THERAPEUTIC USE OF ADIPOSE-DERIVED STROMAL CELLS IN A MURINE MODEL OF ACUTE PANCREATITIS
Alexandra M. Roch*1, Thomas K. Maatman1, Todd G. Cook2, Howard Wu3, Keith L. March4, Nicholas J. Zyromski1
1Surgery, Indiana School of Medicine, Indianapolis, IN; 2Medicine, Indiana University School of Medicine, Indianapolis, IN; 3Pathology, Indiana University School of Medicine, Indianapolis, IN; 4University of Florida, Gainesville, FL
Background: Although 80% Of patients with acute pancreatitis will have a mild self-limited course, up to 20% will develop severe pancreatitis with an associated 20% mortality rate. No specific therapy exists for acute pancreatitis and current treatment remains entirely supportive. Adipose stem cells (ASCs) have significant immunomodulatory activity as well as regenerative potential. We hypothesized that systemic administration of ASCs would mitigate local and systemic inflammation in AP.
Methods: All experiments were approved by institutional IACUC. Twenty male brown mice (20-24 weeks old, mean weight 44g) had acute pancreatitis induced by 6 hourly intra peritoneal injections of cerulein. Treatment was initiated at 24 hours via tail vein IV. Four treatment groups included: sham control group (no acute pancreatitis), vehicle injection, human ASC injection, and human ASC conditioned media injection. Mice were sacrificed at 48 hours; blood, pancreas, lungs, and kidneys were analyzed. Acinar cell injury was quantified histologically by a dedicated experienced pathologist and 2 pancreatic surgeons using a published scoring system (edema, inflammation and necrosis). Pancreatic inflammation, engraftment and end-organ failure were studied by immunohistochemistry and PCR technique.
Results: Mice treated with ASCs had less severe AP, as shown by a statistically significantly decreased histopathology score (edema, inflammation and necrosis) (p=0.001). ASCs infusion polarized pancreatic macrophages toward an anti-inflammatory M2 phenotype (determined by immunohistochemistry staining for M2 marker CD206). ASC treatment increased expression of the M2-related markers (resistin like alpha protein) (p<0.01), while suppressing expression of M1-related iNOS and TNFα (p<0.05). When using IV infusion of Hoechst-labeled ASCs, ASCs were found to localize to inflamed tissues: lungs and pancreas. ASC conditioned media IV infusion reduced pancreatic inflammation similarly to ASCs only, highlighting the importance of ASCs secreted factors' paracrine mechanism in modulating inflammation.
Conclusion: Intravenous delivery of human ASC markedly reduces pancreatic inflammation and end organ injury in a murine model of acute pancreatitis. ASCs represent an efficient and attractive therapy for acute pancreatitis.
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