29 Harnessing developmental cues for cardiomyocyte production 2 INTRODUCTION Heart failure often results from the irreversible loss of functional myocardium or malfunctioning of the individual cardiomyocytes that comprise this tissue (De Boer et al., 2003; Fox et al., 2001; Gerber et al., 2000). This loss of functional cardiomyocytes can be acute or gradual and results in adverse remodeling of the remaining healthy myocardium (Olivetti et al., 1997; Saraste et al., 1997). In turn, myocardial dysfunction results in mechanical stress and upregulation of factors including angiotensin and norepinephrine, which all act to further promote detrimental myocardial remodeling (Colucci, 1997; Adhyapak, 2022). These alterations to extracellular matrix composition, cytoskeletal architecture and cell-cell connections occur in parallel with changes to the cardiac gene profile, such as reinduction of a fetal gene program (Parker et al., 1990; Bray et al., 2008). Although clinical therapies for heart failure have significantly improved with multiple lines of heart failure drugs and mechanical circulatory support devices (Cook et al., 2015; Mancini and Burkhoff, 2005; Shen et al., 2022; Ponikowski et al., 2016), these treatments do not repair or replace malfunctioning myocardium. A central hurdle is that the adult heart is a largely postmitotic organ, where annual turnover is between 1-2% in young adults, and less than 0.5% in older adults (Bergmann et al., 2009; 2015). Thus, it is unsurprising that the adult heart lacks regenerative capacity post injury. In contrast, before birth, expansion of fetal cardiomyocytes is crucial for proper cardiogenesis and is tightly regulated by Wnt and Hippo signaling, with varying cardiomyocyte proliferation rates depending on location and developmental stage (Drenckhahn et al., 2008; Sturzu et al., 2015; Buikema et al., 2013; Rochais et al., 2009; von Gise et al., 2012; Qyang et al., 2007). Remarkably, the early postnatal mammalian heart possesses regenerative potential (Haubner et al., 2016), but this regenerative response is lost 1 week after birth and scar tissue is formed in response to injury instead (Porrello et al., 2011; Ye et al., 2018; Zhu et al., 2018b). Translational cardiology aims to repair or replace a broken heart with autologous material (Laflamme and Murry, 2011; Ptaszek et al., 2012). The advent of patient-specific pluripotent stem cell sources represented a major advance for the field (Burridge et al., 2012), but the generation of large numbers of functional cardiomyocytes remains challenging due to their low proliferative rates (Tani et al., 2022). Here, we review how lessons from in vivo cardiomyocyte proliferation during mammalian cardiac development have been translated into technology to generate cardiomyocytes from human pluripotent stem cell sources. LESSONS FROM CARDIAC DEVELOPMENT Mesoderm formation During development, most heart structures arise from the mesodermal germ layer. Mesoderm formation takes place at Carnegie stages (CS) 6-7 in humans and embryonic day (E) 6.5 in
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