Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation
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- Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation
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In the liver, ductal cells rarely proliferate during homeostasis but do so transiently after tissue injury. These cells can be expanded as organoids that recapitulate several of the cell-autonomous mechanisms of regeneration but lack the stromal interactions of the native tissue. Here, using organoid co-cultures that recapitulate the ductal-to-mesenchymal cell architecture of the portal tract, we demonstrate that a subpopulation of mouse periportal mesenchymal cells exerts dual control on proliferation of the epithelium. Ductal cell proliferation is either induced and sustained or, conversely, completely abolished, depending on the number of direct mesenchymal cell contacts, through a mechanism mediated, at least in part, by Notch signaling. Our findings expand the concept of the cellular niche in epithelial tissues, whereby not only soluble factors but also cell-cell contacts are the key regulatory cues involved in the control of cellular behaviors, suggesting a critical role for cell-cell contacts during regeneration.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cell Stem Cell |
| Vol/bind | 28 |
| Udgave nummer | 11 |
| Sider (fra-til) | 1907-1921.e8 |
| Antal sider | 24 |
| ISSN | 1934-5909 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
M.H. is a Lise Meitner Fellow from the Max-Planck-Gesellschaft . This work was funded by a Wellcome Trust Sir Henry Dale Fellowship awarded to M.H. ( 104151/Z/14/Z ). L.C.-E. was funded by a Wellcome Trust Four-Year PhD Studentship from the Stem Cell Biology and Medicine Program. T.N.K. was supported by an AstraZeneca Graduate Studentship. N.C.H. is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (ref. 219542/Z/19/Z ), Medical Research Council , and a Chan Zuckerberg Initiative Seed Network Grant. F.H. is an H2020 ERC Advanced Investigator ( 695669 ). P.S. received grants from the Novo Nordisk Foundation ( NNF16076 and NNF10717 ). This work was partially funded by an H2020 LSMF4LIFE ( ECH2020-668350 awarded to M.H.) and the Wellcome Trust ( WT108438/C/15/Z awarded to F.H.) We acknowledge the Gurdon Institute core funding ( Wellcome Trust 092096 and CRUK C6946/A14492 ). We also thank Mr. Robert Arnes-Benito for technical assistance, Prof. Anne Grapin-Botton and Prof. Magdalena Zernicka-Goetz for providing mouse strains, Mr. Kay Harnish and Dr. Charles Bradshaw (both from the Gurdon Institute), Dr. Jan Peychl and Dr. Sebastian Bundschuh (both from MPI-CBG), and the Gurdon Institute and MPI-CBG animal facilities for help with bioinformatics, imaging, and animal care; Dr. Andy Riddell (Cambridge Stem Cell Institute), Ms. Joana Cerveira (Department of Pathology, University of Cambridge), and Ms. Julia Jarrells and Ms. Ina Nuesslein (both MPI-CBG) for assistance with fluorescence-activated cell sorting (FACS); Dr. Maike Paramor (Cambridge Stem Cell Institute) for library preparation; and Mr. Hans Kleine-Brüggeney for the chip design.
Funding Information:
M.H. is a Lise Meitner Fellow from the Max-Planck-Gesellschaft. This work was funded by a Wellcome Trust Sir Henry Dale Fellowship awarded to M.H. (104151/Z/14/Z). L.C.-E. was funded by a Wellcome Trust Four-Year PhD Studentship from the Stem Cell Biology and Medicine Program. T.N.K. was supported by an AstraZeneca Graduate Studentship. N.C.H. is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (ref. 219542/Z/19/Z), Medical Research Council, and a Chan Zuckerberg Initiative Seed Network Grant. F.H. is an H2020 ERC Advanced Investigator (695669). P.S. received grants from the Novo Nordisk Foundation (NNF16076 and NNF10717). This work was partially funded by an H2020 LSMF4LIFE (ECH2020-668350 awarded to M.H.) and the Wellcome Trust (WT108438/C/15/Z awarded to F.H.) We acknowledge the Gurdon Institute core funding (Wellcome Trust 092096 and CRUK C6946/A14492). We also thank Mr. Robert Arnes-Benito for technical assistance, Prof. Anne Grapin-Botton and Prof. Magdalena Zernicka-Goetz for providing mouse strains, Mr. Kay Harnish and Dr. Charles Bradshaw (both from the Gurdon Institute), Dr. Jan Peychl and Dr. Sebastian Bundschuh (both from MPI-CBG), and the Gurdon Institute and MPI-CBG animal facilities for help with bioinformatics, imaging, and animal care; Dr. Andy Riddell (Cambridge Stem Cell Institute), Ms. Joana Cerveira (Department of Pathology, University of Cambridge), and Ms. Julia Jarrells and Ms. Ina Nuesslein (both MPI-CBG) for assistance with fluorescence-activated cell sorting (FACS); Dr. Maike Paramor (Cambridge Stem Cell Institute) for library preparation; and Mr. Hans Kleine-Br?ggeney for the chip design. M.H. and L.C.-E. designed the project. L.C.-E. and A.M.D. performed most of the experiments and, together with M.H. interpreted results. L.C.-E. A.M.D. and T.N.K. performed and F.H. supervised the microfluidics experiments. O.S. N.P. B.S. and G.B. performed experiments, and C.P. performed bioinformatics analyses. R.D. J.R.W.-K. and N.C.H. provided and analyzed the scRNA-seq data. R.B. F.J. and N.P.M. assisted with image analysis. P.S. provided mice. L.C.-E. A.M.D. and M.H. wrote the manuscript. All authors read and commented on the manuscript. M.H. is inventor in a patent on liver organoids and is on the advisory board of the journal Cell Stem Cell.
Publisher Copyright:
© 2021 The Authors
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