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Published on: June 3, 2018
Hepatocyte growth factor (HGF) enhances cardiac commitment of differentiating embryonic stem cells by activating PI3
Cristiana Roggia1, Christian Ukena, Michael Böhm
1Klinik für Innere Medizin III (Kardiologie, Angiologie, Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany.
Insights
Hepatocyte growth factor (HGF) promotes cardiac differentiation of embryonic stem cells (ESCs). HGF enhances cardiomyocyte marker expression via the PI3 kinase/Akt pathway, aiding potential clinical applications.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Molecular Medicine
Background:
- Hepatocyte growth factor (HGF) and its receptor c-Met are present during early cardiac development.
- Limited data exists on HGF's role in embryonic stem cell (ESC) cardiac differentiation and its molecular mechanisms.
Purpose of the Study:
- To investigate the effect of HGF on ESC cardiac differentiation.
- To elucidate the molecular pathways involved in HGF-mediated cardiac differentiation.
Main Methods:
- Culturing and differentiating mouse ESCs.
- Assessing embryoid body formation and beating.
- Measuring cardiac-specific gene and protein expression (Nkx 2.5, GATA-4, alpha-MHC, beta-MHC, ANF, MLC2v, Troponin T).
- Utilizing PI3 kinase inhibitors (Wortmannin, LY294002) to probe signaling pathways.
Main Results:
- HGF significantly increased the number of beating embryoid bodies from differentiating ESCs.
- HGF upregulated cardiac-specific transcription factors (Nkx 2.5, GATA-4) and cardiomyocyte markers.
- PI3 kinase/Akt pathway inhibition blocked HGF-induced Nkx 2.5 expression.
Conclusions:
- HGF is a key growth factor promoting ESC cardiac differentiation and/or proliferation.
- The PI3 kinase/Akt pathway mediates HGF's effect on Nkx 2.5 expression.
- HGF holds potential for in vitro generation of cardiomyocytes for treating cardiac diseases.
Abstract:
Hepatocyte growth factor (HGF) is a pleiotropic cytokine promoting proliferation, migration and survival in several cell types. HGF and its cognate receptor c-Met are expressed in cardiac cells during early cardiogenesis, but data concerning its role in cardiac differentiation of embryonic stem cells (ESCs) and the underlying molecular mechanisms involved are limited. In the present study we show that HGF significantly increases the number of beating embryoid bodies of differentiating ESCs without affecting beating frequency. Furthermore, HGF up-regulates the expression of the cardiac-specific transcription factors Nkx 2.5 and GATA-4 and of markers of differentiated cardiomyocytes, i.e. alpha-MHC, beta-MHC, ANF, MLC2v and Troponin T. The HGF-induced increase in Nkx 2.5 expression was inhibited by co-treatment with the PI3 kinase inhibitors Wortmannin and LY294002, but not by its inactive homolog LY303511, suggesting an involvement of the PI3 kinase/Akt pathway in this effect. We conclude that HGF is an important growth factor involved in cardiac differentiation and/or proliferation of ESCs and may therefore be critical for the in vitro generation of pre- or fully differentiated cardiomyocytes as required for clinical use of embryonic stem cells in cardiac diseases.
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