Cellular senescence in human myoblasts is overcome by human telomerase reverse transcriptase and cyclin-dependent kinase 4: consequences in aging muscle and therapeutic strategies for muscular dystrophies.
Cultured human myoblasts fail to immortalize following the introduction of telomerase. The availability of an immortalization protocol for normal human myoblasts would allow one to isolate cellular models from various neuromuscular diseases, thus opening the possibility to develop and test novel therapeutic strategies. The parameters limiting the efficacy of myoblast transfer therapy (MTT) could be assessed in such models. Finally, the presence of an unlimited number of cell divisions, and thus the ability to clone cells after experimental manipulations, reduces the risks of insertional mutagenesis by many orders of magnitude. This opportunity for genetic modification provides an approach for creating a universal donor that has been altered to be more therapeutically useful than its normal counterpart. It can be engineered to function under conditions of chronic damage (which are very different than the massive regeneration conditions that recapitulate normal development), and to overcome the biological problems such as cell death and failure to proliferate and migrate that limit current MTT strategies. We describe here the production and characterization of a human myogenic cell line, LHCN-M2, that has overcome replicative aging due to the expression of telomerase and cyclin-dependent kinase 4. We demonstrate that it functions as well as young myoblasts in xenotransplant experiments in immunocompromized mice under conditions of regeneration following muscle damage.
Zhu
Chun-Hong
CH
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9039, USA.
Mouly
Vincent
V
Cooper
Racquel N
RN
Mamchaoui
Kamel
K
Bigot
Anne
A
Shay
Jerry W
JW
Di Santo
James P
JP
Butler-Browne
Gillian S
GS
Wright
Woodring E
WE
D000375:Aging / Q000502:physiology*; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D018816:Genes, cdc; D006801:Humans; D051379:Mice; D024510:Muscle Development; D009132:Muscles / Q000502:physiology*; D009136:Muscular Dystrophies / Q000628:therapy; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology / Q000502:physiology* / Q000637:transplantation; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere; D014183:Transplantation, Heterologous
C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C509186:TERT protein, human; D019098:Telomerase