Unravelling the Pluripotency Paradox in Fetal and Placental Mesenchymal Stem Cells: Oct-4 Expression and the Case of the Emperor’s New Clothes

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.