Department of Developmental Biology and Cancer Research, The institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Dev Biol. 2011 Nov 1;359(1):26-36. doi: 10.1016/j.ydbio.2011.08.006. Epub 2011 Aug 17.
During pancreas development, endocrine and exocrine cells arise from a common multipotent progenitor pool. How these cell fate decisions are coordinated with tissue morphogenesis is poorly understood. Here we have examined ductal morphology, endocrine progenitor cell fate and Notch signaling in Ngn3(-/-) mice, which do not produce islet cells. Ngn3 deficiency results in reduced branching and enlarged pancreatic duct-like structures, concomitant with Ngn3 promoter activation throughout the ductal epithelium and reduced Notch signaling. Conversely, forced generation of surplus endocrine progenitor cells causes reduced duct caliber and an excessive number of tip cells. Thus, endocrine progenitor cells normally provide a feedback signal to adjacent multipotent ductal progenitor cells that activates Notch signaling, inhibits further endocrine differentiation and promotes proper morphogenesis. These results uncover a novel layer of regulation coordinating pancreas morphogenesis and endocrine/exocrine differentiation, and suggest ways to enhance the yield of beta cells from stem cells.
在胰腺发育过程中，内分泌细胞和外分泌细胞来源于一个共同的多能祖细胞池。这些细胞命运决定如何与组织形态发生协调尚不清楚。在这里，我们研究了 Ngn3(-/-) 小鼠的导管形态、内分泌祖细胞命运和 Notch 信号，这些小鼠不产生胰岛细胞。Ngn3 缺乏导致分支减少和胰腺导管样结构增大，同时 Ngn3 启动子在整个导管上皮中激活，Notch 信号减少。相反，强制产生多余的内分泌祖细胞会导致导管口径减小和尖端细胞数量过多。因此，内分泌祖细胞通常会向相邻的多能导管祖细胞提供反馈信号，激活 Notch 信号，抑制进一步的内分泌分化，并促进适当的形态发生。这些结果揭示了一种新的调节层，协调胰腺形态发生和内分泌/外分泌分化，并提出了从干细胞中增强β细胞产量的方法。
