TGFbeta/Activin/Nodal pathway in inhibition of human embryonic stem cell differentiation by mechanical strain.

  • Saha S
  • Ji L
  • de Pablo J
 et al. 
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Cyclic biaxial mechanical strain has been reported to inhibit human embryonic stem cell differentiation without selecting against survival of differentiated or undifferentiated cells. We show that TGFbeta/Activin/Nodal signaling plays a crucial role in repression of human embryonic stem cell (hESC) differentiation under mechanical strain. Strain-induced transcription of TGFbeta1, Activin A, and Nodal, and upregulated Similar to Mothers Against Decapentaplegic homolog (Smad)2/3 phosphorylation in undifferentiated hESC. TGFbeta/Activin/Nodal receptor inhibitor SB431542 stimulated differentiation of hESCs cultured under biaxial strain. Exogenous addition of TGFbeta1, Activin A, or Nodal alone was insufficient to stimulate hESC self-renewal to replicate behavior of hESCs in presence of strain. However, exogenous TGFbeta1 and Activin A in combination partially replicated the self-renewing phenotype induced by strain but when combined with strain did not further stimulate self-renewal. In presence of mechanical strain, addition of a neutralizing antibody to TGFbeta1 promoted hESC differentiation whereas inhibition of Activin A by Follistatin promoted hESC differentiation to a lesser extent. Together, these findings show that TGFbeta superfamily activation of Smad2/3 is required for repression of spontaneous differentiation under strain and suggest that strain may induce autocrine or paracrine signaling through TGFbeta superfamily ligands.

Author-supplied keywords

  • Activins
  • Apoptosis
  • Cell Differentiation
  • Cell Survival
  • Cells, Cultured
  • Elasticity
  • Embryonic Stem Cells
  • Humans
  • Mechanotransduction, Cellular
  • Nodal Protein
  • Shear Strength
  • Signal Transduction
  • Stress, Mechanical
  • Transforming Growth Factor beta
  • research support, u.s. gov't, non-p.h.s.

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  • Somen Saha

  • Lin Ji

  • Juan J de Pablo

  • Sean P Palecek

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