RT Journal Article
SR Electronic
T1 Lgr5+ stem/progenitor cells reside at the apex of the embryonic hepatoblast pool
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 485870
DO 10.1101/485870
A1 Nicole Prior
A1 Christopher J. Hindley
A1 Fabian Rost
A1 Elena Meléndez Esteban
A1 Winnie W. Y. Lau
A1 Berthold Göttgens
A1 Steffen Rulands
A1 Benjamin D. Simons
A1 Meritxell Huch
YR 2018
UL http://biorxiv.org/content/early/2018/12/04/485870.abstract
AB Abstract During mouse embryogenesis, progenitors within the liver known as hepatoblasts give rise to adult hepatocyte and cholangiocyte cells. Hepatoblasts, which are specified at E8.5-E9.0, have been regarded as a homogeneous population of progenitors, which initiate differentiation into hepatocytes and cholangiocytes from E13.5 onwards. Recently, sub-populations of transcriptionally different hepatoblasts have been identified as already present at E11.5 by single cell RNAseq (scRNAseq) analysis. However, whether these transcriptional differences result from functionally heterogeneous hepatoblast populations is unknown. Here we show that the hepatoblast pool is not only transcriptionally but also functionally heterogeneous and that a sub-population of E9.5-E10.0 hepatoblasts exhibits a previously unidentified early commitment to cholangiocyte fate. Importantly, we also identify a sub-population of bona-fide E9.5 hepatoblasts which express the adult stem cell marker Lgr5 and contribute to liver development by generating both hepatocyte and cholangiocyte progeny that persist for the life-span of the mouse. Using a combination of lineage tracing and scRNAseq, we show that Lgr5 marks E9.5-E10.0 bi-potent liver progenitors residing at the apex of a hierarchy of the hepatoblast population. Notably, isolated Lgr5+ hepatoblasts can be clonally expanded in vitro into embryonic liver organoids, which can commit to hepatocyte or cholangiocyte fates dependent upon the culture conditions. Our study represents the first functional demonstration of heterogeneity within E9.5 hepatoblasts and identifies Lgr5 as a marker for a sub-population of truly bi-potent liver progenitors.Summary Statement Lgr5 positive bi-potential hepatoblasts contribute to liver development and reside at the apex of an embryonic liver progenitor pool.