Efficient direct conversion of human fibroblasts into myogenic lineage induced by co-transduction with MYCL and MYOD1

• Published in: Biochemical and biophysical research communications Vol. 488; no. 2; pp. 368 - 373
• Main Authors: Wakao, Junko, Kishida, Tsunao, Fumino, Shigehisa, Kimura, Koseki, Yamamoto, Kenta, Kotani, Shin-ichiro, Mizushima, Katsura, Naito, Yuji, Yoshikawa, Toshikazu, Tajiri, Tatsuro, Mazda, Osam
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.06.2017
• Subjects: Cell Line; Congenital muscle defects; Direct conversion; Direct reprogramming; Fibroblasts - metabolism; Humans; Muscle Development - genetics; Myoblasts; MyoD Protein - genetics; MyoD Protein - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Regenerative medicine; Direct reprogramming; Regenerative medicine; Congenital muscle defects; Myoblasts; Direct conversion
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.05.059

The skeletal muscle consists of contractile myofibers and plays essential roles for maintenance of body posture, movement, and metabolic regulation. During the development and regeneration of the skeletal muscle tissue, the myoblasts fuse into multinucleated myotubes that subsequently form myofibers. Transplantation of myoblasts may make possible a novel regenerative therapy against defects or dysfunction of the skeletal muscle. It is reported that rodent fibroblasts are converted into myoblast-like cells and fuse to form syncytium after forced expression of exogenous myogenic differentiation 1 (MYOD1) that is a key transcription factor for myoblast differentiation. But human fibroblasts are less efficiently converted into myoblasts and rarely fused by MYOD1 alone. Here we found that transduction of v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog (MYCL) gene in combination with MYOD1 gene induced myoblast-like phenotypes in human fibroblasts more strongly than MYOD1 gene alone. The rate of conversion was approximately 90%. The directly converted myoblasts (dMBs) underwent fusion in an ERK5 pathway-dependent manner. The dMBs also formed myofiber-like structure in vivo after an inoculation into mice at the subcutaneous tissue. The present results strongly suggest that the combination of MYCL plus MYOD1 may promote direct conversion of human fibroblasts into functional myoblasts that could potentially be used for regenerative therapy for muscle diseases and congenital muscle defects. •MYCL promoted conversion of human fibroblasts into myoblasts induced by MYOD1.•The directly converted myoblasts (dMBs) were induced at an efficiency of 90%.•dMBs fused into multinuclear myotubes in an ERK5-dependent manner.•dMBs formed a myofiber-like structure in vivo after an inoculation into mice.