A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog.
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.
Ichida
Justin K
JK
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Blanchard
Joel
J
Lam
Kelvin
K
Son
Esther Y
EY
Chung
Julia E
JE
Egli
Dieter
D
Loh
Kyle M
KM
Carter
Ava C
AC
Di Giorgio
Francesco P
FP
Koszka
Kathryn
K
Huangfu
Danwei
D
Akutsu
Hidenori
H
Liu
David R
DR
Rubin
Lee L
LL
Eggan
Kevin
K
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
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