A small molecule primes embryonic stem cells for differentiation.
Embryonic stem cells (ESCs) are an attractive source of cells for disease modeling in vitro and may eventually provide access to cells/tissues for the treatment of many degenerative diseases. However, applications of ESC-derived cell types are largely hindered by the lack of highly efficient methods for lineage-specific differentiation. Using a high-content screen, we have identified a small molecule, named stauprimide, that increases the efficiency of the directed differentiation of mouse and human ESCs in synergy with defined extracellular signaling cues. Affinity-based methods revealed that stauprimide interacts with NME2 and inhibits its nuclear localization. This, in turn, leads to downregulation of c-Myc, a key regulator of the pluripotent state. Thus, our findings identify a chemical tool that primes ESCs for efficient differentiation through a mechanism that affects c-Myc expression, and this study points to an important role for NME2 in ESC self-renewal.
The Skaggs Institute of Chemical Biology and the Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Shoutian
S
Zhu
Heiko
H
Wurdak
Jian
J
Wang
Costas A
CA
Lyssiotis
Eric C
EC
Peters
Charles Y
CY
Cho
Xu
X
Wu
Peter G
PG
Schultz
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004707:Endoderm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016259:Genes, myc; D006801:Humans; D051379:Mice; D054778:NM23 Nucleoside Diphosphate Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D054778:NM23 Nucleoside Diphosphate Kinases; C542929:staurprimide; D019311:Staurosporine