Autophagy and mTORC1 regulate the stochastic phase of somatic cell reprogramming

Area of Science:

• Cell Biology
• Stem Cell Biology
• Molecular Biology

Background:

• Cellular reprogramming converts somatic cells into induced pluripotent stem cells (iPSCs).
• Autophagy, a cellular degradation process, plays a role in various cellular functions, including development and stress response.
• The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a key regulator of cell growth, metabolism, and autophagy.

Purpose of the Study:

• To investigate the role and regulation of autophagy during the reprogramming of mouse fibroblasts to iPSCs.
• To elucidate the involvement of mTORC1 signaling and specific reprogramming factors in modulating autophagy during this process.
• To understand how autophagy influences cellular changes and reprogramming efficiency.

Main Methods:

• Utilized reprogramming of mouse fibroblasts using four reprogramming factors (Sox2, Oct4, Klf4, c-Myc).
• Assessed autophagy induction and its relationship with mTORC1 signaling and p53 activation.
• Analyzed the distinct roles of individual reprogramming factors in regulating autophagy-related genes.
• Investigated the impact of autophagy inhibition and p62 accumulation on reprogramming efficiency.

Main Results:

• Autophagy is robustly induced during reprogramming, independent of p53 activation.
• Reprogramming factors synergistically downregulate mTORC1 and differentially regulate autophagy-related genes.
• mTORC1 inhibition promotes reprogramming via cell reshaping, while autophagy paradoxically impairs it by degrading p62.
• Accumulation of p62 in autophagy-deficient cells enhances reprogramming efficiency.

Conclusions:

• A complex signaling network involving mTORC1 inhibition and autophagy induction governs early reprogramming.
• The balance between mTORC1 signaling and autophagy is critical for efficient reprogramming to pluripotency.
• Autophagy's role in reprogramming is multifaceted, involving both beneficial and detrimental effects dependent on context and regulation.