Nanog overcomes reprogramming barriers and induces pluripotency in minimal conditions

Thorold W. Theunissen, Anouk L. Van Oosten, Gonalo Castelo-Branco, John Hall, Austin Smith, José C.R. Silva

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

Induced pluripotency requires the expression of defined factors and culture conditions that support the self-renewal of embryonic stem (ES) cells [1]. Small molecule inhibition of MAP kinase (MEK) and glycogen synthase kinase 3 (GSK3) with LIF (2i/LIF) provides an optimal culture environment for mouse ES cells [2] and promotes transition to naive pluripotency in partially reprogrammed (pre-iPS) cells [3]. Here we show that 2i/LIF treatment in clonal lines of pre-iPS cells results in the activation of endogenous Nanog and rapid downregulation of retroviral Oct4 expression. Nanog enables somatic cell reprogramming in serum-free medium supplemented with LIF, a culture condition which does not support induced pluripotency or the self-renewal of ES cells, and is sufficient to reprogram epiblast-derived stem cells to naive pluripotency in serum-free medium alone. Nanog also enhances reprogramming in cooperation with kinase inhibition or 5-aza-cytidine, a small molecule inhibitor of DNA methylation. These results highlight the capacity of Nanog to overcome multiple barriers to reprogramming and reveal a synergy between Nanog and chemical inhibitors that promote reprogramming. We conclude that Nanog induces pluripotency in minimal conditions. This provides a strategy for imposing naive pluripotency in mammalian cells independently of species-specific culture requirements.

Original languageEnglish
Pages (from-to)65-71
Number of pages7
JournalCurrent Biology
Volume21
Issue number1
DOIs
StatePublished - Jan 11 2011

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