title: A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog.
abstract: The combined activity of three transcription factors can reprogram adult cells into induced pluripotent stem cells (iPSCs). However, the transgenic methods used for delivering reprogramming factors have raised concerns regarding the future utility of the resulting stem cells. These uncertainties could be overcome if each transgenic factor were replaced with a small molecule that either directly activated its expression from the somatic genome or in some way compensated for its activity. To this end, we have used high-content chemical screening to identify small molecules that can replace Sox2 in reprogramming. We show that one of these molecules functions in reprogramming by inhibiting Tgf-beta signaling in a stable and trapped intermediate cell type that forms during the process. We find that this inhibition promotes the completion of reprogramming through induction of the transcription factor Nanog.
authors.affiliation: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Ichida
authors.forename: Joel
authors.initials: J
authors.lastname: Blanchard
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lam
authors.forename: Esther Y
authors.initials: EY
authors.lastname: Son
authors.forename: Julia E
authors.initials: JE
authors.lastname: Chung
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Loh
authors.forename: Ava C
authors.initials: AC
authors.lastname: Carter
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Di Giorgio
authors.forename: Kathryn
authors.initials: K
authors.lastname: Koszka
authors.forename: Danwei
authors.initials: D
authors.lastname: Huangfu
authors.forename: Hidenori
authors.initials: H
authors.lastname: Akutsu
authors.forename: David R
authors.initials: DR
authors.lastname: Liu
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D054338:Cell Transdifferentiation; D004149:Dioxoles / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000071317:Nanog Homeobox Protein; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000911:Antibodies, Monoclonal; D001549:Benzamides; D004149:Dioxoles; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D011720:Pyrazoles; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; C550621:RepSox; D055748:SOXB1 Transcription Factors; D054852:Small Molecule Libraries; C527783:Sox2 protein, mouse; D016212:Transforming Growth Factor beta