Phan-Hug Franziska, Guimiot Fabien, Lelièvre Vincent, Delezoide Anne-Lise, Czernichow Paul, Breant Bernadette, Blondeau Bertrand
INSERM, [Fetopathology Department, Université Denis Diderot-Paris 7, 75019 Paris, France.
Pediatr Res. 2008 Oct;64(4):346-51. doi: 10.1203/PDR.0b013e318180a38f.
Glucocorticoids have been suggested to play a role in programming late adult disorders like diabetes during fetal life. Recent work in rodents showed their role in pancreas development by modulating the expression of transcription factors. The aim of this work was to investigate their possible implication in human pancreas development. The ontogenesis of glucocorticoid receptor (GR) and several pancreatic transcription factors was studied by immunohistochemistry and RT-PCR on human fetal pancreatic specimens. At 6 wk of development (wd) insulin promoting factor 1 (IPF1) was expressed in the majority of epithelial cells forming tubular structures while GR was present in the mesenchyme, suggesting an early role of glucocorticoids, before endocrine and exocrine differentiation. Only GR alpha (active form) mRNA was expressed from 6 wk onwards while GR beta (inactive form) was never observed. The first insulin cells did not express IPF1 or GR. Islet formation occurred from 10 wd as IPF1-positive cells started to express simultaneously insulin and GR. This coexpression in beta cells persisted until adulthood. The mRNA expression profiles confirmed immunohistochemistry and showed the early expression of crucial transcription factors. In conclusion, the presence of the active GR isoform around islet formation supports the novel idea that glucocorticoids could modulate human pancreas development.
糖皮质激素被认为在胎儿期就对诸如糖尿病等成人后期疾病的发生发展起作用。近期在啮齿动物中的研究表明，它们通过调节转录因子的表达在胰腺发育中发挥作用。本研究旨在探讨其在人类胰腺发育中的潜在作用。通过免疫组织化学和逆转录聚合酶链反应（RT-PCR）对人类胎儿胰腺标本进行研究，以了解糖皮质激素受体（GR）和几种胰腺转录因子的个体发生情况。在发育6周（wd）时，胰岛素促进因子1（IPF1）在形成管状结构的大多数上皮细胞中表达，而GR存在于间充质中，这表明在内分泌和外分泌分化之前，糖皮质激素就已发挥早期作用。从6周起仅表达GRα（活性形式）的mRNA，而从未观察到GRβ（非活性形式）。最初的胰岛素细胞不表达IPF1或GR。从10周起开始形成胰岛，此时IPF1阳性细胞开始同时表达胰岛素和GR。β细胞中的这种共表达持续至成年期。mRNA表达谱证实了免疫组织化学结果，并显示了关键转录因子的早期表达。总之，在胰岛形成期左右存在活性GR亚型支持了糖皮质激素可能调节人类胰腺发育这一新观点。
