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Vol. 16, Issue 7, 3140-3151, July 2005

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Dedifferentiation of Adult Human Myoblasts Induced by Ciliary Neurotrophic Factor In Vitro

Xiaoping Chen ^* , Zebin Mao , Shuhong Liu ^*, Hong Liu ^*, Xuan Wang ^*, Haitao Wu ^*, Yan Wu ^*, Tong Zhao ^*, Wenhong Fan ^*, Yong Li , David T. Yew ^||, Pawel M. Kindler ^||, Linsong Li ^¶, Qihua He ^¶, Lingjia Qian ^#, Xiaomin Wang ^@, and Ming Fan ^*

^* Department of Neurophysiology, Institute of Basic Medical Sciences, Beijing 100850, China; Institute of Space Medical Engineering, Beijing 100094, China; Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China; Children's Hospital of Pittsburgh, Pittsburgh, PA 15213; ^|| Department of Anatomy, School of Basic Medical Science, Hong Kong Chinese University, Satian, Hong Kong; ^¶ Peking University Stem Cell Center, Beijing 100083, China; ^# Institute of Hygiene and Environmental Medicine, Tianjing 300050, China; and ^@ Department of Physiology, Capital Medical University, Youanmen, Beijing 100054, China

Submitted March 16, 2005; Revised April 4, 2005; Accepted April 13, 2005
Monitoring Editor: Marianne Bronner-Fraser

Ciliary neurotrophic factor (CNTF) is primarily known for its important cellular effects within the nervous system. However, recent studies indicate that its receptor can be highly expressed in denervated skeletal muscle. Here, we investigated the direct effect of CNTF on skeletal myoblasts of adult human. Surprisingly, we found that CNTF induced the myogenic lineage-committed myoblasts at a clonal level to dedifferentiate into multipotent progenitor cells—they not only could proliferate for over 20 passages with the expression absence of myogenic specific factors Myf5 and MyoD, but they were also capable of differentiating into new phenotypes, mainly neurons, glial cells, smooth muscle cells, and adipocytes. These "progenitor cells" retained their myogenic memory and were capable of redifferentiating into myotubes. Furthermore, CNTF could activate the p44/p42 MAPK and down-regulate the expression of myogenic regulatory factors (MRFs). Finally, PD98059, a specific inhibitor of p44/p42 MAPK pathway, was able to abolish the effects of CNTF on both myoblast fate and MRF expression. Our results demonstrate the myogenic lineage-committed human myoblasts can dedifferentiate at a clonal level and CNTF is a novel regulator of skeletal myoblast dedifferentiation via p44/p42 MAPK pathway.

Address correspondence to: Ming Fan (fanming{at}nic.bmi.ac.cn).

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