Adaptive Landscape Shaped by Core Endogenous Network Coordinates Complex Early Progenitor Fate Commitments in Embryonic Pancreas

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.

Endocrine Pancreas Development and Dysfunction Through the Lens of Single-Cell RNA-Sequencing

“…The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2021.629212/full#supplementary-material . The following scRNA-Seq studies are not discussed in the manuscript, but are included in Supplementary Tables: ( Grün et al, 2016 ; Wollny et al, 2016 ; Stanescu et al, 2017 ; Wang J. et al, 2020 ).…”

Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip

“…Differences between in vitro and in vivo progenitors have been observed during endocrine development, which also did not report a distinct trunk-like stage 66 – 68 . From in vivo mouse scRNA-seq data, additional developmental routes of pancreatic progenitors have been postulated 69 , and the development of a ductal subpopulation from Pdx1 + Ptf1a - pancreatic progenitor cells has been directly demonstrated in vivo by lineage tracing experiments 70 , 71 . Thus, it appears that the heterogeneity of pancreatic progenitors is larger than expected.…”

Developmentally-Inspired Biomimetic Culture Models to Produce Functional Islet-Like Cells From Pluripotent Precursors

“…Complex in silico models and improved culture systems may be required to tease apart the many confounded effects of the dynamic cellular microenvironment. Previously, mathematical models of the interactions between biomechanical stimuli and regulatory gene networks have been used to predict MSC ( Peng et al, 2017 ) and pancreatic cell fate decisions ( Zhou et al, 2011 , 2016 ; de Back et al, 2013 ; Wang et al, 2020 ). Novel in silico models which deal with cell generated forces in aggregate culture ( Lee et al, 2019 ) while varying stiffness or cell organization over time could help us understand how mechanotransduction changes throughout a differentiating aggregate.…”