Hartman Institute for Therapeutic Organ Regeneration

Discovery of a Small-Molecule BMP Sensitizer for Human Embryonic Stem Cell Differentiation.

TitleDiscovery of a Small-Molecule BMP Sensitizer for Human Embryonic Stem Cell Differentiation.
Publication TypeJournal Article
Year of Publication2016
AuthorsFeng L, Cook B, Tsai S-Y, Zhou T, LaFlamme B, Evans T, Chen S
JournalCell Rep
Volume15
Issue9
Pagination2063-75
Date Published2016 May 31
ISSN2211-1247
KeywordsAnimals, Bone Morphogenetic Protein 4, Carbazoles, Cell Differentiation, Cell Lineage, Cellular Reprogramming, Checkpoint Kinase 1, Human Embryonic Stem Cells, Humans, Mesoderm, Mice, Models, Biological, Myoblasts, Osteoblasts, Signal Transduction, Smad Proteins, Small Molecule Libraries, Trophoblasts
Abstract

<p>Sorely missing from the "toolkit" for directed differentiation of stem/progenitor cells are agonists of the BMP-signaling pathway. Using a high-throughput chemical screen, we discovered that PD407824, a checkpoint kinase 1 (CHK1) inhibitor, increases the sensitivity of cells to sub-threshold amounts of BMP4. We show utility of the compound in the directed differentiation of human embryonic stem cells toward mesoderm or cytotrophoblast stem cells. Blocking CHK1 activity using pharmacological compounds or CHK1 knockout using single guide RNA (sgRNA) confirmed that CHK1 inhibition increases the sensitivity to BMP4 treatment. Additional mechanistic studies indicate that CHK1 inhibition depletes p21 levels, thereby activating CDK8/9, which then phosphorylates the SMAD2/3 linker region, leading to decreased levels of SMAD2/3 protein and enhanced levels of nuclear SMAD1. This study provides insight into mechanisms controlling the BMP/transforming growth factor beta (TGF-β) signaling pathways and a useful pharmacological reagent for directed differentiation of stem cells.</p>

DOI10.1016/j.celrep.2016.04.066
Alternate JournalCell Rep
PubMed ID27210748
PubMed Central IDPMC4889468
Grant ListK01 DK096031 / DK / NIDDK NIH HHS / United States
R01 HL056182 / HL / NHLBI NIH HHS / United States
DP2 DK098093 / DK / NIDDK NIH HHS / United States
R01 HL111400 / HL / NHLBI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
R37 HL056182 / HL / NHLBI NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
1300 York Ave, Box 136 New York, NY 10065