ERRs Mediate a Metabolic Switch Required for Somatic Cell Reprogramming to Pluripotency

Area of Science:

• Stem Cell Biology
• Cell Metabolism
• Epigenetics and Nuclear Receptors

Background:

• Cellular metabolism adapts to external needs, but internal metabolic drivers of induced pluripotent stem cell (iPSC) generation are not fully understood.
• While glycolysis rises during reprogramming, the role of other metabolic pathways, particularly oxidative phosphorylation (OXPHOS), remains to be clarified.

Purpose of the Study:

• To investigate the intrinsic metabolic demands that drive the iPSC reprogramming process.
• To identify key molecular players and metabolic pathways involved in the early stages of reprogramming.

Main Methods:

• Examined the transient induction of estrogen-related nuclear receptors (ERRα and ERRγ) and their co-factors (PGC-1α and PGC-1β) during reprogramming.
• Assessed the requirement of ERRα/ERRγ for the oxidative phosphorylation (OXPHOS) burst and iPSC generation in human and mouse cells.
• Utilized cell sorting (Sca1/CD34 markers) and transcriptional profiling to identify and characterize reprogramming progenitor cells.

Main Results:

• A transient induction of ERRα/ERRγ and PGC-1α/PGC-1β occurs early in reprogramming, leading to a significant burst of OXPHOS activity.
• Upregulation of ERRα (in human) or ERRγ (in mouse) is essential for this OXPHOS burst and for successful iPSC generation.
• A rare Sca1(-)/CD34(-) cell population was identified as highly enriched in bona fide reprogramming progenitors, characterized by ERRγ and PGC-1β expression and metabolic reprogramming.

Conclusions:

• Reprogramming to induced pluripotency involves a previously unrecognized, ERR-dependent metabolic gate characterized by an OXPHOS burst.
• This metabolic switch, regulated by estrogen-related nuclear receptors, is a critical prerequisite for establishing pluripotency.
• Targeting this ERR-dependent metabolic pathway could offer new strategies for enhancing reprogramming efficiency.