Sca-1+ cardiosphere-derived cells are enriched for Isl1-expressing cardiac precursors and improve cardiac function after myocardial injury.

Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
PLoS ONE (Impact Factor: 3.53). 01/2012; 7(1):e30329. DOI: 10.1371/journal.pone.0030329
Source: PubMed

ABSTRACT Endogenous cardiac progenitor cells are a promising option for cell-therapy for myocardial infarction (MI). However, obtaining adequate numbers of cardiac progenitors after MI remains a challenge. Cardiospheres (CSs) have been proposed to have cardiac regenerative properties; however, their cellular composition and how they may be influenced by the tissue milieu remains unclear.
Using "middle aged" mice as CSs donors, we found that acute MI induced a dramatic increase in the number of CSs in a mouse model of MI, and this increase was attenuated back to baseline over time. We also observed that CSs from post-MI hearts engrafted in ischemic myocardium induced angiogenesis and restored cardiac function. To determine the role of Sca-1(+)CD45(-) cells within CSs, we cloned these from single cell isolates. Expression of Islet-1 (Isl1) in Sca-1(+)CD45(-) cells from CSs was 3-fold higher than in whole CSs. Cloned Sca-1(+)CD45(-) cells had the ability to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro. We also observed that cloned cells engrafted in ischemic myocardium induced angiogenesis, differentiated into endothelial and smooth muscle cells and improved cardiac function in post-MI hearts.
These studies demonstrate that cloned Sca-1(+)CD45(-) cells derived from CSs from infarcted "middle aged" hearts are enriched for second heart field (i.e., Isl-1(+)) precursors that give rise to both myocardial and vascular tissues, and may be an appropriate source of progenitor cells for autologous cell-therapy post-MI.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Stem cell therapy has the potential to regenerate heart tissue after myocardial infarction (MI). The regeneration is dependent upon cardiac differentiation of the delivered stem cells. We hypothesized that timing of the stem cell delivery determines the extent of cardiac differentiation as cell differentiation is dependent on matrix properties such as biomechanics, structure and morphology, and these properties in cardiac extracellular matrix continuously vary with time after MI. Towards elucidating the relationship between ECM properties and cardiac differentiation, we created an in vitro model based on ECM-mimicking fibers and a type of cardiac progenitor cell, cardiosphere-derived cells (CDCs). A simultaneous fiber electrospinning and cell electrospraying technique was utilized to fabricate constructs. By blending a highly soft hydrogel with a relatively stiff polyurethane and modulating fabrication parameters, tissue constructs with similar cell adhesion property but different global modulus, single fiber modulus, fiber density, and fiber alignment were achieved. The CDCs remained alive within the constructs during a 1-week culture period. CDC cardiac differentiation was dependent on the scaffold modulus, fiber volume fraction, and fiber alignment. Two constructs with relatively low scaffold modulus ∼50-60 kPa most significantly directed the CDC differentiation into mature cardiomyocytes as evidenced by gene expressions of cardiac troponin T (cTnT), calcium channel (CACNA1c) and cardiac myosin heavy chain (MYH6), and protein expressions of cardiac troponin I (cTnI) and connexin 43 (CX43). Of these two low modulus constructs, the extent of differentiation was greater for lower fiber alignment and higher fiber volume fraction. These results suggest that cardiac ECM properties may have an effect on cardiac differentiation of delivered stem cells.
    Acta biomaterialia 04/2014; 10(8). DOI:10.1016/j.actbio.2014.04.018 · 5.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The identification, in the adult, of cardiomyocyte (CM) turnover events and of cardiac progenitor cells (CPCs) has revolutionized the field of cardiovascular medicine. However, the low rate of CPCs differentiation events reported both in vitro and in vivo, even after injury, raised concerns on the biological significance of these subsets. In this Comprehensive Review, we discuss the current understanding of cardiac Lin-Sca-1+ cells in light of what is also known for similar phenotype cell-compartments in other organs.
    Stem Cells and Development 06/2014; DOI:10.1089/scd.2014.0197 · 4.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The adult mammalian heart was once believed to be a post-mitotic organ without any capacity for regeneration, but recent findings have challenged this dogma. A modified view assigns the mammalian heart a measurable capacity for regeneration throughout its lifetime, with the implication that endogenous regenerative capacity can be therapeutically stimulated in the injury setting. Although extremely limited in adult mammals, the natural capacity for organ regeneration is a conserved trait in certain vertebrates. Urodele amphibians and teleosts are well known examples of such animals that can efficiently regenerate various organs including the heart as adults. By understanding how these animals regenerate a damaged heart, one might obtain valuable insights into how regeneration can be augmented in injured human hearts. Among the regenerative vertebrate models, the teleost zebrafish, Danio rerio, is arguably the best characterized with respect to cardiac regenerative responses. Knowledge is still limited, but a decade of research in this model has led to results that may help to understand how cardiac regeneration is naturally stimulated and maintained. This review surveys recent advances in the field and discusses current understanding of the endogenous mechanisms of cardiac regeneration in zebrafish.
    Stem Cell Research 07/2014; DOI:10.1016/j.scr.2014.07.003 · 3.91 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014