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In this study, we demonstrate that sphere formation triggers immortalization and stable reprogramming of mouse fibroblasts. Cell contact signaling in spheres causes downregulation of the epithelial‐to‐mesenchymal transition transcription factor Zeb1 leading to rapid mesenchymal‐to‐epithelial transition. Hypoxia within spheres together with loss of Zeb1 repression synergize to cause superinduction of Hif1a, which in turn leads to induction of the DNA demethylase Aid/Aicda, demethylation of the  Oct4  promoter/enhancer and multipotency. Oct4 and Nanog expression diminish when cells are removed from the hypoxic environment of spheres and placed in monolayer culture, but the cells retain multipotential capacity, demonstrating stable reprogramming and a gene expression pattern resembling adult stem cells. Oct4 has been shown to induce Dnmt1 in mesenchymal stem cells, and we link Oct4 and Dnmt1 to silencing of cell cycle inhibitory cyclin dependent kinase inhibitors and Arf, and immortalization of the reprogrammed fibroblasts. Sphere formation then represents a novel and rapid protocol for immortalization and stable reprogramming of fibroblasts to multipotency that does not require exogenous expression of a stem cell factor or a lineage‐specifying transcription factor. S TEM  C ells  2013;31:1350–1362

stem cells

Repression of Zeb1 and Hypoxia Cause Sequential Mesenchymal‐to‐Epithelial Transition and Induction of Aid, Oct4, and Dnmt1, Leading to Immortalization and Multipotential Reprogramming of Fibroblasts in Spheres