Signaling Network Crosstalk in Human Pluripotent Cells: A Smad2/3-Regulated Switch that Controls the Balance between Self-Renewal and Differentiation

• Type of Material: Article
• Authors: Amar M. Singh, University of Georgia; David Reynolds, University of Georgia; Timothy Cliff, University of Georgia; Satoshi Ohtsuka, University of Georgia; Alexa Mattheyses, Emory University; Yuhua Sun, University of Georgia; Laura Menendez, University of Georgia; Michael Kulik, University of Georgia; Stephen Dalton, University of Georgia
• Language: English
• Date: 2012-03-02
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.stem.2012.01.014
• Title of Journal or Parent Work: Cell Stem Cell
• ISSN: 1934-5909
• Volume: 10
• Issue: 3
• Start Page: 312
• End Page: 326
• Grant/Funding Information: This work was supported by grants to SD from the National Institute of Child Health and Human Development (HD049647); and the National Institute for General Medical Sciences (GM75334).
• Keywords: FIBROBLAST-GROWTH-FACTOR; Cell & Tissue Engineering; HEMATOPOIETIC-CELLS; NANOG EXPRESSION; WNT/BETA-CATENIN; Science & Technology; DEFINITIVE ENDODERM; BETA-CATENIN; MAINTAINS PLURIPOTENCY; Cell Biology; Life Sciences & Biomedicine; EMBRYONIC STEM-CELLS; EFFICIENT DIFFERENTIATION; DEFINED CONDITIONS
• Research Categories: Chemistry, Biochemistry; Biology, Cell

Abstract

A general mechanism for how intracellular signaling pathways in human pluripotent cells are coordinated and how they maintain self-renewal remain to be elucidated. In this report, we describe a signaling mechanism where PI3K/Akt activity maintains self-renewal by restraining prodifferentiation signaling through suppression of the Raf/Mek/Erk and canonical Wnt signaling pathways. When active, PI3K/Akt establishes conditions where Activin A/Smad2,3 performs a pro-self-renewal function by activating target genes, including Nanog. When PI3K/Akt signaling is low, Wnt effectors are activated and function in conjunction with Smad2,3 to promote differentiation. The switch in Smad2,3 activity after inactivation of PI3K/Akt requires the activation of canonical Wnt signaling by Erk, which targets Gsk3β. In sum, we define a signaling framework that converges on Smad2,3 and determines its ability to regulate the balance between alternative cell states. This signaling paradigm has far-reaching implications for cell fate decisions during early embryonic development.