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Suppressing P16Ink4a and P14ARF pathways overcomes apoptosis in individualized human embryonic stem cells

Wenqian Wang1, Yanling Zhu2,3, Ke Huang4,3

  • 1Department of Hematology, Sun Yat-Sen University, Guangzhou, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|December 15, 2016
PubMed

Insights

Human embryonic stem cells (hESCs) undergo apoptosis upon dissociation due to the Ink4A-ARF senescence pathway. Suppressing this pathway, alongside actin-myosin hyperactivation, enhances hESC survival and cloning efficiency.

Area of Science:

  • Stem Cell Biology
  • Cellular Senescence
  • Apoptosis Research

Background:

  • Dissociation induces apoptosis in human embryonic stem cells (hESCs), unlike mouse ESCs.
  • Rho-associated kinase-dependent actin-myosin hyperactivation is a known mechanism for hESC apoptosis.
  • The role of other pathways in hESC apoptosis upon dissociation remains to be fully elucidated.

Purpose of the Study:

  • To identify additional mechanisms causing apoptosis in individualized hESCs.
  • To investigate the role of the Ink4A-ARF pathway in dissociation-induced hESC apoptosis.
  • To explore strategies for improving hESC survival and passaging.

Main Methods:

  • Investigated the induction of P16INK4A and P14ARF in dissociated hESCs.
  • Overexpressed BMI1, an Ink4A-ARF suppressor, in hESCs.
  • Assessed the effect of BMI1 on hESC survival and cloning efficiency.
  • Examined the interplay between Ink4A-ARF, actin-myosin activation, and hESC survival.
  • Tested dual inhibition of Ink4A-ARF and actin-myosin pathways for hESC passaging.

Main Results:

  • P16INK4A and P14ARF were immediately induced in hESCs upon dissociation, but not in mouse ESCs.
  • BMI1 overexpression promoted hESC survival and cloning efficiency by binding the Ink4A-ARF locus.
  • BMI1 did not affect dissociation-induced actin-myosin activation, indicating an independent pathway.
  • Dual inhibition of Ink4A-ARF and actin-myosin pathways enabled successful hESC passaging on gelatin.

Conclusions:

  • The Ink4A-ARF-mediated senescence pathway is a significant contributor to apoptosis in individualized hESCs.
  • BMI1 acts as a survival factor for hESCs by suppressing the Ink4A-ARF pathway.
  • Targeting both Ink4A-ARF and actin-myosin pathways offers a novel strategy for improving hESC culture and passaging.
  • Understanding these mechanisms is crucial for differentiating naive and primed ESC characteristics.
Keywords:
BMI1hESCsmESCssenescence

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