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

  • Saha S
  • Ji L
  • de Pablo J
 et al. 
  • 16

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Abstract

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/*metabolism
  • Apoptosis/physiology
  • Cell Differentiation/physiology
  • Cell Survival
  • Cells, Cultured
  • Elasticity
  • Embryonic Stem Cells/*cytology/*physiology
  • Humans
  • Mechanotransduction, Cellular/*physiology
  • Nodal Protein
  • Shear Strength
  • Signal Transduction/*physiology
  • Stress, Mechanical
  • Transforming Growth Factor beta/*metabolism

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Authors

  • S Saha

  • L Ji

  • J J de Pablo

  • S P Palecek

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