnancy in women with Crohn’s perianal fistula treated with adipose-derived stem cells: a safety study. Stem Cells Transl. Med. 2015;4:598–602.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Álvaro-Gracia JM, Jover JA, García-Vicuña R et al. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann. Rheum. Dis. 2016;76:196–202.PubMedCrossRefGoogle Scholar
  30. 30.
    Kim HW, Song WJ, Li Q et al. Canine adipose tissue-derived mesenchymal stem cells ameliorate severe acute pancreatitis by regulating T cells in rats. J Vet Sci 2016;17:539–48.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Lampel M, Kern HF. Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue. Virchows Arch A Pathol Anat Histol. 1977;373:97–117.PubMedCrossRefGoogle Scholar
  32. 32.
    Watanabe O, Baccino FM, Steer ML, Meldolesi J. Supramaximal caerulein stimulation and ultrastructure of rat pancreatic acinar cell: early morphological changes during development of experimental pancreatitis. Am J Physiol. 1984;246:457–67.Google Scholar
  33. 33.
    Niederau C, Ferrell LD, Grendell JH. Caerulein-induced acute necrotizing pancreatitis in mice: protective effects of proglumide, benzotript, and secretin. Gastroenterology. 1985;88:1192–204.PubMedCrossRefGoogle Scholar
  34. 34.
    Su KH, Cuthbertson C, Christophi C. Review of experimental animal models of acute pancreatitis. HPB (Oxford). 2006;8(4):264–286.PubMedCrossRefGoogle Scholar
  35. 35.
    Zyromski NJ, Mathur A, Pitt HA et al. A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis. American journal of physiology. Gastrointestinal and liver physiology 2008;295:552–8.CrossRefGoogle Scholar
  36. 36.
  37. 37.
    Ong WK, Tan CS, Chan KL, et al. Identification of specific cell-surface markers of adipose-derived stem cells from subcutaneous and visceral fat depots. Stem Cell Reports. 2014;2(2):171–179.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Weir C, Morel-Kopp MC, Gill A et al. Mesenchymal stem cells: isolation, characterisation and in vivo fluorescent dye tracking. Heart, lung & circulation 2008;17:395–403.CrossRefGoogle Scholar
  39. 39.
    Ziegler KM, Wade TE, Wang S et al. Validation of a novel, physiologic model of experimental acute pancreatitis in the mouse. American journal of translational research 2011;3:159–165.PubMedGoogle Scholar
  40. 40.
    Traktuev DO, Prater DN, Merfeld-Clauss S et al. Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. Circulation research 2009;104:1410–20.PubMedCrossRefGoogle Scholar
  41. 41.
    Tu XH, Song JX, Xue XJ et al. Role of bone marrow-derived mesenchymal stem cells in a rat model of severe acute pancreatitis. World J Gastroenterol 2012;18:2270–9.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Meng HB, Gong J, Zhou B, et al. Therapeutic effect ofhuman umbilical cord-derived mesenchymal stem cells in rat severe acute pancreatitis. Int J Clin Exp Pathol 2013;6:2703–12.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Yang B, Bai B, Liu CX et al. Effect of umbilical cord mesenchymal stem cells on treatment of severe acute pancreatitis in rats. Cytotherapy 2013;15:154–62.PubMedCrossRefGoogle Scholar
  44. 44.
    Hua J, He ZG, Qian DH, et al. Angiopoietin-1 gene-modified human mesenchymal stem cells promote angiogenesis and reduce acute pancreatitis in rats. Int J Clin Exp Pathol. 2014;7:3580–95.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Jung KH, Yi T, Son MK, et al. Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis. Arch Pharm 2015;38:742–51.CrossRefGoogle Scholar
  46. 46.
    Qian D, Gong J, He Z et al. Bone marrow-derived mesenchymal stem cells repair necrotic pancreatic tissue and promote angiogenesis by secreting cellular growth factors involved in the SDF-1 alpha/CXCR4 axis in rats. Stem Cells Int vol. 2015, Article ID 306836, 20 pages, 2015.CrossRefGoogle Scholar
  47. 47.
    Yin G, Hu G, Wan R, et al. Role of microvesicles from bone marrow mesenchymal stem cells in acute pancreatitis. Pancreas 2016;45;1282–93.PubMedCrossRefGoogle Scholar
  48. 48.
    He Z, Hua J, Qian D, et al. Intravenous hMSCs ameliorate acute pancreatitis in mice via secretion of tumor necrosis factor-alpha stimulated gene/protein 6. Sci Rep 2016;6: 38438PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kawakubo K, Ohnishi S, Fukita H et al. Effect of fetal membrane-derived mesenchymal stem cell transplantation in rats with acute and chronic pancreatitis. Pancreas 2016;45:707–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Zhao H, He Z, Huang D et al. Infusion of bone marrow mesenchymal stem cells attenuates experimental severe acute pancreatitis in rats. Stem Cells Int 2016;2016:7174319.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Lu F, Wang F, Chen Z, et al. Effect of mesenchymal stem cells on small intestinal injury in a rat model of acute necrotizing pancreatitis. Stem Cell Res Ther 2017;8:12.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Patrikoski M, Mannerström B, and Miettinen S, “Perspectives for Clinical Translation of Adipose Stromal/Stem Cells,” Stem Cells International 2019; vol. 2019, Article ID 5858247, 21 pages.CrossRefGoogle Scholar
  53. 53.
    Melief SM, Zwaginga JJ, Fibbe WE and Relofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem cells translational medicine2013;2:446–55.CrossRefGoogle Scholar
  54. 54.
    Mikami Y, Takeda K, Shibuya K et al. Do peritoneal macrophages play an essential role in the progression of acute pancreatitis in rats? Pancreas. 2003;27:253–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Shrivastava P, Bhatia M. Essential role of monocytes and macrophages in the progression of acute pancreatitis. World J Gastroenterol. 2010;16(32):3995–4002.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Maatman TK, Mahajan S, Roch AM et al. High rates of readmission in necrotizing pancreatitis: Natural history of opportunity for improvement? J Gastrointest Surg 2019Google Scholar
  57. 57.
    Pastor CM, Matthay MA and Frossard JL. Pancreatitis-associated acute lung injury: new insights. Chest 2003;124:2341–51.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Raghu MG, Wig JD, Kocchar R et al. Lung complications in acute pancreatitis. JOP : Journal of the pancreas 2007;8:177–85.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Talvik R, Liigant A, Sissak HM and O’Konnel-Bronina N. Respiratory failure in acute pancreatitis. Intensive care medicine 1977;3:97–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Tran DD, Oe PL, de Fijter CW et al. Acute renal failure in patients with acute pancreatitis: prevalence, risk factors, and outcome. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 1993;8:1079–84.Google Scholar
  61. 61.
    Lu H, Poirier C, Cook T et al. Conditioned media from adipose stromal cells limit lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis. J Transl Med 2015;13:67.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Lange C, Togel F, Ittrich H et al. Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney international 2005;68:1613–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Rehman J, Traktuev D, Li J et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109(10): 1292–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Wang M, Yuan Q, Xie L. Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application. Stem Cells Int. 2018;2018:3057624.PubMedPubMedCentralGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2019

Authors and Affiliations

  • Alexandra M. Roch
    • 1
  • Thomas K. Maatman
    • 1
  • Todd G. Cook
    • 1
  • Howard H. Wu
    • 2
  • Stephanie Merfeld-Clauss
    • 3
  • Dmitry O. Traktuev
    • 3
  • Keith L. March
    • 3
  • Nicholas J. Zyromski
    • 1
    Email author
  1. 1.Department of SurgeryIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of PathologyIndiana University School of MedicineIndianapolisUSA
  3. 3.Department of Medicine, Division of Cardiovascular Medicine, Center for Regenerative medicineUniversity of FloridaGainesvilleUSA

Personalised recommendations