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PMID: 19818703 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog.

Cell stem cell ·Vol. 5 ·No. 5 ·2009-11-06 ·Pages 491-503

Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC, Di Giorgio FP, Koszka K, Huangfu D, Akutsu H, Liu DR, Rubin LL, Eggan K

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.

MeSH Terms
Animals Antibodies, Monoclonal Benzamides/pharmacology Cell Line Cell Transdifferentiation Dioxoles/pharmacology High-Throughput Screening Assays Homeodomain Proteins/genetics,metabolism Induced Pluripotent Stem Cells/immunology,metabolism,pathology Mice Nanog Homeobox Protein Pyrazoles/pharmacology Pyridines/pharmacology Receptors, Transforming Growth Factor beta/antagonists & inhibitors SOXB1 Transcription Factors/genetics,metabolism Signal Transduction Small Molecule Libraries/pharmacology Transduction, Genetic Transforming Growth Factor beta/antagonists & inhibitors,immunology
Chemicals
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide Antibodies, Monoclonal Benzamides Dioxoles Homeodomain Proteins Nanog Homeobox Protein Nanog protein, mouse Pyrazoles Pyridines Receptors, Transforming Growth Factor beta RepSox SOXB1 Transcription Factors Small Molecule Libraries Sox2 protein, mouse Transforming Growth Factor beta
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Ichida Justin K
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Blanchard Joel
Lam Kelvin
Son Esther Y
Chung Julia E
Egli Dieter
Loh Kyle M
Carter Ava C
Di Giorgio Francesco P
Koszka Kathryn
Huangfu Danwei
Akutsu Hidenori
Liu David R
Rubin Lee L
Eggan Kevin
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Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2009.09.012
Published
2009-11-06
Epub
2009-00-08
Pages
491-503
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC3335195
Subset
IM
Grants
NICHD NIH HHS · R01 HD046732 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · GM065400 · United States
NICHD NIH HHS · R01 HD046732-07 · United States
NIGMS NIH HHS · R01 GM065400 · United States
NICHD NIH HHS · R01 HD046732-01A1 · United States
NICHD NIH HHS · R01 HD046732-06 · United States
External Links
PubMed source DOI: 10.1016/j.stem.2009.09.012 PMC Full Text View journal details
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