Acquisition of pluripotency through continued environmental influence on OCT4-induced plastic human fibroblasts

•Environmental conditions influence OCT4-induced plastic Fibs toward pluripotency.•OCT4-derived iPSCs possess biomolecular and functional hallmarks of pluripotency.•OCT4-derived iPSC colonies form independently of lineage specific progenitors.•Acquisition of pluripotency is one of multiple cell fate choices from plastic Fibs.

The combination of OCT4 expression and short-term exposure to reprogramming media induces a state of transcriptional plasticity in human fibroblasts, capable of responding to changes in the extracellular environment that facilitate direct cell fate conversion toward lineage specific progenitors. Here we reveal that continued exposure of OCT4-induced plastic human fibroblasts to reprogramming media (RM) is sufficient to induce pluripotency. OCT4-derived induced pluripotent stem cell (iPSCOCT4) colonies emerged after prolonged culture in RM, and formed independently of lineage specific progenitors. Human iPSCOCT4 are morphologically indistinguishable from conventionally derived iPSCs and express core proteins involved in maintenance of pluripotency. iPSCOCT4 display in vivo functional pluripotency as measured by teratoma formation consisting of the three germ layers, and are capable of targeted in vitro differentiation. Our study indicates that acquisition of pluripotency is one of multiple cell fate choices that can be facilitated through environmental stimulation of OCT4-induced plasticity, and suggests the role of other reprogramming factors to induce pluripotency can be substituted by prolonged culture of plastic fibroblasts.