Matsuda Hiroki, Parsons Michael J, Leach Steven D
Department of Surgery and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS One. 2013 Sep 17;8(9):e74350. doi: 10.1371/journal.pone.0074350. eCollection 2013.
Aldh1 expression is known to mark candidate progenitor populations in adult and embryonic mouse pancreas, and Aldh1 enzymatic activity has been identified as a potent regulator of pancreatic endocrine differentiation in zebrafish. However, the location and identity of Aldh1-expressing cells in zebrafish pancreas remain unknown. In this study we demonstrate that Aldh1-expressing cells are located immediately adjacent to 2F11-positive pancreatic ductal epithelial cells, and that their abundance dramatically increases during zebrafish secondary islet formation. These cells also express neurod, a marker of endocrine progenitor cells, but do not express markers of more mature endocrine cells such as pax6b or insulin. Using formal cre/lox-based lineage tracing, we further show that Aldh1-expressing pancreatic epithelial cells are the direct progeny of pancreatic notch-responsive progenitor cells, identifying them as a critical intermediate between multi-lineage progenitors and mature endocrine cells. Pharmacologic manipulation of Aldh1 enzymatic activity accelerates cell entry into the Aldh1-expressing endocrine progenitor pool, and also leads to the premature maturation of these cells, as evidenced by accelerated pax6b expression. Together, these findings suggest that Aldh1-expressing cells act as both participants and regulators of endocrine differentiation during zebrafish secondary islet formation.
已知醛脱氢酶1（Aldh1）的表达可标记成年和胚胎期小鼠胰腺中的候选祖细胞群体，并且已确定Aldh1的酶活性是斑马鱼胰腺内分泌分化的有效调节因子。然而，斑马鱼胰腺中表达Aldh1的细胞的位置和特性仍然未知。在本研究中，我们证明表达Aldh1的细胞紧邻2F11阳性的胰腺导管上皮细胞，并且在斑马鱼次级胰岛形成过程中其数量显著增加。这些细胞还表达神经源性分化蛋白（Neurod），这是一种内分泌祖细胞的标志物，但不表达更成熟内分泌细胞的标志物，如配对盒基因6b（Pax6b）或胰岛素。使用基于正式的cre/lox谱系追踪技术，我们进一步表明，表达Aldh1的胰腺上皮细胞是胰腺Notch反应性祖细胞的直接后代，确定它们为多谱系祖细胞和成熟内分泌细胞之间的关键中间体。对Aldh1酶活性进行药理学操作可加速细胞进入表达Aldh1的内分泌祖细胞池，并且还导致这些细胞过早成熟，这通过加速的Pax6b表达得到证明。总之，这些发现表明，在斑马鱼次级胰岛形成过程中，表达Aldh1的细胞既是内分泌分化的参与者，也是调节者。
