title: Unravelling the pluripotency paradox in fetal and placental mesenchymal stem cells: Oct-4 expression and the case of The Emperor's New Clothes.
abstract: Mesenchymal stem cells (MSC) from fetal-placental tissues have translational advantages over their adult counterparts, and have variably been reported to express pluripotency markers. OCT-4 expression in fetal-placental MSC has been documented in some studies, paradoxically without tumourogenicity in vivo. It is possible that OCT-4 expression is insufficient to induce true "stemness", but this issue is important for the translational safety of fetal-derived MSC. To clarify this, we undertook a systematic literature review on OCT-4 in fetal or adnexal MSC to show that most studies report OCT-4 message or protein expression, but no study provides definitive evidence of true OCT-4A expression. Discrepant findings were attributable not to different culture conditions, tissue sources, or gestational ages but instead to techniques used. In assessing OCT-4 as a pluripotency marker, we highlight the challenges in detecting the correct OCT-4 isoform (OCT-4A) associated with pluripotency. Although specific detection of OCT-4A mRNA is achievable, it appears unlikely that any antibody can reliably distinguish between OCT-4A and the pseudogene OCT-4B. Finally, using five robust techniques we demonstrate that fetal derived-MSC do not express OCT-4A (or by default OCT-4B). Reports suggesting OCT-4 expression in fetal-derived MSC warrant reassessment, paying attention to gene and protein isoforms, pseudogenes, and antibody choice as well as primer design. Critical examination of the OCT-4 literature leads us to suggest that OCT-4 expression in fetal MSC may be a case of "The Emperor's New Clothes" with early reports of (false) positive expression amplified in subsequent studies without critical attention to emerging refinements in knowledge and methodology.
authors.affiliation: UQ Centre for Clinical Research, University of Queensland, Herston campus, Brisbane 4029, Australia. j.ryan2@uq.edu.au
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Ryan
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
authors.forename: Pascale V
authors.initials: PV
authors.lastname: Guillot
authors.forename: Jerry K Y
authors.initials: JK
authors.lastname: Chan
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Fisk
mesh_terms: D000818:Animals; D005260:Female; D005333:Fetus / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy
chemical_list: D050814:Octamer Transcription Factor-3