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Embryonic Stem Cells/induced Pluripotent Stem Cells
Article first published online: 24 APR 2013
Copyright © 2013 AlphaMed Press
Volume 31, Issue 5, pages 928–940, May 2013
How to Cite
Renger, A., Zafiriou, M.-P., Noack, C., Pavlova, E., Becker, A., Sharkova, K., Bergmann, M. W., El-Armouche, A., Zimmermann, W.-H. and Zelarayán, L. C. (2013), The Four and a Half LIM-Domain 2 Controls Early Cardiac Cell Commitment and Expansion Via Regulating β-Catenin-Dependent Transcription. STEM CELLS, 31: 928–940. doi: 10.1002/stem.1332
A.R.: conception and design, performed research, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; M.P.Z. and C.N.: conception and design, performed research, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; E.P., A.B., and K.S.: performed research and final approval of manuscript; M.W.B.: financial support and final approval of manuscript; A.E.A.: data analysis and interpretation, manuscript writing, and final approval of manuscript; W.H.Z.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript; L.C.Z.: conception and design, performed research, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS January 22, 2013.
- Issue published online: 24 APR 2013
- Article first published online: 24 APR 2013
- Accepted manuscript online: 22 JAN 2013 08:54AM EST
- Manuscript Accepted: 21 DEC 2012
- Manuscript Received: 22 AUG 2012
- Deutsche Forschungsgemeinschaft. Grant Numbers: ZE900/1-1, ZI708/7-1, 8-1, 10-1, SFB1002, exFLIII)
- Jürgen Manchot and the Ernst und Berta Grimmke Foundations. Grant Number: 7/07
- Federal Ministry of Science and Education. Grant Number: EU FP7 CareMI
- German Center for Cardiovascular Research
- Four and a half LIM-domain 2;
- Mouse embryonic stem cell;
The multiphasic regulation of the Wnt/β-catenin canonical pathway is essential for cardiogenesis in vivo and in vitro. To achieve tight regulation of the Wnt/β-catenin signaling, tissue- and cell-specific coactivators and repressors need to be recruited. The identification of such factors may help to elucidate mechanisms leading to enhanced cardiac differentiation efficiency in vitro as well as promote regeneration in vivo. Using a yeast-two-hybrid screen, we identified four-and-a-half-LIM-domain 2 (FHL2) as a cardiac-specific β-catenin interaction partner and activator of Wnt/β-catenin-dependent transcription. We analyzed the role of this interaction for early cardiogenesis in an in vitro model by making use of embryoid body cultures from mouse embryonic stem cells (ESCs). In this model, stable FHL2 gain-of-function promoted mesodermal cell formation and cell proliferation while arresting cardiac differentiation in an early cardiogenic mesodermal progenitor state. Mechanistically, FHL2 overexpression enhanced nuclear accumulation of β-catenin and activated Wnt/β-catenin-dependent transcription leading to sustained upregulation of the early cardiogenic gene Igfbp5. In an alternative P19 cell model, transient FHL2 overexpression led to early activation of Wnt/β-catenin-dependent transcription, but not sustained high-level of Igfbp5 expression. This resulted in enhanced cardiogenesis. We propose that early Wnt/β-catenin-dependent transcriptional activation mediated by FHL2 is important for the transition to and expansion of early cardiogenic mesodermal cells. Collectively, our findings offer mechanistic insight into the early cardiogenic code and may be further exploited to enhance cardiac progenitor cell activity in vitro and in vivo. STEM CELLS 2013;31:928–940