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BAK/BAX-Mediated Apoptosis Is a Myc-Induced Roadblock to Reprogramming

Esther J Y Kim1, Minna-Liisa Anko2, Christoffer Flensberg1

  • 1The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.

Stem Cell Reports
|January 24, 2018
PubMed

Insights

Blocking apoptosis enhances induced pluripotent stem cell (iPSC) generation when using the OKSM factors. This finding reveals that Myc-induced apoptosis is a key barrier to efficient iPSC reprogramming.

Area of Science:

  • Cell biology
  • Stem cell research
  • Molecular biology

Background:

  • Induced pluripotent stem cell (iPSC) generation is crucial for regenerative medicine but remains inefficient.
  • The combination of OCT4, KLF4, SOX2, and MYC (OKSM) is commonly used for reprogramming.
  • Apoptosis, or programmed cell death, is a known obstacle during the reprogramming process.

Purpose of the Study:

  • To investigate the role of apoptosis in limiting reprogramming efficiency.
  • To determine if inhibiting apoptosis can enhance iPSC generation.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) genetically engineered to lack the apoptosis mediators BAK and BAX.
  • Compared reprogramming efficiency with and without MYC in these apoptosis-deficient MEFs.

Main Results:

  • Reprogramming efficiency was significantly enhanced in MEFs lacking BAK and BAX, but only when MYC was included in the reprogramming cocktail (OKSM).
  • The absence of MYC (OKS) in apoptosis-deficient MEFs did not show the same enhancement, indicating MYC's role in inducing apoptosis.
  • Overexpression of MYC was identified as a major contributor to apoptosis during reprogramming.

Conclusions:

  • Myc-induced apoptosis presents a significant roadblock to efficient iPSC reprogramming under OKSM conditions.
  • Blocking apoptosis pathways, such as those mediated by BAK and BAX, can improve iPSC derivation.
  • These findings suggest that targeting apoptosis could be a viable strategy to enhance iPSC generation for research and therapeutic applications.
Keywords:
BAKBAXMYCinduced pluripotent stem cellsmitochondrial apoptosismouse embryonic fibroblasts: reprogrammingp53

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