Sca-1 negatively regulates proliferation and differentiation of muscle cells

Department of Cell Biology, Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Developmental Biology (Impact Factor: 3.55). 08/2005; 283(1):240-52. DOI: 10.1016/j.ydbio.2005.04.016
Source: PubMed


Satellite cells are tissue-specific stem cells critical for skeletal muscle growth and regeneration. Upon exposure to appropriate stimuli, satellite cells produce progeny myoblasts. Heterogeneity within a population of myoblasts ensures that a subset of myoblasts readily differentiate to form myotubes, whereas other myoblasts remain undifferentiated and thus available for future muscle growth. The mechanisms that contribute to this heterogeneity in myoblasts are largely unknown. We show that satellite cells are Sca-1(neg) but give rise to myoblasts that are heterogeneous for sca-1 expression. The majority of myoblasts are sca-1(neg), rapidly divide, and are capable of undergoing myogenic differentiation to form myotubes. In contrast, a minority population is sca-1(pos), divides slower, and does not readily form myotubes. Sca-1 expression is not static but rather dynamically modulated by the microenvironment. Gain-of-function and loss-of-function experiments demonstrate that sca-1 has a functional role in regulating proliferation and differentiation of myoblasts. Myofiber size of sca-1 null muscles is altered in an age-dependent manner, with increased size observed in younger mice and decreased size in older mice. These studies reveal a novel system that reversibly modulates the myogenic behavior of myoblasts. These studies provide evidence that, rather than being a fixed property, myoblast heterogeneity can be modulated by the microenvironment.

Download full-text


Available from: Grace K Pavlath, Feb 15, 2014
21 Reads
  • Source
    • "However, the in vitro study of stem cells often does not consider a niche environment. Rather, attempts to study stem cells have predominantly focused on the isolation of purified subsets of cells with specific markers or functions12345678910. Yet, several reports suggest that a population level exists for various stem cell types including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs)111213and muscle stem cells14151617181920. In support of this, several groups have shown that an individual cell from a stem cell population can re-establish the heterogeneous parent population2122232425. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding stem cell (SC) population dynamics is essential for developing models that can be used in basic science and medicine, to aid in predicting cells fate. These models can be used as tools e.g. in studying patho-physiological events at the cellular and tissue level, predicting (mal)functions along the developmental course, and personalized regenerative medicine. Using time-lapsed imaging and statistical tools, we show that the dynamics of SC populations involve a heterogeneous structure consisting of multiple sub-population behaviors. Using non-Gaussian statistical approaches, we identify the co-existence of fast and slow dividing subpopulations, and quiescent cells, in stem cells from three species. The mathematical analysis also shows that, instead of developing independently, SCs exhibit a time-dependent fractal behavior as they interact with each other through molecular and tactile signals. These findings suggest that more sophisticated models of SC dynamics should view SC populations as a collective and avoid the simplifying homogeneity assumption by accounting for the presence of more than one dividing sub-population, and their multi-fractal characteristics.
    Scientific Reports 04/2014; 4:4826. DOI:10.1038/srep04826 · 5.58 Impact Factor
  • Source
    • "Plasmids PM4 (which encodes a retroviral vector containing the cDNA for Ly6a/Sca-1 as well as the eGFP and zeocin resistance gene cDNAs) and pTJ66 (the control plasmid which encodes a retroviral vector that contains eGFP and zeocin resistance cDNAs) were gifts of Dr. G. K. Pavlath of Emory University [17]. Retrovirus was produced by lipofectamine facilitated transient transfection of helper-free retroviral vector producer Phoenix cell lines with plasmids PM4 or pTJ66. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stem cell antigen-1 (Ly6a/Sca-1) is a gene that is expressed in activated lymphocytes, hematopoietic stem cells and stem cells of a variety of tissues in mice. Despite decades of study its functions remain poorly defined. These studies explored the impact of expression of this stem cell associated gene in acute lymphoid leukemia. Higher levels of Ly6a/Sca-1 expression led to more aggressive leukemia growth in vivo and earlier death of hosts. Leukemias expressing higher levels of Ly6a/Sca-1 exhibited higher levels of matrix metalloproteinases. The results suggest the hypothesis that the more aggressive behavior of Ly6a/Sca-1 expressing leukemias is due at least in part to greater capacity to degrade microenvironmental stroma and invade tissues.
    PLoS ONE 02/2014; 9(2):e88966. DOI:10.1371/journal.pone.0088966 · 3.23 Impact Factor
  • Source
    • "Previous reports with limb muscles demonstrated that the bulk of satellite cells could be isolated from " crude " cell preparations (i.e., released from skeletal muscle by enzymatic dissociation) based on triple negative selection for CD31, CD45 and Sca1 and positive selection for CD34 and α7-integrin cell surface antigens (Ieronimakis et al., 2010; Sacco et al., 2008). Furthermore, additional studies performed in the context of limb muscle revealed a rare subpopulation of Sca1 þ satellite cells (Mitchell et al., 2005; Tanaka et al., 2009). The number of such Sca1 þ myogenic cells increased in regenerating muscle, possibly related to satellite cell proliferation (Kafadar et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Extraocular muscles (EOM) represent a unique muscle group that controls eye movements and originates from head mesoderm, while the more typically studied body and limb muscles are somite-derived. Aiming to investigate myogenic progenitors (satellite cells) in EOM versus limb and diaphragm of adult mice, we have been using flow cytometry in combination with myogenic-specific Cre-loxP lineage marking for cell isolation. While analyzing cells from the EOM of mice that harbor Myf5(Cre)-driven GFP expression, we identified in addition to the expected GFP(+) myogenic cells (presumably satellite cells), a second dominant GFP(+) population distinguished as being Sca1(+), non-myogenic, and exhibiting a fibro/adipogenic potential. This unexpected population was not only unique to EOM compared to the other muscles but also specific to the Myf5(Cre)-driven reporter when compared to the MyoD(Cre) driver. Histological studies of periocular tissue preparations demonstrated the presence of Myf5(Cre)-driven GFP(+) cells in connective tissue locations adjacent to the muscle masses, including cells in the vasculature. These vasculature-associated GFP(+) cells were further identified as mural cells based on the presence of the specific XLacZ4 transgene. Unlike the EOM satellite cells that originate from a Pax3-negative lineage, these non-myogenic Myf5(Cre)-driven GFP(+) cells appear to be related to cells of a Pax3-expressing origin, presumably derived from the neural crest. In all, our lineage tracing based on multiple reporter lines has demonstrated that regardless of common ancestral expression of Myf5, there is a clear distinction between periocular myogenic and non-myogenic cell lineages according to their mutually exclusive antecedence of Pax3 and MyoD gene activity.
    Developmental Biology 08/2013; 385(2). DOI:10.1016/j.ydbio.2013.08.010 · 3.55 Impact Factor
Show more