Title: Reprogramming of Pancreatic β Cells into Induced Pluripotent Stem Cells
Abstract: Induced pluripotent stem (iPS) cells have been derived from fibroblast, stomach, and liver cultures at extremely low frequencies by ectopic expression of the transcription factors Oct4, Sox2, c-myc, and Klf4, a process coined direct or in vitro reprogramming [1Aoi T. Yae K. Nakagawa M. Ichisaka T. Okita K. Takahashi K. Chiba T. Yamanaka S. Generation of pluripotent stem cells from adult mouse liver and stomach cells.Science. 2008; (in press. Published online February 14, 2008)https://doi.org/10.1126/science.1154884Crossref Scopus (823) Google Scholar, 2Maherali N. Sridharan R. Xie W. Utikal J. Eminli S. Arnold K. Stadtfeld M. Yachechko R. Tchieu J. Jaenisch R. et al.Directly reprogrammed fibroblasts show global epigenetic reprogramming and widespread tissue contribution.Cell Stem Cell. 2007; 1: 55-70Abstract Full Text Full Text PDF PubMed Scopus (1337) Google Scholar, 3Wernig M. Meissner A. Foreman R. Brambrink T. Ku M. Hochedlinger K. Bernstein B.E. Jaenisch R. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.Nature. 2007; 448: 318-324Crossref PubMed Scopus (2137) Google Scholar, 4Okita K. Ichisaka T. Yamanaka S. Generation of germline-competent induced pluripotent stem cells.Nature. 2007; 448: 313-317Crossref PubMed Scopus (3360) Google Scholar, 5Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.Cell. 2007; 131: 861-872Abstract Full Text Full Text PDF PubMed Scopus (13505) Google Scholar, 6Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (17010) Google Scholar, 7Yu J. Vodyanik M.A. Smuga-Otto K. Antosiewicz-Bourget J. Frane J.L. Tian S. Nie J. Jonsdottir G.A. Ruotti V. Stewart R. et al.Induced pluripotent stem cell lines derived from human somatic cells.Science. 2007; 318: 1917-1920Crossref PubMed Scopus (7589) Google Scholar, 8Park I.H. Zhao R. West J.A. Yabuuchi A. Huo H. Ince T.A. Lerou P.H. Lensch M.W. Daley G.Q. Reprogramming of human somatic cells to pluripotency with defined factors.Nature. 2008; 451: 141-146Crossref PubMed Scopus (2281) Google Scholar]. iPS cells are molecularly and functionally highly similar to embryonic stem cells (ESCs), including their ability to contribute to all tissues as well as the germline in mice. The heterogeneity of the starting cell populations and the low efficiency of reprogramming suggested that a rare cell type, such as an adult stem cell, might be the cell of origin for iPS cells and that differentiated cells are refractory to reprogramming. Here, we used inducible lentiviruses [9Stadtfeld M. Maherali N. Breault D.T. Hochedlinger K. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse.Cell Stem Cell. 2008; 2: 230-240Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar] to express Oct4, Sox2, c-myc, and Klf4 in pancreatic β cells to assess whether a defined terminally differentiated cell type remains amenable to reprogramming. Genetically marked β cells gave rise to iPS cells that expressed pluripotency markers, formed teratomas, and contributed to cell types of all germ layers in chimeric animals. Our results provide genetic proof that terminally differentiated cells can be reprogrammed into pluripotent cells, suggesting that in vitro reprogramming is not restricted to certain cell types or differentiation stages.