Skoudy Anouchka, Rovira Meritxell, Savatier Pierre, Martin Franz, León-Quinto Trinidad, Soria Bernat, Real Francisco X
Unitat de Biologia Cel.lular i Molecular, Institut Municipal d'Investigació Mèdica, 08003 Barcelona, Spain.
Biochem J. 2004 May 1;379(Pt 3):749-56. doi: 10.1042/BJ20031784.
Extracellular signalling cues play a major role in the activation of differentiation programmes. Mouse embryonic stem (ES) cells are pluripotent and can differentiate into a wide variety of specialized cells. Recently, protocols designed to induce endocrine pancreatic differentiation in vitro have been designed but little information is currently available concerning the potential of ES cells to differentiate into acinar pancreatic cells. By using conditioned media of cultured foetal pancreatic rudiments, we demonstrate that ES cells can respond in vitro to signalling pathways involved in exocrine development and differentiation. In particular, modulation of the hedgehog, transforming growth factor beta, retinoid, and fibroblast growth factor pathways in ES cell-derived embryoid bodies (EB) resulted in increased levels of transcripts encoding pancreatic transcription factors and cytodifferentiation markers, as demonstrated by RT-PCR. In EB undergoing spontaneous differentiation, expression of the majority of the acinar genes (i.e. amylase, carboxypeptidase A and elastase) was induced after the expression of endocrine genes, as occurs in vivo during development. These data indicate that ES cells can undergo exocrine pancreatic differentiation with a kinetic pattern of expression reminiscent of pancreas development in vivo and that ES cells can be coaxed to express an acinar phenotype by activation of signalling pathways known to play a role in pancreatic development and differentiation.
细胞外信号线索在分化程序的激活中起主要作用。小鼠胚胎干细胞（ES细胞）具有多能性，能够分化为多种特化细胞。最近，已经设计出了在体外诱导内分泌胰腺分化的方案，但目前关于ES细胞分化为腺泡胰腺细胞的潜力的信息还很少。通过使用培养的胎儿胰腺原基的条件培养基，我们证明ES细胞在体外能够对参与外分泌发育和分化的信号通路作出反应。特别是，如逆转录聚合酶链反应（RT-PCR）所示，在ES细胞来源的胚状体（EB）中调节刺猬信号通路、转化生长因子β、视黄酸和成纤维细胞生长因子信号通路，导致编码胰腺转录因子和细胞分化标志物的转录本水平升高。在经历自发分化的EB中，大多数腺泡基因（即淀粉酶、羧肽酶A和弹性蛋白酶）的表达是在内分泌基因表达之后被诱导的，这与发育过程中的体内情况一致。这些数据表明，ES细胞能够经历外分泌胰腺分化，其表达动力学模式让人联想到体内胰腺发育，并且通过激活已知在胰腺发育和分化中起作用的信号通路，可以诱导ES细胞表达腺泡表型。
