2. Academic Validation
  3. Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling

Cardiomyocyte differentiation of pluripotent stem cells with SB203580 analogues correlates with Wnt pathway CK1 inhibition independent of p38 MAPK signaling

  • J Mol Cell Cardiol. 2015 Mar;80:56-70. doi: 10.1016/j.yjmcc.2014.12.003.
Filip Laco 1,  Joo-Leng Low 2,  Jasmin Seow 1,  Tsung Liang Woo 1,  Qixing Zhong 3,  Jayasree Seayad 2,  Zhenfeng Liu 4,  Heiming Wei 5,  Shaul Reuveny 1,  David A Elliott 6,  Christina L L Chai 7,  Steve K W Oh 8
Affiliations

Affiliations

  • 1 Bioprocessing Technology Institute, 20 Biopolis Way, Centros #06-01, Singapore 138668, Singapore.
  • 2 Institute of Chemical and Engineering Sciences, 8 Biomedical Grove, Neuros #07-01, Singapore 138665, Singapore.
  • 3 Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
  • 4 National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore; Cardiovascular & Metabolic Disorders Program, DUKE-NUS Graduate Medical School Singapore, Singapore.
  • 5 National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
  • 6 Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, Melbourne, Australia.
  • 7 Institute of Chemical and Engineering Sciences, 8 Biomedical Grove, Neuros #07-01, Singapore 138665, Singapore; Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
  • 8 Bioprocessing Technology Institute, 20 Biopolis Way, Centros #06-01, Singapore 138668, Singapore. Electronic address: steve_oh@bti.a-star.edu.sg.
PMID: 25528965 DOI: 10.1016/j.yjmcc.2014.12.003
Abstract

Differentiation of human pluripotent stem cells as embryoid bodies (EBs) has been achieved previously with p38alfa MAPK inhibitors such as SB203580 with moderate efficiency of 10-15%. We synthesized and screened 42 compounds that are 2,4,5-trisubstituted azole analogues of SB203580 for efficient cardiomyocyte differentiation. Our screen identified novel compounds that have similar cardiac differentiation activity as SB203580. However, the cardiac differentiation did not correlate with p38alfa MAPK inhibition, indicating an alternative mechanism in cardiac differentiation. Upon profiling several 2,4,5-trisubstituted azole compounds against a panel of 97 kinases we identified several off targets, among them casein kinases 1 (CK1). The cardiomyogenic activities of SB203580 and its analogues showed a correlation with post mesoderm Wnt/beta-catenin pathway inhibition of CK1 epsilon and delta. These findings united the mechanism of 2,4,5-trisubstituted azole with the current theory of Wnt/beta-catenin regulated pathway of cardiac differentiation. Consequently an efficient cardiomyocyte protocol was developed with Wnt activator CHIR99021 and 2,4,5-trisubstituted azoles to give high yields of 50-70% cardiomyocytes and a 2-fold increase in growth.

Keywords

Cardiomyocyte differentiation; Casein kinase 1; Kinase inhibitors; Stem cell; Wnt signaling pathway; p38 MAPK.

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