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Embryonic Stem Cell Transplantation Correlates With Endogenous Neurogenin 3 Expression and Pancreas Regeneration in Streptozotocin-injured Mice

Maho Kodama, Katsura Tsukamoto, Kimiko Yoshida, Kazunori Aoki, Shiro Kanegasaki and Gary Quinn

Section for Studies on Metastasis (MK,GQ) and Genetics Division (KY,KA), National Cancer Center Research Institute, Tokyo, Japan; Sanwa Kagaku Kenkyusho Co., Ltd., Research Management Department, Mie, Japan (KT); and Central Laboratory, Effector Cell Institute, Inc., Tokyo, Japan (SK,GQ)

Correspondence to: Gary Quinn, PhD, Central Laboratory, Effector Cell Institute, Inc., 4-7-7 Aobadai, Meguro-ku, Tokyo 153-0042, Japan. E-mail: garyquinn99{at}hotmail.com

Pancreatic β cell regeneration remains poorly understood, yet stimulation of adult β cell neogenesis could lead to therapies for type 1 and type 2 diabetes. We studied the effect of embryonic stem (ES) cell transplantation on pancreas regeneration following β cell injury. Female Balb/c nude mice were treated with streptozotocin to induce hyperglycemia and received an ES cell transplant 24 hr later beneath the renal capsule. Transplantation of ES cells prevented hyperglycemia in a subset of mice, maintaining euglycemia and mild glucose tolerance up to 5 weeks. Pancreata of euglycemic mice showed histological evidence of β cell regeneration and expression of pancreas and duodenum transcription factor-1 (PDX-1) and neurogenin 3 (Ngn3) in ductal epithelium. Cell tracing analysis indicated that significant β cell neogenesis from progenitor cells occurred between 2 to 3 weeks following injury in ES cell–transplanted mice but not in sham-transplanted animals. Significantly, whereas pancreas-localized ES cells or their derivatives were adjacent to sites of regeneration, neogenic pancreatic epithelia, including Ngn3⁺ cells, were endogenous. In conclusion, transplanted ES cells can migrate to the injured pancreas. Transplantation is associated with enhanced endogenous regeneration characterized by expression of Ngn3 and increased β cell differentiation from endogenous progenitor cells. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 57:1149–1158, 2009)

Key Words: pancreas regeneration • diabetes • neurogenin 3 • PDX-1 • pancreatic islets • embryonic stem cells • streptozotocin • islet • pancreatic β cells • cell transplantation

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