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Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine

Abstract

The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.

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Figure 1: Sox9 is expressed in adult intestinal crypt, pancreatic duct and bile duct.
Figure 2: Physiological cell supply from the Sox9-expressing progenitors in the adult intestine, pancreas and liver.
Figure 3: Accelerated hepatocyte differentiation from the Sox9-expressing precursors during liver regeneration (ap).
Figure 4: Sox9 expression in the embryonic intestine, pancreas, liver and bile duct.
Figure 5: Behavior of Sox9-expressing cells during organogenesis of the intestine, pancreas and liver.
Figure 6: The proposed interdependent relationship among the structure, function and homeostasis of the intestine, liver and pancreas and Sox9 expression is linked to progenitor status.

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Acknowledgements

We thank A. Fukuda and M. Gannon for critical discussions and reading of the manuscript, Y. Ishiura and K. Fukazawa for technical help, C.V.E. Wright for Pdx1 antibody, P. Soriano for Rosa26R mice and the staff of the Institute of Laboratory Animals of Kyoto University for animal care. This work was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the US National Institutes of Health.

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Contributions

Y.K. and K.F. designed the study, analyzed the data and prepared the manuscript. K.F. performed the experiments. H.A. and R.R.B. generated mice. T.S. screened mouse lines. J.M.D. cultured embryonic stem cells. E.N., M.H., S.K., T.K., S.H., A.E., M. Koizumi, T.M., M. Kawaguchi, K.T., R.K. and R.D. gave technical support and discussion. T.N. and S.U. supervised the project.

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Correspondence to Yoshiya Kawaguchi or Haruhiko Akiyama.

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The authors declare no competing financial interests.

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Supplementary Figures 1–13 and Supplementary Tables 1–5 (PDF 4905 kb)

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Furuyama, K., Kawaguchi, Y., Akiyama, H. et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43, 34–41 (2011). https://doi.org/10.1038/ng.722

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