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

Abstract

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 MGFCt24E 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.

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

“…Similar to the results derived from human cell lines, studies using animal cell lines models have shown that exogenous administration or overexpression of synthetic peptides, generated from different regions within the E domain of human (Ec) (28,31,33,145,146), trout (Ea) (144,147) or rodent (Ea and Eb) sequences (38) in human, rodent or porcine cells in culture showed unique though inconsistent effects in promoting cell proliferation and migration, and in delaying or inhibiting cell differentiation. In particular, actions associated with peptides derived from mammalian Ea domain have only recently been established, with rodent Ea-peptide reported to possess bioactivity (38).…”

“…Thus, during the last decade, many in vitro and in vivo studies have investigated the aspect of the differential IGF-I isoforms or their E-peptides actions in various conditions and pathologies (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). This concept was further supported by recent findings which revealed differential, E-peptide-or IGF-I isoform-specific signaling (31,33,34,(38)(39)(40).…”

“…Although, by the general consensus, IGF-I is thought to exert its biological actions predominantly through mature peptide, differential biological activities have been reported for the different IGF-I isoforms (propeptides), or for their E-peptides, exogenously administrated or overexpressed in various in vivo (28,29,36,(132)(133)(134) and in vitro models (20,27,(31)(32)(33)135,136), implying that there are peptides other than the IGF-I ligand that also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects (31,36).…”

“…Considering particularly the bioactivity of the E-peptides, in vitro studies have suggested that the E-peptides of the human IGF-I precursors may act as independent growth factors, since their synthetic analogs, generated from unique regions within the E domains, were demonstrated to possess mitogenic (20,27,34,35,73,141), angiogenic (142) and migratory activity (28,141,143), and regulate cell differentiation (27,28) in various human cells or cell lines. Antitumor activity of human Eb-peptide also has been reported in some cancer cells (144).…”

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

“…When the predominant idea in this field was that the "lack of migration ability" was the key factor to explain the local fusion of the grafted cells, several studies attempted to attack this problem by inducing in the grafted myoblasts the secretion of enzymes that are crucial for the intratissular motion of cells by degrading the extracellular matrix [133][134][135][136][137][138]. Some of these studies reported an improved migration of myoblasts under particular experimental conditions in vitro and in vivo in mice.…”