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PNAS:陈永龙等发现转录因子hhex决定腹部胰腺前体细胞形成

来源:广州生物医药与健康研究院 2012-05-30 09:48

近日,中国科学院广州生物医药与健康研究院陈永龙研究组与香港中文大学赵晖研究组合作,借助通过基因芯片筛选获得的首个腹部胰腺前体细胞特异表达的标记基因vpp1,在非洲爪蛙胚胎中发现转录因子hhex决定腹部胰腺前体细胞的形成。

过表达单一转录因子hhex足以将大量将来形成肠道的内胚层细胞转变为vpp1阳性的腹部胰腺前体细胞,进而在爪蛙蝌蚪中形成一个巨大的胰腺,其中成熟的、合成胰岛素的胰岛β细胞的发育与正常胰腺中的完全相同。反之,hhex敲减后,vpp1阳性细胞急剧减少,最终导致腹部胰腺的缺失。该成果近日在《美国国家科学院院刊》(PNAS)在线发表。

阐明从受精卵发育开始到各种不同组织器官的细胞谱系的建立过程,是进行干细胞定向诱导分化并最终将其推向临床应用的基础。该研究揭示了预定形成腹部胰腺前体细胞的命运决定。在原肠作用期间,hhex与vpp1的表达有部分重叠,非重叠部分的hhex阳性细胞主要是预定形成肝脏的前体细胞,目前还不清楚为什么在爪蛙胚胎中过表达hhex只能选择性地诱导形成巨大的腹部胰腺而不能使肝脏增大。研究人员希望更进一步的研究可以阐明来源于内胚层的不同类型细胞谱系的建立和命运决定的机制,为干细胞的定向诱导分化(如胰岛β细胞的分化)和应用奠定基础。

该项研究受到科技部973项目和中科院项目百人计划资助。(生物谷Bioon.com)

Homeoprotein hhex-induced conversion of intestinal to ventral pancreatic precursors results in the formation of giant pancreata in Xenopus embryos

Hui Zhaoa,1, Dandan Hanb,c,1, Igor B. Dawidd,2, Tomas Pielere,2, and Yonglong Chenb,2

Liver and ventral pancreas develop from neighboring territories within the endoderm of gastrulae. ventral pancreatic precursor 1 (vpp1) is a marker gene that is differentially expressed in a cell population within the dorsal endoderm in a pattern partially overlapping with that of hematopoietically expressed homeobox (hhex) during gastrulation. In tail bud embryos, vpp1 expression specifically demarcates two ventral pancreatic buds, whereas hhex expression is mainly restricted to the liver diverticulum. Ectopic expression of a critical dose of hhex led to a greatly enlarged vpp1-positive domain and, subsequently, to the formation of giant ventral pancreata, putatively by conversion of intestinal to ventral pancreatic precursor cells. Conversely, antisense morpholino oligonucleotide-mediated knockdown of hhex resulted in a down-regulation of vpp1 expression and a specific loss of the ventral pancreas. Furthermore, titration of hhex with a dexamethasone-inducible hhex-VP16GR fusion construct suggested that endogenous hhex activity during gastrulation is essential for the formation of ventral pancreatic progenitor cells. These observations suggest that, beyond its role in liver development, hhex controls specification of a vpp1-positive endodermal cell population during gastrulation that is required for the formation of the ventral pancreas.

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