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Pancreatic Endocrine and Exocrine Cell Ontogeny From Renal Capsule–transplanted Embryonic Stem Cells in Streptozocin-injured Mice

Maho Kodama, Fumitaka Takeshita, Shiro Kanegasaki, Takahiro Ochiya and Gary Quinn

Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo, Japan (MK,FT,TO,GQ), and Central Laboratory, Effector Cell Institute, Tokyo, Japan (SK,GQ)

Correspondence to: Gary Quinn, PhD, Section for Studies on Metastasis, National Cancer Center Research Institute, 1-1 Tsukiji, 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: garyquinn99{at}hotmail.com

In this study, we describe pancreatic cell ontogeny in renal capsule–transplanted embryonic stem cells (ES) after injury by streptozocin (STZ), showing pancreatogenesis in situ. Seven-week-old female BALB/c nude mice were treated with either a single 175- or 200-mg/kg STZ dose, a regimen that induces substantial β-cell damage without overt hyperglycemia, and transplanted 24 hr later with 1 x 10⁵ ES. Immunohistochemistry was performed on ES tissue at 15, 21, and 28 days after transplantation using antibodies against stage- and lineage-specific pancreatic markers. After 21 days, PDX-1+ pancreatic foci first appeared in the renal capsule and expressed both amylase and endocrine hormones (insulin, glucagon, and somatostatin). These foci increased in size by day 28 because of acinar and duct cell proliferation, whereas endocrine cells remained non-dividing, and made up 2–4% of ES tumor volume. PDX-1, Nkx6.1, Ngn3, and ISL-1 protein localization patterns in pancreatic foci were comparable with embryonic pancreatogenesis. A prevalence of multihormonal endocrine cells, a characteristic of adult β-cell regeneration, indicated a possible divergence from embryonic islet cell development. The results indicate that β-cell damage, without overt hyperglycemia, induces a process of fetal-like pancreatogenesis in renal capsule–transplanted ES, leading to β-cell neogenesis. (J Histochem Cytochem 56:33–44, 2008)

Key Words: regeneration • embryonic stem cells • pancreatic β cells • pancreatogenesis • differentiation • diabetes • pancreas • hormone

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