Lentivirus-mediated reprogramming of somatic cells in the absence of transgenic transcription factors.
Retroviral vectors remain the most efficient and widely applied system for induction of pluripotency. However, mutagenic effects have been documented in both laboratory and clinical gene therapy studies, principally as a result of dysregulated host gene expression in the proximity of defined integration sites. Here, we report that cells with characteristics of pluripotent stem cells can be produced from normal human fibroblasts in the absence of reprogramming transcription factors (TFs) during lentiviral (LV) vector-mediated gene transfer. This occurred via induced alterations in host gene and microRNA (miRNA) expression and detrimental changes in karyotype. These findings demonstrate that vector-induced genotoxicity may alone play a role in somatic cell reprogramming derivation and urges caution when using integrating vectors in this setting. Clearer understanding of this process may additionally reveal novel insights into reprogramming pathways.
British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Nicole M
NM
Kane
Ali
A
Nowrouzi
Sayandip
S
Mukherjee
Michael P
MP
Blundell
Jenny A
JA
Greig
Wai Kwong
WK
Lee
Miles D
MD
Houslay
Graeme
G
Milligan
Joanne C
JC
Mountford
Christof
C
von Kalle
Manfred
M
Schmidt
Adrian J
AJ
Thrasher
Andrew H
AH
Baker
D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology*; D020869:Gene Expression Profiling; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics*
D035683:MicroRNAs; D014157:Transcription Factors