BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors

Stem Cell Reports. 2016 Jan 12;6(1):64-73. doi: 10.1016/j.stemcr.2015.12.004.

Abstract

Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Krüppel-like factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Self Renewal / genetics
  • Cell Self Renewal / physiology*
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Knockout
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad1 Protein / genetics
  • Smad1 Protein / metabolism
  • Smad5 Protein / genetics
  • Smad5 Protein / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism

Substances

  • Bone Morphogenetic Protein 4
  • GKLF protein
  • Klf2 protein, mouse
  • Klf5 protein, mouse
  • Kruppel-Like Transcription Factors
  • Smad1 Protein
  • Smad5 Protein