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  • It has been proposed that the beneficial effects of cell

    2018-11-06

    It has been proposed that the beneficial effects of cell-based therapies might be mediated via several direct and indirect mechanisms, including recruitment of endogenous progenitors, differentiation into functional cardiomyocytes and vascular cells, induction of angiogenesis, promotion of perfusion, reduction of fibrosis and inhibition of apoptosis (Vunjak-Novakovic et al., 2011; Sanganalmath and Bolli, 2013; Loffredo et al., 2011). These repair processes are, in fact, mediated by proteins and small molecules and, therefore, replenishing the damaged heart with therapeutic paracrine factors in vivo may be sufficient to directly activate repair mechanisms, opening a new avenue to regenerative medicine without cellular transplantation (for a review, see Green and Lee, 2013). To search for these therapeutic paracrine factors, we can learn from the ischemic heart which secretes “Mayday” signals (e.g. stromal cell-derived factor-1) for recruiting progenitor oxyntomodulin Supplier that express the homing receptor (e.g. CXCR4) and home to the peri-infarct zone (Segers et al., 2007); or from studies using heterochronic parabiosis, a surgical technique in which joining of two mice leads to a shared circulation, that identified rejuvenative circulating factors (e.g. growth differentiation factor 11) secreted by the young, healthy mice which could improve cardiac function in old mice with age-related cardiac hypertrophy (Loffredo et al., 2013). Moreover, we may also learn from a growing human fetal heart to identify paracrine factors (e.g. vascular endothelial growth factor, VEGF) responsible for proliferation of endogenous cardiac progenitor cells (Lui et al., 2013; Qyang et al., 2007) and their subsequent differentiation into different cellular lineages of the heart, namely cardiomyocytes, and smooth muscle and endothelial cells.
    Lineage-mapping studies: searching for therapeutic paracrine factors during cardiogenesis Over the past four decades, hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) (Nemir et al., 2012) have been commercially available for clinical use to treat granulocytopenias, anemia, and neutropenia in patients with malignancies or congenital bone marrow failure (Groopman et al., 1989; Vose and Armitage, 1995). Indeed, there is a tightly-regulated network of hematopoietic growth factors or cytokines secreted by immune cells, including G-CSF, M-CSF, GM-CSF, EPO, stem-cell factor (SCF), interleukins, interferons and tumor necrosis factor. These paracrine factors are involved in self-renewal, mobilization and differentiation of hematopoietic stem cells, and in maturation and activation of their differentiated myeloid or lymphoid cells to maintain proper functions of the immune system. Similar to hematopoietic stem cells, multipotent cardiovascular progenitor cells are also capable of differentiating into different cellular lineages of the heart such as cardiomyocytes, pacemaker cells, smooth muscle cells and endothelial cells during mammalian cardiogenesis. Recent advances in the cre/lox technology enable us to identify distinct cardiovascular progenitor cells and label their derivatives in murine lineage-tracing models. The heart develops from defined multipotent cardiovascular progenitor cells located at the first heart field marked by expression of Tbx5 and Nkx2.5 (Herrmann et al., 2011); the second heart field marked by expression of Isl1 (Qyang et al., 2007; Laugwitz et al., 2005; Moretti et al., 2006); and the epicardium and epicardium-derived progenitor cells (EPDCs) are marked by expression of WT1 (Smart et al., 2011; Zangi et al., 2013; Zhou et al., 2008) (Fig. 1). These progenitors are capable of differentiating into the three major cellular lineages of the heart including cardiomyocytes, and smooth muscle and endothelial cells as demonstrated by lineage-tracing experiments. Despite the discovery of these multipotent cardiovascular progenitor cells, which are capable of further differentiating into mature cardiac muscle with intact calcium dynamics and action potentials (Laugwitz et al., 2005), clinical application of the embryonic Tbx5+, Nkx2.5+ or Isl1+ cardiovascular progenitor cells for autologous cell-based therapy is limited by their absence in the adult heart. In the normal adult heart, there is an endogenous pool of WT1+ EPDCs, albeit the numbers are very low (Smart et al., 2011; Zangi et al., 2013; Zhou et al., 2011). The WT1+ EPDCs readily differentiate into cardiac fibroblasts and smooth muscle cells, but have limited capacity to form endothelial cells, and make little, if any, contribution to cardiomyocytes in both the normal and infarcted adult hearts (Smart et al., 2011; Zangi et al., 2013; Zhou et al., 2011). Additional factors such as thymosin beta-4 (Smart et al., 2011) and VEGFA (Zangi et al., 2013) have been used to amplify the endogenous WT1+ EPDCs and activate their cardiac differentiation potential following MI.