Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Dis Model Mech. 2012 Jul;5(4):503-14. doi: 10.1242/dmm.007799. Epub 2012 Jan 19.
The size of the pancreas is determined by intrinsic factors, such as the number of progenitor cells, and by extrinsic signals that control the fate and proliferation of those progenitors. Both the exocrine and endocrine compartments of the pancreas undergo dramatic expansion after birth and are capable of at least partial regeneration following injury. Whether the expansion of these lineages relies on similar mechanisms is unknown. Although we have shown that the Wnt signaling component β-catenin is selectively required in mouse embryos for the generation of exocrine acinar cells, this protein has been ascribed various functions in the postnatal pancreas, including proliferation and regeneration of islet as well as acinar cells. To address whether β-catenin remains important for the maintenance and expansion of mature acinar cells, we have established a system to follow the behavior and fate of β-catenin-deficient cells during postnatal growth and regeneration in mice. We find that β-catenin is continuously required for the establishment and maintenance of acinar cell mass, extending from embryonic specification through juvenile and adult self-renewal and regeneration. This requirement is not shared with islet cells, which proliferate and function normally in the absence of β-catenin. These results make distinct predictions for the relative role of Wnt-β-catenin signaling in the etiology of human endocrine and exocrine disease. We suggest that loss of Wnt-β-catenin activity is unlikely to drive islet dysfunction, as occurs in type 2 diabetes, but that β-catenin is likely to promote human acinar cell proliferation following injury, and might therefore contribute to the resolution of acute or chronic pancreatitis.
胰腺的大小由内在因素决定，如祖细胞的数量，以及控制这些祖细胞命运和增殖的外在信号。胰腺的外分泌和内分泌部分在出生后都会经历显著的扩张，并在受伤后能够至少部分再生。这些谱系的扩张是否依赖于相似的机制尚不清楚。尽管我们已经表明，Wnt 信号成分β-连环蛋白在小鼠胚胎中选择性地需要产生外分泌腺泡细胞，但这种蛋白质在出生后的胰腺中被赋予了各种功能，包括胰岛和腺泡细胞的增殖和再生。为了解决β-连环蛋白是否仍然对成熟腺泡细胞的维持和扩张很重要，我们建立了一个系统来研究β-连环蛋白缺陷细胞在小鼠出生后生长和再生过程中的行为和命运。我们发现，β-连环蛋白在腺泡细胞质量的建立和维持中持续需要，从胚胎特化延伸到幼年和成年的自我更新和再生。这一需求与胰岛细胞不同，β-连环蛋白缺失的胰岛细胞可以正常增殖和发挥功能。这些结果对 Wnt-β-连环蛋白信号在人类内分泌和外分泌疾病病因学中的相对作用做出了明确的预测。我们认为，Wnt-β-连环蛋白活性的丧失不太可能导致胰岛功能障碍，如 2 型糖尿病中发生的那样，但β-连环蛋白可能会促进人类腺泡细胞在受伤后的增殖，并因此可能有助于缓解急性或慢性胰腺炎。
