Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages

Abstract

The purification, renewal and differentiation of native cardiac progenitors would form a mechanistic underpinning for unravelling steps for cardiac cell lineage formation, and their links to forms of congenital and adult cardiac diseases. Until now there has been little evidence for native cardiac precursor cells in the postnatal heart. Herein, we report the identification of isl1+ cardiac progenitors in postnatal rat, mouse and human myocardium. A cardiac mesenchymal feeder layer allows renewal of the isolated progenitor cells with maintenance of their capability to adopt a fully differentiated cardiomyocyte phenotype. Tamoxifen-inducible Cre/lox technology enables selective marking of this progenitor cell population including its progeny, at a defined time, and purification to relative homogeneity. Co-culture studies with neonatal myocytes indicate that isl1+ cells represent authentic, endogenous cardiac progenitors (cardioblasts) that display highly efficient conversion to a mature cardiac phenotype with stable expression of myocytic markers (25%) in the absence of cell fusion, intact Ca2+-cycling, and the generation of action potentials. The discovery of native cardioblasts represents a genetically based system to identify steps in cardiac cell lineage formation and maturation in development and disease.

Migration of Resident Cardiac Stem Cells in Myocardial Infarction

“…Cardiac stem/progenitor cells expressing LIM homeodomain transcriptional factor Islet-1 (Isl-1 þ ) were recently identified by Laugwitz and colleagues (Laugwitz et al, 2005). These Isl-1 þ cells were isolated from very young animals, do not express c-kit but harbor cardiomyogenic potential both in vitro and in vivo.…”

“…Mouse and human c-kit þ , CD31 þ , CD34 þ c-kit, CXCR4 Messina et al, 2004;Davis et al, 2009;Smith et al, 2007;Tang et al, 2009 Isl Laugwitz et al, 2005;Weinberger et al, 2012 CSCs, cardiac stem cells; CSP, cardiac side population.…”

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

“…22 Laugwitz et al 23 demonstrated the presence of an Isl-1 + population of cardiac stem cells in the postnatal mouse, rat, and human heart, most prominently in the outflow tract and right atrium. Further studies showed that Isl-1 marks a population of multipotent cardiac stem cells contributing to smooth muscle, endothelial, and pacemaker cell lineages in the embryonic and postnatal heart 24,25 and implicate Isl-1 + Nkx2.5 + Flk-1 + cells as the most primitive cardiac stem cells.…”

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

“…56,57 Another group of resident cardiac progenitor cells is characterized by the expression of the antigen 'islet 1' (isl1), and these isl1+ cells develop into cells with a mature cardiac phenotype including intact Ca 2+ -cycling and the generation of action potentials. 58 As mentioned earlier, SP cells can be isolated from the heart, and thus constitute a fifth cardiac progenitor phenotype that can acquire an adult cardiomyocyte phenotype when placed in a permissive environment. 42,43 Finally, cells have been isolated from myocyte depleted fractions of murine and human atria and ventricles that form spheres when cultured in 'cardiosphere growing medium'.…”