Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells (Cell, 2010, 142:787-799)

報告日期: 2010/12/21
報告時間: 16:00/16:50
報告學生: 吳美芳
講評老師: 張南山

Full text:

Generation of Rat Pancreas in Mouse by Interspecific Blastocyst Injection of Pluripotent Stem Cells
Kobayashi T. et al. Cell 142 787-799 2010
Presenter: 吳美芳
Commentator: 張南山
Transplantation of islet is considered to be the best way to treat diabetes; nonetheless, limited donor’s tissues and immune-rejection remain the major hurdles. Generation of patient-specific induced pluripotent stem cells (iPSCs) may provide a solution. iPSCs were firstly produced from adult somatic cells following introduction of four pluripotency-associated transcription factors, Oct-4, Sox-2, Klf-4 and C-myc, and they were capable of giving rise to all three germ layer-derived cells, including the islet cells (Takahashi and Yamanaka, 2006). Numerous approaches have been developed for derivation of islet cells from pluripotent cells (Alipio et al., 2010, Kroon et al., 2008), however, low generation efficiency and the risk of tumour formation have hindered application of these cells for treating diabetes. A xenogenic blastocyst complementation system reported in the current study may overcome these difficulties. 
Pancreatic and duodenal homeobox1 (Pdx1) gene deficiency has been shown to contribute to pancreatic agenesis. Taking the advantages of iPSCs, the authors demonstrated that iPSC-derived pancreas can develop in the chimeric mice generated from injection of iPSC into the blastocysts of Pdx1-/- mice, a process called blastocyst complementation. Glucose tolerance testing (GTT) confirmed that these iPSC-derived islets were functional and capable of secreting insulin to maintain normal glucose level in Pdx1-null chimeric mice. Moreover, transplantation of iPSC-derived islets normalised blood glucose level in diabetic mice. In addition to generation of intraspecific chimeras, injection of mouse iPSCs into rat blastocysts or rat iPSCs into mouse blastocysts have led to development of interspecific chimeras. FACS analysis revealed that donor-derived cells can be detected in mouse and rat interspecific chimeras. Immunostaning results confirmed that injected mouse or rat iPSC into rat or mouse blastocysts contributed to development of various types of tissues in interspecific chimeras. Following successful generation of interspecific chimera, the authors showed that xenogenic rat pancreas can also be generated in Pdx-null mice by interspecific blastocyst complementation. The majority of pancreatic cells in Pdx1-/- mice were derived from rat iPSCs. Moreover, GTT results suggested that rat-derived islet cells were functional and responsive to glucose stimuli.  
        Taken together, these results indicate that development of xenogenic iPSC-derived organ is possible, and may serve as an alterative approach for regenerative medicine to solve the problems associated with organ transplantation. 
Alipio, Z., et al. 2010. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic β-like cells. Proceedings of the National Academy of Sciences, 107, 13426-13431.
Kroon, E., et al. 2008. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol, 26, 443-52.
Takahashi, K. & Yamanaka, S. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663-76.