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Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells

Masatoshi Ohgushi1, Michiru Matsumura, Mototsugu Eiraku

  • 1Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.

Cell Stem Cell
|August 5, 2010
PubMed

Insights

Human embryonic stem cells (hESCs) undergo apoptosis upon dissociation due to actomyosin hyperactivation. This process, regulated by Abr, can be suppressed by inhibiting ROCK or myosin, revealing a key mechanism in stem cell biology.

Area of Science:

  • Stem Cell Biology
  • Cellular Signaling
  • Apoptosis Research

Background:

  • Human embryonic stem cells (hESCs) exhibit distinct vulnerabilities compared to mouse ESCs (mESCs), particularly concerning dissociation-induced apoptosis.
  • Loss of intercellular contact triggers non-anoikis apoptosis in hESCs, linked to actomyosin hyperactivation.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying dissociation-induced apoptosis in hESCs.
  • To identify upstream regulators controlling actomyosin hyperactivation and apoptosis in hESCs.

Main Methods:

  • Utilized Blebbistatin (myosin inhibitor) to assess actomyosin involvement.
  • Investigated the role of Rho-Guanine nucleotide Exchange Factor (Rho-GEF) family factor Abr.
  • Analyzed Rho and Rac signaling pathways in dissociated hESCs and mESCs.

Main Results:

  • Dissociation triggers ROCK-dependent actomyosin hyperactivation and non-anoikis apoptosis in hESCs, preventable by Blebbistatin.
  • Abr is identified as a crucial upstream regulator, mediating Rho activation and Rac inhibition upon cell dissociation.
  • Abr depletion or inhibition of Rho/ROCK signaling prevents dissociation-induced apoptosis in hESCs.

Conclusions:

  • The Abr-dependent "Rho-high/Rac-low" state is critical for initiating actomyosin hyperactivation and apoptosis in dissociated hESCs.
  • Understanding this pathway offers potential strategies for improving hESC culture and manipulation.

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