A Synthetic Mechano Growth Factor E Peptide Enhances Myogenic Precursor Cell Transplantation Success

Unité de recherche en Génétique humaine, Centre Hospitalier de l'Université Laval, Ste-Foy, Québec, Canada.
American Journal of Transplantation (Impact Factor: 5.68). 11/2007; 7(10):2247-59. DOI: 10.1111/j.1600-6143.2007.01927.x
Source: PubMed


Myogenic precursor cell (MPC) transplantation is a good strategy to introduce dystrophin expression in muscles of Duchenne muscular dystrophy (DMD) patients. Insulin-like growth factor (IGF-1) promotes MPC activities, such as survival, proliferation, migration and differentiation, which could enhance the success of their transplantation. Alternative splicing of the IGF-1 mRNA produces different muscle isoforms. The mechano growth factor (MGF) is an isoform, especially expressed after a mechanical stress. A 24 amino acids peptide corresponding to the C-terminal part of the MGF E domain (MGF-Ct24E peptide) was synthesized. This peptide had been shown to enhance the proliferation and delay the terminal differentiation of C(2)C(12) myoblasts. The present study showed that the MGF-Ct24E peptide improved human MPC transplantation by modulating their proliferation and differentiation. Indeed, intramuscular or systemic delivery of this synthetic peptide significantly promoted engraftment of human MPCs in mice. In vitro experiments demonstrated that the MGF-Ct24E peptide enhanced MPC proliferation by a different mechanism than the binding to the IGF-1 receptor. Moreover, MGF-Ct24E peptide delayed human MPC differentiation while having no outcome on survival. Those combined effects are probably responsible for the enhanced transplantation success. Thus, the MGF-Ct24E peptide is an interesting agent to increase MPC transplantation success in DMD patients.

Download full-text


Available from: Jacques P Tremblay, Nov 09, 2014
  • Source
    • "Blocking the IGF-1 receptor (IGF-1R) did not influence the outcome of the experiment. More recent studies in several other cell types have consistently confirmed that MGF-mediated effects are not dependent on the IGF-1R [20], [53], [54]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.
    PLoS ONE 10/2013; 8(10):e76133. DOI:10.1371/journal.pone.0076133 · 3.23 Impact Factor
  • Source
    • "Alternatively, if the E-peptides do have independent activity, they likely signal through their own Epeptide receptor. Many studies have blocked IGF-IR with neutralizing antibodies, and demonstrate retention of hEB and synthetic MGF activity for heightened proliferation and migration of different cell lines (Siegfried et al., 1992; Yang and Goldspink, 2002; Mills et al., 2007a,b; Philippou et al., 2009; Stavropoulou et al., 2009). These results suggest that E-peptides have activity independent of IGF-IR signaling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin-like growth factor I (IGF-I) is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1 gene undergoes several post-translational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). However, the significance of the additional forms and peptides produced from Igf1 is not clear. For instance, the C-terminal extensions called the E-peptides that are part of pro-IGF-I, have been implicated in playing roles in cell growth, including cell proliferation and migration and muscle hypertrophy in an IGF-IR independent manner. However, the activity of these peptides has been controversial. IGF-IR independent actions suggest the existence of an E-peptide receptor, yet such a protein has not been discovered. We propose a new concept: there is no E-peptide receptor, rather the E-peptides coordinate with IGF-I to modulate activity of the IGF-IR. Growing evidence reveals that the presence of an E-peptide alters IGF-I activity, whether as part of pro-IGF-I, or as a separate peptide. In this review, we will examine the past literature on IGF-I processing and E-peptide actions in skeletal muscle, address the previous attempts to separate IGF-I and E-peptide effects, propose a new model for IGF-I/E-peptide synergy, and suggest future experiments to test if the E-peptides truly modulate IGF-I activity.
    Frontiers in Endocrinology 03/2013; 4:42. DOI:10.3389/fendo.2013.00042
  • Source
    • "Much attention has been paid to EB particularly in muscle, where this form has been deemed “Mechano Growth Factor” (MGF) due to rapid transcriptional upregulation of Igf1b after stretch, overload, and injury [35], [36], [37], [38]. Exposure to MGF/EB peptides has been shown to increase myoblast proliferation and migration, and overexpression of Igf1b delays differentiation [39], [40], [41]. Many of these effects were apparent even when IGF-IR was blocked via a neutralizing antibody, indicating that EB-peptide actions were independent of IGF-I signaling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin-like growth factor-I (IGF-I) is an essential growth factor that regulates the processes necessary for cell proliferation, differentiation, and survival. The Igf1 gene encodes mature IGF-I and a carboxy-terminal extension called the E-peptide. In rodents, alternative splicing and post-translational processing produce two E-peptides (EA and EB). EB has been studied extensively and has been reported to promote cell proliferation and migration independently of IGF-I and its receptor (IGF-IR), but the mechanism by which EB causes these actions has not been identified. Further, the properties of EA have not been evaluated. Therefore, the goals of this study were to determine if EA and EB possessed similar activity and if these actions were IGF-IR independent. We utilized synthetic peptides for EA, EB, and a scrambled control to examine cellular responses. Both E-peptides increased MAPK signaling, which was blocked by pharmacologic IGF-IR inhibition. Although the E-peptides did not directly induce IGF-IR phosphorylation, the presence of either E-peptide increased IGF-IR activation by IGF-I, and this was achieved through enhanced cell surface bioavailability of the receptor. To determine if E-peptide biological actions required the IGF-IR, we took advantage of the murine C2C12 cell line as a platform to examine the key steps of skeletal muscle proliferation, migration and differentiation. EB increased myoblast proliferation and migration while EA delayed differentiation. The proliferation and migration effects were inhibited by MAPK or IGF-IR signaling blockade. Thus, in contrast to previous studies, we find that E-peptide signaling, mitogenic, and motogenic effects are dependent upon IGF-IR. We propose that the E-peptides have little independent activity, but instead affect growth via modulating IGF-I signaling, thereby increasing the complexity of IGF-I biological activity.
    PLoS ONE 09/2012; 7(9):e45588. DOI:10.1371/journal.pone.0045588 · 3.23 Impact Factor
Show more