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  • The following are the supplementary data related to this

    2018-10-26

    The following are the supplementary data related to this article.
    Conflict-of-interest disclosure
    Acknowledgments The authors would like to thank Ms. Kathleen Makielski for proofreading the manuscript. This work was supported by National Natural Science Foundation of China (grant number 81372627), Science and Technology Project for Innovation Leaders of Changsha (grant number K1501029-31), National Basic Research Program of China (973 program, grant numbers 2011CB964901, 2012CB944901), the Ministry of Science and Technology of China (863 program, grant number 2011AA020113), Natural Science Foundation of Hunan Province (grant number 13JJ3038).
    Introduction Human pluripotent stem BLU 9931 (HPSCs) present a promising therapeutic approach for a number of conditions, owing to their indisputable and varied ability to differentiate into many cell types (Takahashi et al., 2007; Xu et al., 2015; Qiu et al., 2015). Human cardiomyocytes derived from pluripotent stem cells (hPSC-CMs), provide a promising cell resource in future cell-based therapies for heart infarction treatments (Caspi et al., 2007; Chong et al., 2014; Laflamme et al., 2007; Matsa et al., 2014; Shiba et al., 2012; van Laake et al., 2007). Although hPSC-CMs have been successfully transplanted into non-human primate (monkey) models for heart repair (Chong et al., 2014), issues such as differences in cardio-physiology between species, and immuno-rejection, continue to hinder the long-term observation and accurate evaluation of cell transplantation therapies. The use of monkey iPSC-CMs in cell-based heart repair research with a monkey model, especially the same individual, would therefore avoid these issues. Because monkeys share a high degree of genetic, anatomic, physiological, and cardiological similarity with humans (Oishi et al., 2014; Han et al., 2007; Hosseinkhani et al., 2007a,b; Khaitovich et al., 2005), they represent an ideal in vivo model for drug testing. Furthermore, monkey iPSC-CMs would provide a good cellular model for in vitro drug testing. The combination of monkey iPSC-CMs and primate models for drug discovery could provide a two dimensional strategy for assessing heart-related drugs. More research efforts are underway for the cardiac differentiation of hPSCs, which can be efficiently induced into CMs using growth factors or small molecules that regulate Wnt signaling (Lian et al., 2012; Mummery et al., 2012; Yang et al., 2008). Moreover, hPSCs can be directionally differentiated into high homogeneous atrial and ventricular CMs by manipulating the retinoic acid pathway after mesodermal cell formation (Gassanov et al., 2008; Xavier-Neto et al., 1999; Zhang et al., 2011). Conversely, research has shown that even though monkey CMs can differentiate from monkey ESCs, which were cultured on mouse embryonic fibroblast (MEF) feeder cells, using an embryoid body (EB) based approach, the differentiation efficiency and purity cannot satisfy the amount of cells needed for transplantation studies and large-scale drug discovery (Hosseinkhani et al., 2007a,b; Chen et al., 2008; Schwanke et al., 2006). Here we report that rhesus iPSCs (riPSCs) were generated successfully from rhesus monkey dermal fibroblasts using episomal vectors to deliver human genes (Okita et al., 2011). To support efficient growth of these cells, we developed a feeder-free culture system which supported riPSCs long-term self-renewal. These cells were further differentiated into atrial and ventricular CMs using the small molecules, CHIR99021 (glycogen synthase kinase 3 inhibitor), IWR-1 (Wnt pathway inhibitor), and RA/BMS493 (RA pathway inhibitor). The riPSC-CMs possessed human cardiomyocyte characteristics, including cardiac-specific gene expression, electrophysiology and chronotropic drug response. These characteristics make riPSC-CMs an ideal cell type for studies of human heart regenerative therapy and drug discovery.