Lgr5+ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool.
Huch Ortega, Meritxell
Development (Cambridge, England)
Company of Biologists
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Prior, N., Hindley, C., Rost, F., Meléndez, E., Lau, W., Gottgens, B., Rulands, S., et al. (2019). Lgr5+ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool.. Development (Cambridge, England), 146 (12)https://doi.org/10.1242/dev.174557
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 sub-populations of transcriptionally distinct hepatoblasts at E11.5. Here we show that hepatoblasts are not only transcriptionally but also functionally heterogeneous, and that a sub-population 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 life span 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. Notably, 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 sub53 population of bipotent liver progenitors.
Liver, Cells, Cultured, Epithelial Cells, Hepatocytes, Stem Cells, Animals, Mice, Receptors, G-Protein-Coupled, Microscopy, Confocal, Cell Culture Techniques, Cell Count, Cell Differentiation, Gene Expression Regulation, Developmental, Base Sequence, Cell Lineage, Embryonic Development, Homeostasis, Alleles, Female, Male
M.H. is a Wellcome Trust Sir Henry Dale Fellow and is jointly funded by the Wellcome Trust and the Royal Society (104151/Z/14/Z); M.H. and N.P. are funded by a Horizon 2020 grant (LSFM4LIFE). C.H. was funded by a Cambridge Stem Cell Institute Seed funding for interdisciplinary research awarded to M.H. and B.D.S., B.D.S acknowledges funding from the Royal Society E.P. Abraham Research Professorship (RP\R1\180165) and Wellcome Trust (098357/Z/12/Z). W.L. and B.G. were supported by programmatic funding from the Wellcome Trust, CRUK and Bloodwise, core infrastructure support from the Wellcome and MRC to the Wellcome & MRC Cambridge Stem Cell Institute, and an MRC Clinical Research Infrastructure grant supporting single cell molecular analysis. S.R. was funded on a Herchel-Smith Fellowship. The authors acknowledge core funding to the Gurdon Institute from the Wellcome Trust (092096) and CRUK (C6946/A14492).
WELLCOME TRUST (098357/Z/12/Z)
Royal Society (RP/R1/180165)
WELLCOME TRUST (105031/D/14/Z)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
WELLCOME TRUST (104151/Z/14/Z)
External DOI: https://doi.org/10.1242/dev.174557
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292965
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