Abstract
The classical development hierarchy of pancreatic cell fate commitments describes that multipotent progenitors (MPs) first bifurcate into tip cells and trunk cells, and then these cells give rise to acinar cells and endocrine/ductal cells separately. However, lineage tracings reveal that pancreatic progenitors are highly heterogeneous in tip and trunk domains in embryonic pancreas. The progenitor fate commitments from multipotency to unipotency during early pancreas development is insufficiently characterized. In pursuing a mechanistic understanding of the complexity in progenitor fate commitments, we construct a core endogenous network for pancreatic lineage decisions based on genetic regulations and quantified its intrinsic dynamic properties using dynamic modeling. The dynamics reveal a developmental landscape with high complexity that has not been clarified. Not only well-characterized pancreatic cells are reproduced, but also previously unrecognized progenitors—tip progenitor (TiP), trunk progenitor (TrP), later endocrine progenitor (LEP), and acinar progenitors (AciP/AciP2) are predicted. Further analyses show that TrP and LEP mediate endocrine lineage maturation, while TiP, AciP, AciP2 and TrP mediate acinar and ductal lineage maturation. The predicted cell fate commitments are validated by analyzing single-cell RNA sequencing (scRNA-seq) data. Significantly, this is the first time that a redefined hierarchy with detailed early pancreatic progenitor fate commitment is obtained.
Highlights
There are three major mature cell types in the adult pancreas, they are exocrine acinar and ductal cells, and endocrine cells
Complete endocrine lineage commitment path mediated by trunk progenitor (TrP) and later endocrine progenitor (LEP), and more complex exocrine acinar and ductal lineage commitment paths mediated by tip progenitor (TiP), acinar progenitor (AciP), TrP, and TrP2 are revealed
Though complex gene regulations involve in pancreas development[45], several master TFs are prominent by playing a pivotal role in determining lineage decisions (Fig. 1a)
Summary
There are three major mature cell types in the adult pancreas, they are exocrine acinar and ductal cells, and endocrine cells. In the mouse, MPs can Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of www.nature.com/scientificreports directly give rise to a small proportion of endocrine progenitors from E8.5 to E11.017. These observations, which are mainly based on morphogenesis, are generalized as the classical hierarchy[11,13]. Modeling the pancreatic progenitor fate commitments is plagued by complex gene regulations in pancreas development. By quantifying the dynamic property of the network, we obtained an adaptive landscape governing the development process Both well-characterized pancreatic cell types and previously unrecognized progenitors—TrP, LEP, TiP, AciP, and AciP2, are predicted. This is the first time that the detailed early pancreatic progenitor fate commitments in the embryonic pancreas are obtained
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