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Quantitative lineage analysis identifies a hepato-pancreato-biliary progenitor niche

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David Willnow, Uwe Benary, Anca Margineanu, Maria Lillina Vignola, Fabian Konrath, Igor M. Pongrac, Zahra Karimaddini, Alessandra Vigilante, Jana Wolf, Francesca M. Spagnoli

Original languageEnglish
Pages (from-to)87-91
Number of pages5
Issue number7874
Published2 Sep 2021

Bibliographical note

Funding Information: Acknowledgements We thank all the members of the Spagnoli laboratory for their useful comments and suggestions on the study; H. Naumann for technical help; G. Pazour for IFT57 antibody; A. Christ and T. Willnow for the GLI2 and SMO antibodies; the MDC Transgenic Unit for technical help in generating the Prox1-rtTA mouse strain; and C. Beisel of the Genomics Facility of D-BSSE for NGS RNA sequencing. Maintenance of the two-photon microscopy setup was supported by the staff of the Advanced Light Microscopy technology platform via funding from the MDC in the Helmholtz Association. This research was supported by funds from the Helmholtz Association (FMS, JW), European Union’s Horizon 2020 Research and Innovation Programme (Pan3DP Grant agreement no. 800981) (FMS, DW); D.W. was a recipient of a BIH (Tr. PhD) fellowship. U.B. was a recipient of an EMBO Short-Term Fellowship (7853). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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Studies based on single cells have revealed vast cellular heterogeneity in stem cell and progenitor compartments, suggesting continuous differentiation trajectories with intermixing of cells at various states of lineage commitment and notable degrees of plasticity during organogenesis1–5. The hepato-pancreato-biliary organ system relies on a small endoderm progenitor compartment that gives rise to a variety of different adult tissues, including the liver, pancreas, gall bladder and extra-hepatic bile ducts6,7. Experimental manipulation of various developmental signals in the mouse embryo has underscored important cellular plasticity in this embryonic territory6. This is reflected in the existence of human genetic syndromes as well as congenital malformations featuring multi-organ phenotypes in liver, pancreas and gall bladder6. Nevertheless, the precise lineage hierarchy and succession of events leading to the segregation of an endoderm progenitor compartment into hepatic, biliary and pancreatic structures have not yet been established. Here we combine computational modelling approaches with genetic lineage tracing to accurately reconstruct the hepato-pancreato-biliary lineage tree. We show that a multipotent progenitor subpopulation persists in the pancreato-biliary organ rudiment, contributing cells not only to the pancreas and gall bladder but also to the liver. Moreover, using single-cell RNA sequencing and functional experiments we define a specialized niche that supports this subpopulation in a multipotent state for an extended time during development. Together these findings indicate sustained plasticity underlying hepato-pancreato-biliary development that might also explain the rapid expansion of the liver while attenuating pancreato-biliary growth.

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