FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1.
FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1.
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DOI：
10.1101/gad.268961.115
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发表时间：
2015-12-01
影响因子：
10.5
通讯作者：
Duncan SA
中科院分区：
文献类型：
--
作者：
Twaroski K;Mallanna SK;Jing R;DiFurio F;Urick A;Duncan SA
Twaroski等人。发现裸露角质层同系物1(NKD1)在内胚层向肝祖细胞的转变过程中受到FGFR活性的直接调节。NKD1的缺失抑制了人诱导的多能干细胞形成的肝祖细胞，而这种表型可以通过使用经典的WNT信号的药理拮抗剂来挽救。成纤维细胞生长因子(FGFs)通过激活成纤维细胞生长因子受体(FGFRs)在最终内胚层中决定肝脏的命运。虽然涉及肝脏规范的信号通路已被很好地了解，但FGFs在内胚层内诱导肝脏特征的机制尚不清楚。在这里，我们报告了在从内胚层到肝祖细胞的转变过程中，FGFR活性直接调节其表达的基因的鉴定。已鉴定的FGFR即刻早期基因包括编码转录因子、生长因子和信号分子的基因。其中一个直接早期基因编码裸露角质层同源基因1(NKD1)，它是典型的WNT(无翼型MMTV整合位点)信号的抑制子。我们发现，NKD1的缺失抑制了人类诱导的多能干细胞形成的肝祖细胞，这种表型可以通过使用经典的WNT信号的药理拮抗剂来挽救。我们得出结论，成纤维细胞生长因子至少在很大程度上通过诱导NKD1的表达来暂时抑制典型的WNT途径，从而决定肝脏的命运。
Twaroski et al. identified naked cuticle homolog 1 (NKD1) as being directly regulated by FGFR activity during the transition from endoderm to hepatic progenitor cell. Loss of NKD1 suppresses the formation of hepatic progenitor cells from human induced pluripotent stem cells, and this phenotype can be rescued by using a pharmacological antagonist of canonical WNT signaling. Fibroblast growth factors (FGFs) are required to specify hepatic fate within the definitive endoderm through activation of the FGF receptors (FGFRs). While the signaling pathways involved in hepatic specification are well understood, the mechanisms through which FGFs induce hepatic character within the endoderm are ill defined. Here we report the identification of genes whose expression is directly regulated by FGFR activity during the transition from endoderm to hepatic progenitor cell. The FGFR immediate early genes that were identified include those encoding transcription factors, growth factors, and signaling molecules. One of these immediate early genes encodes naked cuticle homolog 1 (NKD1), which is a repressor of canonical WNT (wingless-type MMTV integration site) signaling. We show that loss of NKD1 suppresses the formation of hepatic progenitor cells from human induced pluripotent stem cells and that this phenotype can be rescued by using a pharmacological antagonist of canonical WNT signaling. We conclude that FGF specifies hepatic fate at least in large part by inducing expression of NKD1 to transiently suppress the canonical WNT pathway.