**4. BMP induction of stem cells and progenitor cells to a cardiac fate**

Controlled differentiation of stem cells has relevance in translational research for pre-clinical cell grafting and for establishing cardiomyocyte cultures for drug discovery and toxicology. As primary inducers of cardiac differentiation, BMP cytokines have important roles in growth factor-based stem cell therapies for cardiac tissue repair. Use of growth factor peptides to induce cardiac muscle formation from embryonic stem (ES) cells has been researched for over a decade. BMP ligands have been proven to be important inductors of cardiac fate in multiple ES cell types. In mouse ES cells (mESC), BMP2 or BMP4 can activate cardiac differentiation, in combination with other factors such as Activin A or fibroblast growth factor 2 (FGF2) (Johansson and Wiles 1995; Kawai et al. 2004; Behfar et al. 2002). In the pluripotent mouse embryonal carcinoma cell line, P19C16, treatment with BMP4 promotes cardiomyocyte formation and expression of α-MHC (Monzen et al. 1999; Monzen et al. 2001). Addition of noggin, a BMP inhibitor, prevents differentiation and this can be abolished by overexpressing BMP2, or SMAD1 and SMAD4 (Monzen et al. 1999; Monzen et al. 2001). In human ES cells (hESC), BMP4 promotes a cardiac fate (Takei et al. 2009; Kattman et al. 2011). BMP stimulation induces *Sox17* expression, which is important for directing mesoderm toward a cardiac fate (Stefanovic et al. 2009). Addition of BMP2 or BMP4 in hESC, along with Activin A and other factors, can reliably induce multipotent cardiovascular progenitors that can generate multiple cell lineages such as cardiomyocytes, smooth muscle cells, and endothelial cells *in vitro* and *in vivo* (Laflamme et al. 2007; Tomescot et al. 2007; Yang et al. 2008; Liu et al. 2007). Human induced pluripotent stem cells (iPSC) can also be induced to undergo cardiomyogenesis using similar multistep additions of factors, including BMP4 (Takahashi et al. 2007; Carvajal-Vergara et al. 2010; Kattman et al.

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