Generation of mouse models for type 1 diabetes by selective depletion of pancreatic beta cells using toxin receptor-mediated cell knockout

• Published in: Biochemical and biophysical research communications 2013-07, Vol.436 (3), p.400-405
• Main Authors: Matsuoka, Kunie, Saito, Michiko, Shibata, Kosuke, Sekine, Michiko, Shitara, Hiroshi, Taya, Choji, Zhang, Xiaohong, Takahashi, Tsuneo A., Kohno, Kenji, Kikkawa, Yoshiaki, Yonekawa, Hiromichi
• Format: Article
• Language: English
• Subjects: Allogeneic transplantation; Animals; Antigens, CD34 - metabolism; Cord Blood Stem Cell Transplantation; Diabetes; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - pathology; Diphtheria toxin; Diphtheria Toxin - adverse effects; Diphtheria Toxin - metabolism; Gene Knockout Techniques; Glucose - pharmacology; Humans; Hyperglycemia - pathology; Hyperglycemia - therapy; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Insulins - administration & dosage; Insulins - blood; Mice; Mice, Inbred C57BL; Mice, SCID; Mice, Transgenic; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Transgenic mice; Transplantation, Heterologous; Transplantation, Homologous; Xenogeneic transplantation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.05.114

•Novel transgenic mouse models for T1D were established by TRECK method.•They were established on C57BL/6 and SCID background.•DT administration resulted severe ablation of pancreatic β cells within 3days.•Hyperglycemia of SCID-Tg mice is cured by allogeneic and xenogeneic transplantation.•These Tg mice are highly useful for diabetogenic research. By using the toxin receptor-mediated cell knockout (TRECK) method, we have generated two transgenic (Tg) murine lines that model type 1 (insulin-dependent) diabetes. The first strain, C.B-17/Icr-Prkdcscid/Prkdcscid-INS-TRECK-Tg, carries the diphtheria toxin receptor (hDTR) driven by the human insulin gene promoter, while the other strain, C57BL/6-ins2(BAC)-TRECK-Tg, expresses hDTR cDNA under the control of the mouse insulin II gene promoter. With regard to the C.B-17/Icr-Prkdcscid/Prkdcscid-INS-TRECK-Tg strain, only one of three Tg strains exhibited proper expression of hDTR in pancreatic β cells. By contrast, hDTR was expressed in the pancreatic β cells of all four of the generated C57BL/6-ins2(BAC)-TRECK-Tg strains. Hyperglycemia, severe ablation of pancreatic β cells and depletion of serum insulin were observed within 3days after the administration of diphtheria toxin (DT) in these Tg mice. Subcutaneous injection of a suitable dosage of insulin was sufficient for recovery from hyperglycemia in all of the examined strains. Using the C.B-17/Icr-Prkdcscid/Prkdcscid-INS-TRECK-Tg model, we tried to perform regenerative therapeutic approaches: allogeneic transplantation of pancreatic islet cells from C57BL/6 and xenogeneic transplantation of CD34+ human umbilical cord blood cells. Both approaches successfully rescued C.B-17/Icr-Prkdcscid/Prkdcscid-INS-TRECK-Tg mice from hyperglycemia caused by DT administration. The high specificity with which DT causes depletion in pancreatic β cells of these Tg mice is highly useful for diabetogenic research.