Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells
Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells
复制标题
DOI：
10.1242/dev.055236
复制
发表时间：
2011-03-01
期刊：
影响因子：
4.6
通讯作者：
Keller, Gordon
中科院分区：
文献类型：
--
作者：
Nostro, M. Cristina;Sarangi, Farida;Keller, Gordon
从人多能干细胞中产生产生胰岛素的β细胞依赖于有效的内胚层诱导和这种胚层的适当模式和规范，以达到胰腺的命运。在本研究中，我们阐明了TGF β家族成员和典型WNT信号在这些发育阶段的时间要求，并表明节点/激活素A信号的持续时间在建立合适的内胚层群体以确定胰腺谱系方面起着关键作用。研究发现，WNT信号可诱导后内胚层细胞凋亡，并在最佳浓度下促进胰腺系细胞的发育。在特定阶段抑制BMP信号通路对于胰岛素表达细胞的产生至关重要，并且在所测试的细胞系中，BMP抑制的程度差异很大。这些途径的最佳阶段特异性操作导致胰岛素表达水平显著增加250倍，并产生含有高达25% c肽+细胞的群体。
The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGF beta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25% C-peptide+cells.