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    • The myocardium lacks the basal apical orientation typical of

    2018-11-08

    The myocardium lacks the basal–apical orientation typical of epithelial organs making it difficult to delineate the precise localization of CSC niches. The epicardial lining has been employed to define anatomically several classes of niches in the adult heart (Castaldo et al., 2008; Di Meglio et al., 2010a, 2010b; Kocabas et al., 2012; Limana et al., 2007, 2010; Smart et al., 2011; Zhou et al., 2008). However, cardiac niches are not limited to the subepicardium and are dispersed throughout the myocardium (Urbanek et al., 2006). CSC niches are more numerous in the atria and apex, which represent protected anatomical areas characterized by low hemodynamic stress (Boni et al., 2008; Goichberg et al., 2011; Gonzalez et al., 2008; Hosoda et al., 2009; Sanada et al., 2014; Urbanek et al., 2006, 2010). The process of myocyte formation lacks directionality; the scattered distribution of the sites of cardiomyogenesis complicates the demonstration of the topography of cardiac niches. The analysis of cardiac niches becomes problematic if we consider that the strategies used for the depletion of bone marrow niches cannot be implemented in the heart. The protocol of lethal and sub-lethal irradiation of the bone marrow does not result in effective ablation of CSCs in the myocardium, preventing the possibility of repopulating empty niches with fluorescently labeled stem cells. Because of its physical properties, the carboxypeptidase b is affected only when 30Gy units of absorbed radiation are utilized. This dose is more than 3-fold higher than that used in the bone marrow and results in profound alterations of the myocardium, diffuse myocyte apoptosis, and high animal mortality (Leri et al., 2007).
    c-kit-positive cells and cardiac niches To establish whether CSC niches are present in the myocardium and whether CSC number is tightly regulated within the niches, the young mouse heart was studied initially by a morphometric approach (Urbanek et al., 2006). The niche was defined as a randomly oriented ellipsoid structure constituted by cellular and extracellular components (Fig. 2A). Within the niches, lineage-negative CSCs are typically clustered together with early committed cells, which continue to express the c-kit receptor but show nuclear localization of the myocyte transcription factor Nkx2.5 and cytoplasmic distribution of the contractile protein α-sarcomeric actin (Fig. 2B). The number of CSCs is higher in the atrial and apical myocardium than in the base-mid-region of the young and old heart (Fig. 2C) (Sanada et al., 2014; Urbanek et al., 2006). The recognition of the anatomical localization of CSCs and their distribution in the cardiac chambers was complemented with functional studies, which were required for understanding the growth kinetics of CSCs in vivo. The transplantation assay, which involves the creation of tissue damage and the injection of exogenous stem cells, is commonly employed. CSCs engraft within the infarcted myocardium, expand their pool and differentiate in cardiomyocytes and coronary vessels (Bearzi et al., 2007; Beltrami et al., 2003; Ellison et al., 2014; Fischer et al., 2009; Konstandin et al., 2013; Mohsin et al., 2012; Smart et al., 2011; Williams et al., 2013). Additionally, a large quantity of newly-formed undifferentiated CSCs can be acquired and delivered to subsequent recipients forming both primitive and specialized muscle cells and vascular structures. This methodology, however, leaves open the question whether the properties displayed by the administered cells are intrinsic to the stem cells or are influenced by the organ injury. Information concerning CSC function in the intact myocardium involves labeling of resident stem cells with nucleotide analogs or lentiviral fluorescent tags (Gonzalez et al., 2008; Hosoda et al., 2009; Sanada et al., 2014; Urbanek et al., 2006). The slow rate of proliferation of stem cells allows their identification within their natural milieu and the evaluation of their committed progeny (Braun et al., 2003). The administration of repeated doses of nucleotide analogs such as BrdU or 3[H]-thymidine results in labeling of cycling cells (Braun et al., 2003). These molecules are incorporated in the nuclei during S-phase. A prolonged chase period leads to the dilution of the label in cells that are rapidly replicating and its maintenance in cells that are rarely or slowly cycling. Thus, the growth and phenotypic changes occurring in CSCs during their transition from an undifferentiated to a specialized compartment can be characterized.