Embryonic stem cell transplantation correlates with endogenous neurogenin 3 expression and pancreas regeneration in streptozotocin-injured mice.
Pancreatic beta cell regeneration remains poorly understood, yet stimulation of adult beta 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 beta 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 beta 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 beta 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 beta cell differentiation from endogenous progenitor cells.
Kodama
Maho
M
Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo, Japan.
Tsukamoto
Katsura
K
Yoshida
Kimiko
K
Aoki
Kazunori
K
Kanegasaki
Shiro
S
Quinn
Gary
G
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D053595:Embryonic Stem Cells / Q000637:transplantation*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010179:Pancreas / Q000293:injuries* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010183:Pancreatic Ducts / Q000473:pathology; D012038:Regeneration; D033581:Stem Cell Transplantation; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D013311:Streptozocin; D015534:Trans-Activators; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein