Reprogramming of pancreatic beta cells into induced pluripotent stem cells.
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 [1-8]. 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 [9] to express Oct4, Sox2, c-myc, and Klf4 in pancreatic beta cells to assess whether a defined terminally differentiated cell type remains amenable to reprogramming. Genetically marked beta 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.
Stadtfeld
Matthias
M
Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, 185 Cambridge Street, Boston, MA 02114, USA.
Brennand
Kristen
K
Hochedlinger
Konrad
K
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002678:Chimera; D005260:Female; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000821:virology; D000090062:Kruppel-Like Factor 4; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013724:Teratoma; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors