A new pro-migratory activity on human myogenic precursor cells for a synthetic peptide within the E domain of the mechano growth factor.
Duchenne muscular dystrophy (DMD) is an inherited disease that leads to progressive muscle wasting. Myogenic precursor cell transplantation is an approach that can introduce the normal dystrophin gene in the muscle fibers of the patients. Unfortunately, these myogenic precursor cells do not migrate well in the muscle and thus many injections have to be done to enable a good graft success. Recent reports have shown that there is extensive splicing of the IGF-1 gene in muscles. The MGF isoform contains a C-terminal 24 amino acids peptide in the E domain (MGF-Ct24E) that has intrinsic properties. It can promote the proliferation while delaying the differentiation of C(2)C(12) cells. Here, we demonstrated that this synthetic peptide is a motogenic factor for human precursor myogenic cells in vitro and in vivo. Indeed, MGF-Ct24E peptide can modulate members of the fibrinolytic and metalloproteinase systems, which are implicated in the migration of myogenic cells. MGF-Ct24E peptide enhances the expression of u-PA, u-PAR and MMP-7 while reducing PAI-1 activity. Moreover, it has no effect on the gelatinases MMP-2 and -9. Those combined effects can favour cell migration. Finally, we present some results suggesting that the MGF-Ct24E peptide induces these cell responses through a mechanism that does not involve the IGF-1 receptor. Thus, this MGF-Ct24E peptide has a new pro-migratory activity on human myogenic precursor cells that may be helpful in the treatment of DMD. Those results reinforce the possibility that the IGF-1Ec isoform may produce an E domain peptide that can act as a cytokine.
Mills
Philippe
P
Unité de recherche en génétique humaine, CHUQ-CHUL, 2705 boul. Laurier, Ste-Foy, Qc, Canada G1V 4G2.
Lafrenière
Jean-François
JF
Benabdallah
Basma Fattouma
BF
El Fahime
El Mostafa
el M
Tremblay
Jacques-P
JP
D000293:Adolescent; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D005342:Fibrinolysis; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D032446:Myoblasts / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
C524898:PLAUR protein, human; D010455:Peptides; D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D020033:Protein Isoforms; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; C042057:proteolysis-inducing peptide; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D014568:Urokinase-Type Plasminogen Activator; D020783:Matrix Metalloproteinase 7