RT Journal Article
SR Electronic
T1 Non-viral induction of transient cell reprogramming in skeletal muscle to enhance tissue regeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 101188
DO 10.1101/101188
A1 Irene de Lázaro
A1 Acelya Yilmazer
A1 Yein Nam
A1 Sarah Qubisi
A1 Fazilah Maizatul Abdul Razak
A1 Giulio Cossu
A1 Kostas Kostarelos
YR 2017
UL http://biorxiv.org/content/early/2017/01/18/101188.abstract
AB Somatic cells can be reprogrammed to pluripotency in vivo by overexpression of defined transcription factors. While their sustained expression triggers tumorigenesis, transient reprogramming induces pluripotency-like features and proliferation only temporarily, without teratoma formation. We sought to achieve transient reprogramming within mouse skeletal muscle with a localized injection of plasmid DNA (pDNA) and hypothesized that this would enhance regeneration after severe injury. Intramuscular administration of reprogramming pDNA rapidly upregulated pluripotency (Nanog, Ecat1, Rex1) and early myogenesis genes (Pax3) in the healthy gastrocnemius of various mouse strains. Mononucleated cells expressing such markers appeared promptly in clusters among myofibers, but proliferated only transiently and did not lead to the generation of teratomas. Nanog was also upregulated in the gastrocnemius when reprogramming factors were administered 7 days after laceration of its medial head. Enhanced tissue regeneration after reprogramming was manifested by the accelerated appearance of centro-nucleated myofibers and reduced fibrosis. These results suggest that in vivo transient reprogramming may constitute a novel strategy towards the acceleration of regeneration following muscle injury, based on the induction of transiently-proliferative, pluripotent-like cells in situ. Further research to achieve clinically meaningful functional regeneration is warranted.