Activation of an early postnatal splicing program by ESRP2 is critical for liver regeneration

The mammalian liver has the unique capacity to undergo robust regeneration in response to damage. This regenerative capacity was previously attributed to facultative stem cell populations, but several recent lineage-tracing... [ view full abstract ]

The mammalian liver has the unique capacity to undergo robust regeneration in response to damage. This regenerative capacity was previously attributed to facultative stem cell populations, but several recent lineage-tracing studies have shown that most new hepatocytes are derived from pre-existing ones.  However, the underlying principles that drive reprogramming of a quiescent hepatocyte into proliferative state remain elusive.  We performed high-resolution RNA-sequencing of purified hepatocytes isolated from quiescent and toxin-injured mouse livers, identifying extensive remodeling of the hepatic transcriptome: including genes related to cell cycle regulation, RNA modifications, and metabolic processes.  Surprisingly, the remodeling process is accompanied by numerous splice isoform transitions, a majority of which switch to an early postnatal pattern, suggesting hepatocytes reprogram their transcriptome towards an immature state to become proliferative.  We demonstrate that dynamic regulation of Epithelial splicing regulatory protein 2 (ESRP2) upon toxin-injury is essential for activating the early postnatal splicing program within hepatocytes. ESRP2 protein levels decline during the injury phase but are fully restored upon toxin removal.  The livers of ESRP2 knockout mice, compared to controls, exhibit excessive hepatocyte proliferation upon injury, but are unable to return to a physiologically mature state following recovery.  Remarkably, forced expression of ESRP2 during toxin exposure blocks the hepatocyte proliferation and inhibits the adult-to-early postnatal switch in splicing for a large set of RNA transcripts associated with cell cycle control.  We conclude that after sustaining damage, an early postnatal splicing regulatory network is redeployed through dynamic regulation of ESRP2 within adult hepatocytes to facilitate liver regeneration.