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Induction of CCAAT/Enhancer-Binding Protein β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle.
Stem Cells Transl Med. 2016 Apr; 5(4):500-10.SC

Abstract

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is the most common muscular dystrophy. Characterized by rounds of muscle degeneration and regeneration, DMD features progressive muscle wasting and is fatal. One approach for treatment is transplantation of muscle progenitor cells to repair and restore dystrophin expression to damaged muscle. However, the success of this approach has been limited by difficulties in isolating large numbers of myogenic progenitors with strong regenerative potential, poor engraftment, poor survival of donor cells, and limited migration in the diseased muscle. We demonstrate that induction of the transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) using the cyclic adenosine monophosphate phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) results in enhanced myoblast expansion in culture and increased satellite cell marker expression. When equal numbers of IBMX-treated cells were transplanted into dystrophic muscle, they contributed to muscle repair more efficiently than did vehicle-treated cells and engrafted into the satellite cell niche in higher numbers, demonstrating improved cell migration from the site of injury and enhanced survival after transplantation. Thus, pharmacologic stimulation of C/EBPβ expression reprograms myoblasts to a more stem cell-like state, promotes expansion in culture, and improves engraftment such that better transplantation outcomes are achieved.

SIGNIFICANCE

Duchenne muscular dystrophy is a genetic disorder for which no cure exists. One therapeutic approach is transplantation of myogenic progenitors to restore dystrophin to damaged muscle, but this approach is limited by poor engraftment of cultured myoblasts. Transient upregulation of CCAAT/enhancer-binding protein β in primary myoblasts using the phosphodiesterase isobutylmethylxanthine (IBMX) increases satellite cell marker expression in cultured myoblasts, improves their migration, and increases their survival after transplantation. When transplanted into C57BL/10ScSn-mdx/J mice , IBMX-treated myoblasts restored dystrophin expression and were able to occupy the satellite cell niche more efficiently than controls. A myoblast culture approach that reprograms myoblasts to a more primitive state, resulting in improved transplantation outcomes and reinvigorating research into myoblast transplantation as a viable therapeutic approach, is described.

Authors+Show Affiliations

Graduate Program in Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada Nadine.WiperBergeron@uottawa.ca.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26941360

Citation

Lala-Tabbert, Neena, et al. "Induction of CCAAT/Enhancer-Binding Protein Β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle." Stem Cells Translational Medicine, vol. 5, no. 4, 2016, pp. 500-10.
Lala-Tabbert N, Fu D, Wiper-Bergeron N. Induction of CCAAT/Enhancer-Binding Protein β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle. Stem Cells Transl Med. 2016;5(4):500-10.
Lala-Tabbert, N., Fu, D., & Wiper-Bergeron, N. (2016). Induction of CCAAT/Enhancer-Binding Protein β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle. Stem Cells Translational Medicine, 5(4), 500-10. https://doi.org/10.5966/sctm.2015-0169
Lala-Tabbert N, Fu D, Wiper-Bergeron N. Induction of CCAAT/Enhancer-Binding Protein Β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle. Stem Cells Transl Med. 2016;5(4):500-10. PubMed PMID: 26941360.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of CCAAT/Enhancer-Binding Protein β Expression With the Phosphodiesterase Inhibitor Isobutylmethylxanthine Improves Myoblast Engraftment Into Dystrophic Muscle. AU - Lala-Tabbert,Neena, AU - Fu,Dechen, AU - Wiper-Bergeron,Nadine, Y1 - 2016/03/03/ PY - 2015/07/23/received PY - 2015/11/25/accepted PY - 2016/3/5/entrez PY - 2016/3/5/pubmed PY - 2016/6/9/medline KW - CCAAT-enhancer-binding protein-β KW - Muscular dystrophies KW - Pax7 transcription factor KW - Phosphodiesterase inhibitors KW - Skeletal muscle satellite cells KW - Stem cell transplantation SP - 500 EP - 10 JF - Stem cells translational medicine JO - Stem Cells Transl Med VL - 5 IS - 4 N2 - UNLABELLED: Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is the most common muscular dystrophy. Characterized by rounds of muscle degeneration and regeneration, DMD features progressive muscle wasting and is fatal. One approach for treatment is transplantation of muscle progenitor cells to repair and restore dystrophin expression to damaged muscle. However, the success of this approach has been limited by difficulties in isolating large numbers of myogenic progenitors with strong regenerative potential, poor engraftment, poor survival of donor cells, and limited migration in the diseased muscle. We demonstrate that induction of the transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) using the cyclic adenosine monophosphate phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) results in enhanced myoblast expansion in culture and increased satellite cell marker expression. When equal numbers of IBMX-treated cells were transplanted into dystrophic muscle, they contributed to muscle repair more efficiently than did vehicle-treated cells and engrafted into the satellite cell niche in higher numbers, demonstrating improved cell migration from the site of injury and enhanced survival after transplantation. Thus, pharmacologic stimulation of C/EBPβ expression reprograms myoblasts to a more stem cell-like state, promotes expansion in culture, and improves engraftment such that better transplantation outcomes are achieved. SIGNIFICANCE: Duchenne muscular dystrophy is a genetic disorder for which no cure exists. One therapeutic approach is transplantation of myogenic progenitors to restore dystrophin to damaged muscle, but this approach is limited by poor engraftment of cultured myoblasts. Transient upregulation of CCAAT/enhancer-binding protein β in primary myoblasts using the phosphodiesterase isobutylmethylxanthine (IBMX) increases satellite cell marker expression in cultured myoblasts, improves their migration, and increases their survival after transplantation. When transplanted into C57BL/10ScSn-mdx/J mice , IBMX-treated myoblasts restored dystrophin expression and were able to occupy the satellite cell niche more efficiently than controls. A myoblast culture approach that reprograms myoblasts to a more primitive state, resulting in improved transplantation outcomes and reinvigorating research into myoblast transplantation as a viable therapeutic approach, is described. SN - 2157-6564 UR - https://www.unboundmedicine.com/medline/citation/26941360/Induction_of_CCAAT/Enhancer_Binding_Protein_β_Expression_With_the_Phosphodiesterase_Inhibitor_Isobutylmethylxanthine_Improves_Myoblast_Engraftment_Into_Dystrophic_Muscle_ L2 - https://doi.org/10.5966/sctm.2015-0169 DB - PRIME DP - Unbound Medicine ER -