Get 20% Off Journals at LWW.com

HIF2α induces cardiomyogenesis via Wnt/β-catenin signaling in mouse embryonic stem cells.

J Transl Med 2015 Mar 14;13:88. Epub 2015 Mar 14.

Department of Cardiothoracic surgery, Huashan Hospital of Fudan University, 12th Wulumuqi Road, Shanghai, 200040, PR, China.

Background: Embryonic stem cells (ESCs) are pluripotent stem cells and can differentiate into cardiomyocytes when cultured in appropriate conditions. The function of hypoxia-inducible factors (HIFs) has been identified in directing the formation of cardiac lineages. The purpose of this study was to investigate the ability of HIF2α to induce differentiation of ESCs into cardiomyocytes and to explore the potential underlying molecular mechanisms.

Methods: Cardiac differentiation from mouse ESCs was analyzed using the "hanging drop" method, and success was determined by assaying the numbers of beating embryoid bodies and the expression level of cardiac markers. The expression of HIF2α was then manipulated during cardiac differentiation with piggyBac transposon and the lentivirus system. The underlying mechanism was finally examined via administering selective inhibitors of the Wnt/β-catenin signaling pathway.

Results: Overexpressing HIF2α can significantly drive mouse ESCs to form cardiomyocytes. Contrarily, knockdown of HIF2α inhibits the emergence of cardiac cells. In addition, the cardiomyogenesis-promoting effect of HIF2α occurred by increasing the protein level of β-catenin, an effector that contributes to cardiac differentiation at an early stage of ESC differentiation.

Conclusion: HIF2α has a cardiomyogenesis-promoting effect in ESCs via enhancing the activation of the Wnt/β-catenin signaling pathway. Our results may be beneficial for generating and applying cardiomyocytes from ESCs safely and effectively in the future.

Download full-text PDF

Source
http://www.translational-medicine.com/content/13/1/88
Publisher Site
http://dx.doi.org/10.1186/s12967-015-0447-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399227PMC
March 2015
Get 20% Off Journals at LWW.com

Similar Publications

Effect of oxygen on cardiac differentiation in mouse iPS cells: role of hypoxia inducible factor-1 and Wnt/beta-catenin signaling.

PLoS One 2013 12;8(11):e80280. Epub 2013 Nov 12.

Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

Background: Disturbances in oxygen levels have been found to impair cardiac organogenesis. It is known that stem cells and differentiating cells may respond variably to hypoxic conditions, whereby hypoxia may enhance stem cell pluripotency, while differentiation of multiple cell types can be restricted or enhanced under hypoxia. Here we examined whether HIF-1alpha modulated Wnt signaling affected differentiation of iPS cells into beating cardiomyocytes. Read More

View Article and Full-Text PDF
July 2014

Temporal modulation of β-catenin signaling by multicellular aggregation kinetics impacts embryonic stem cell cardiomyogenesis.

Stem Cells Dev 2013 Oct 14;22(19):2665-77. Epub 2013 Jun 14.

1 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University , Atlanta, Georgia .

Pluripotent stem cell differentiation recapitulates aspects of embryonic development, including the regulation of morphogenesis and cell specification via precise spatiotemporal signaling. The assembly and reorganization of cadherins within multicellular aggregates may similarly influence β-catenin signaling dynamics and the associated cardiomyogenic differentiation of pluripotent embryonic stem cells (ESCs). In this study, dynamic changes in β-catenin expression and transcriptional activity were analyzed in response to altered cell adhesion kinetics during embryoid body (EB) formation and differentiation. Read More

View Article and Full-Text PDF
October 2013

Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis.

Proc Natl Acad Sci U S A 2006 Dec 14;103(52):19812-7. Epub 2006 Dec 14.

Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Although Wingless (Wg)/Wnt signaling has been implicated in heart development of multiple organisms, conflicting results have been reported regarding the role of Wnt/beta-catenin pathway in cardiac myogenesis: Wg/armadillo signaling promotes heart development in Drosophila, whereas activation of Wnt/beta-catenin signaling inhibits heart formation in avians and amphibians. Using an in vitro system of mouse ES cell differentiation into cardiomyocytes, we show here that Wnt/beta-catenin signaling exhibits developmental stage-specific, biphasic, and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis. Activation of the Wnt/beta-catenin pathway in the early phase during embryoid body (EB) formation enhances ES cell differentiation into cardiomyocytes while suppressing the differentiation into hematopoietic and vascular cell lineages. Read More

View Article and Full-Text PDF
December 2006

Klf2 and Tfcp2l1, Two Wnt/β-Catenin Targets, Act Synergistically to Induce and Maintain Naive Pluripotency.

Stem Cell Reports 2015 Sep 28;5(3):314-22. Epub 2015 Aug 28.

Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, University of Southern California, Los Angeles, CA 90033, USA. Electronic address:

Activation of Wnt/β-catenin signaling can induce both self-renewal and differentiation in naive pluripotent embryonic stem cells (ESCs). To gain insights into the mechanism by which Wnt/β-catenin regulates ESC fate, we screened and characterized its downstream targets. Here, we show that the self-renewal-promoting effect of Wnt/β-catenin signaling is mainly mediated by two of its downstream targets, Klf2 and Tfcp2l1. Read More

View Article and Full-Text PDF
September 2015