Feedback control of growth, differentiation, and morphogenesis of pancreatic endocrine progenitors in an epithelial plexus niche

Abstract

In the mammalian pancreas, endocrine cells undergo lineage allocation upon emergence from a bipotent duct/endocrine progenitor pool, which resides in the "trunk epithelium." Major questions remain regarding how niche environments are organized within this epithelium to coordinate endocrine differentiation with programs of epithelial growth, maturation, and morphogenesis. We used EdU pulse-chase and tissue-reconstruction approaches to analyze how endocrine progenitors and their differentiating progeny are assembled within the trunk as it undergoes remodeling from an irregular plexus of tubules to form the eventual mature, branched ductal arbor. The bulk of endocrine progenitors is maintained in an epithelial "plexus state," which is a transient intermediate during epithelial maturation within which endocrine cell differentiation is continually robust and surprisingly long-lived. Within the plexus, local feedback effects derived from the differentiating and delaminating endocrine cells nonautonomously regulate the flux of endocrine cell birth as well as proliferative growth of the bipotent cell population using Notch-dependent and Notch-independent influences, respectively. These feedback effects in turn maintain the plexus state to ensure prolonged allocation of endocrine cells late into gestation. These findings begin to define a niche-like environment guiding the genesis of the endocrine pancreas and advance current models for how differentiation is coordinated with the growth and morphogenesis of the developing pancreatic epithelium.

Precommitment low-level Neurog3 expression defines a long-lived mitotic endocrine-biased progenitor pool that drives production of endocrine-committed cells

“…First, low-level Neurog3 expression within the secondary transition pancreatic epithelium seems widespread. Either Neurog3 BAC.Cre ;R26R lineage tracing or a Neurog3 EGFP/+ knock-in reporter detects a large number of intraepithelial cells that potentially represent cells in a Neurog3-expressing pre-endocrine-committed state (Zhang et al 2009;Wang et al 2010;Bankaitis et al 2015). In the study by Villasenor et al (2008), Neurog3 mRNA detection also suggests a Neurog3-expressing epithelial population that is broader than that visualized by Neurog3 immunodetection.…”

“…The trunk domain, a primary component of the epithelial plexus, consists of a pool of duct/endocrine bipotential Sox9 + Hnf1b + Nkx6.1 + cells (Seymour et al 2007;Solar et al 2009). Recently, we reported that distinct modes of epithelial morphogenesis in the peripheral versus core regions of the developing pancreas work in concert to generate the final "epithelial tree" of the mature pancreas (Bankaitis et al 2015). In the core, the epithelial plexus remodels into mature ductal tissues via growth and expansion (E12.5-E15.5) followed by plexus-to-duct transformation (E16.5-E18.5) (Bankaitis et al 2015).…”

“…Recently, we reported that distinct modes of epithelial morphogenesis in the peripheral versus core regions of the developing pancreas work in concert to generate the final "epithelial tree" of the mature pancreas (Bankaitis et al 2015). In the core, the epithelial plexus remodels into mature ductal tissues via growth and expansion (E12.5-E15.5) followed by plexus-to-duct transformation (E16.5-E18.5) (Bankaitis et al 2015). Although the plexus is progressively lost, remodeling into "mature" ducts and ductal branches, it is present during all stages of the secondary transition.…”

“…Although the plexus is progressively lost, remodeling into "mature" ducts and ductal branches, it is present during all stages of the secondary transition. Even at late gestation, plexus-state epithelium generates as many endocrine cells as earlier in the secondary transition, suggesting that the plexus represents a primary endocrine progenitor niche (Bankaitis et al 2015). Within the trunk plexus-state epithelium, the transcription factor Neurog3 is a key trigger factor for endocrine lineage commitment.…”

New ideas connecting the cell cycle and pancreatic endocrine-lineage specification

“…Previous studies of mouse pancreas development suggest a strong reciprocal connection between the number of Neurog3 TA.LO progenitors and the architecture and integrity of the epithelial "plexus state" defined as the endocrine-birthing niche. 1,4,5 To date, production of multilineage islet-like clusters from hESC-derived pancreas progenitors has only been reported following implantation and maturation under the kidney capsule in vivo, allowing the transplant to adopt a complex 3-D structure. 6 Recent studies indicate that Neurog3 is just as critical to human pancreatic endocrine development as in mice, with true Neurog3 null mutations leading to neonatal diabetes and a block in b-cell differentiation from hESC.…”