Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression.
Expression of the transcription factors Oct4, Sox2, Klf4, and c-Myc in mesodermal and endodermal derivatives, including fibroblasts, lymphocytes, liver, stomach, and beta cells, generates induced pluripotent stem (iPS) cells. It remains unknown, however, whether cell types of the ectodermal lineage are equally amenable to reprogramming into iPS cells by the same combination of factors. To test this, we have isolated genetically marked neural progenitor cells (NPCs) from neonatal mouse brains and infected them with viral vectors expressing Oct4, Sox2, Klf4, and c-Myc. Infected NPCs gave rise to iPS cells that expressed markers of embryonic stem cells, showed demethylation of pluripotency genes, formed teratomas, and contributed to viable chimeras. In contrast to other somatic cell types, NPCs expressed high levels of endogenous Sox2 and thus did not require viral Sox2 expression for reprogramming into iPS cells. Our data show that in addition to mesoderm- and endoderm-derived cell types, neural progenitor cells of the ectodermal lineage can be reprogrammed into iPS cells, suggesting that in vitro reprogramming is a universal process. These results also imply that the combination of factors necessary for reprogramming is dependent on cellular context. Disclosure of potential conflicts of interest is found at the end of this article.
Eminli
Sarah
S
Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, Massachusetts 02114, USA.
Utikal
Jochen
J
Arnold
Katrin
K
Jaenisch
Rudolf
R
Hochedlinger
Konrad
K
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*
C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D011993:Recombinant Fusion Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D049452:Green Fluorescent Proteins