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    • The identification of progenitor populations in the adult he

    2018-11-08

    The identification of progenitor populations in the adult heart adds increased complexity to heart development, and raises many interesting questions – for example, are fetal or adult CPCs remnants of earlier embryonic progenitors, have they migrated in from other sources, or have they arisen de novo after dedifferentiation of CMs or other more differentiated cells? A fascinating possibility is that stem cell states can exist in latent form, to be stimulated under certain conditions (Asli and Harvey, 2013). Indeed, the concept of “facultative” stem cells, which are thought to arise from more differentiated FK506 under non-physiological conditions, is gaining traction (Ziv et al., 2013). Fate mapping strategies have been crucial for developing our current understanding of embryonic progenitors and will continue to be important for forging our views on newly identified adult CPC populations.
    Diversity of adult cardiovascular lineages CMs, stromal fibroblasts, vascular and lymphatic endothelial, mural and adventitial cells, myofibroblasts, neurons and immune cells comprise the major cell types of the heart. The relative proportions of these cells vary significantly throughout development and between species. The adult mouse heart is thought to comprise ~56% CMs, 27% fibroblasts, 7% endothelial cells and 10% vascular smooth muscle cells (Banerjee et al., 2007). Cardiac stromal cells, generically termed fibroblasts, remain one of the most poorly characterized cell types in the heart (Davis and Molkentin, 2014). The distinction between fibroblast subtypes based on markers expression, physiologic function or origin is not well advanced (Krenning et al., 2010). The same applies to perivascular cell compartments, which include the autonomic nerves (Hogan and Bautch, 2004; Majesky, 2007; Majesky et al., 2011). There are many studies over the previous decades suggesting multi-lineage potency within the pericyte population and mesenchymal stem/progenitor cell activity within BM and other organs has been claimed to lie within the pericyte fraction (Chen et al., 2013). The vascular adventitia has been proposed to provide a niche for stem/progenitor cells that contribute to more mature vascular cell types (Campagnolo et al., 2010; Chong et al., 2011; Passman et al., 2008). Vascular ECs may also be subdivided based on function; for example, the endocardium and coronary vessels are thought to harbor or nurture cells that give rise to blood cells (Nakano et al., 2013; Zape and Zovein, 2011) and mesenchymal stem-like cells (Azzoni et al., 2014). Stem cell-like plasticity has also been suggested for coronary endothelium (Bearzi et al., 2007; Zheng et al., 2007).
    Lineage tracing and cardiac physiological turnover As extensively reviewed elsewhere in this Special Issue of Stem Cell Research, the long-standing dogma of the mammalian heart as a terminally differentiated organ with little regenerative reserve has been revised over the past decades. Despite poor regenerative capacity after ischemic injury, numerous studies now show a certain degree of CM turnover in adult mammalian hearts, albeit the extent of turnover and the origin of physiological cell replacement are still highly debated topics. The estimated homeostatic CM turnover ranges from 1 to 4% (Bergmann et al., 2009; Malliaras et al., 2013b; Senyo et al., 2013) to over 40% per year (Kajstura et al., 2010), and both proliferative CMs (Bersell et al., 2009; Malliaras et al., 2013b; Senyo et al., 2013) and cardiac-resident adult progenitor cells (Anversa et al., 2013; Ellison et al., 2013; Uchida et al., 2013; van Berlo et al., 2014) have been cited as the source of regenerative reserve. Needless to say, the degree and mechanisms of heart regeneration in mammals and other species are under intense scrutiny, as is the potential for awakening lost regenerative potential.
    Cardiac mesoangioblasts Mesoangioblasts were defined as clonal vessel-derived cells that have skeletal myogenic activity, with the highest concentration in the aorta (De Angelis et al., 1999). The presence of a vascular reservoir that can replenish satellite cells after transplantation has been supported by a number of studies (Bentzinger et al., 2013). Mesoangioblast cultures express stem cell markers C-KIT and SCA-1, and a number of endothelial cell markers, which may explain their ability to efficiently extravasate from vessels into damaged muscle (Bentzinger et al., 2013). When labeled quail or mouse aortas were grafted into host embryos, vessel-derived cells were found dispersed in a variety of mesodermal tissues, including blood, cartilage, bone, SM, and skeletal and cardiac muscle (Minasi et al., 2002). It has been suggested that mesoangioblasts represent broadly potent perivascular mesenchymal stem cells, potentially derived from endothelial cells, important for both developmental organogenesis and tissue repair in the adult via invading vascular networks (Bianco and Cossu, 1999). This concept is derivative of the idea that vessel walls provide a niche for a variety of stem cell populations.