Lgr5+ stem/progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool

Prior N et al. (2019) Development 29 May. dev.174557 DOI: 10.1242/dev.174557. 

Summary 
Lgr5 positive bipotent hepatoblasts contribute to liver development and reside at the apex of a heterogeneous embryonic liver progenitor pool.

Abstract from the paper

During mouse embryogenesis, progenitors within the liver known as hepatoblasts give rise to adult hepatocytes and cholangiocytes. Hepatoblasts, which are specified at E8.5-E9.0, have been regarded as a homogeneous progenitor population that initiate differentiation from E13.5. Recently, scRNA-seq analysis has identified subpopulations of transcriptionally distinct hepatoblasts at E11.5.

Here, we show that hepatoblasts are not only transcriptionally but also functionally heterogeneous, and that a subpopulation of E9.5-E10.0 hepatoblasts exhibit a previously unidentified early commitment to cholangiocyte fate. Importantly, we also identify a sub-population constituting 2% of E9.5-E10.0 hepatoblasts that express the adult stem cell marker Lgr5, and generate both hepatocyte and cholangiocyte progeny that persist for the lifespan of the mouse.

Combining lineage tracing and scRNA-seq, we show that Lgr5 marks E9.5-E10.0 bipotent liver progenitors residing at the apex of a hepatoblast hierarchy. Furthermore, isolated Lgr5+ hepatoblasts can be clonally expanded in vitro into embryonic liver organoids, which can commit to either hepatocyte or cholangiocyte fates.

Our study demonstrates functional heterogeneity within E9.5 hepatoblasts and identifies Lgr5 as a marker for a sub-population of bipotent liver progenitors. 

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