Bankaitis Eric D, Bechard Matthew E, Wright Christopher V E
Vanderbilt University Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Genes Dev. 2015 Oct 15;29(20):2203-16. doi: 10.1101/gad.267914.115.
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.
在哺乳动物的胰腺中，内分泌细胞从位于“主干上皮”的双能导管/内分泌祖细胞池中出现后，会进行谱系分配。关于这种上皮组织中微环境是如何组织的，以协调内分泌分化与上皮生长、成熟和形态发生的程序，仍存在重大问题。我们使用EdU脉冲追踪和组织重建方法，来分析内分泌祖细胞及其分化后代在主干从不规则的小管丛重塑形成最终成熟的分支导管树时，是如何在其中组装的。大部分内分泌祖细胞维持在上皮“丛状状态”，这是上皮成熟过程中的一个短暂中间状态，在此期间内分泌细胞分化持续强劲且持续时间惊人地长。在丛状结构中，分化和分层的内分泌细胞产生的局部反馈效应，分别通过Notch依赖性和Notch非依赖性影响，非自主地调节内分泌细胞产生的通量以及双能细胞群体的增殖生长。这些反馈效应反过来维持丛状状态，以确保内分泌细胞在妊娠后期的长时间分配。这些发现开始定义一种类似微环境的环境，指导内分泌胰腺的发生，并推进了当前关于分化如何与发育中的胰腺上皮的生长和形态发生相协调的模型。
