The FGF receptor inhibitor PD173074 modulates Lefty expression in human induced pluripotent stem cells differently depending on the culture conditions
The FGF receptor inhibitor PD173074 modulates Lefty expression in human induced pluripotent stem cells differently depending on the culture conditions
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FGF 受体抑制剂 PD173074 根据培养条件不同地调节人诱导多能干细胞中的 Lefty 表达
DOI：
10.1016/j.bbamcr.2022.119260
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Wakitani Shoichi
中科院分区：
文献类型：
--
作者：
神澤 聖也;脇谷 晶一;神澤 彩;新倉 匡賢;Wakitani Shoichi
多能干细胞，包括胚胎干细胞（ESC）和诱导多能干细胞（iPSC），是具有分化成体细胞谱系细胞的能力的无限增殖细胞。对多能干细胞的大量研究极大地促进了再生医学、发育生物学和病因学领域的发展。多能性是由已确立的分子基础支持的，包括核心转录因子、表观遗传因子和信号转导途径[1]，[2]，[3]，[4]。然而，这些分子机制也可以在肿瘤发生期间被激发，因为肿瘤细胞和多能干细胞具有各种特征，包括增殖和代谢能力[5]，[6]，[7]，[8]，[9] Jodal-Cripto途径是多能干细胞和肿瘤细胞自我更新的共同分子基础之一。Nodal激活1型和2型激活素受体，通过Smad 2/3的磷酸化调节转录[3]，[10]。由于Nodal和激活素可以通过共同的受体诱导同一组基因的表达，因此被诱导的基因也被称为Nodal/激活素靶标。由于靶基因包括Nodal本身及其抑制剂Lefty，因此Nodal作用可以激活正反馈和负反馈[11]，[12]。Nodal和激活素在受体激活机制方面的差异之一是Cripto（也称为Tdgf 1）的作用。Nodal需要Cripto作为共受体来激活信号转导途径，而Cripto拮抗激活素[13]。Cripto对于维持小鼠和人类中处于致敏状态的干细胞的多能性至关重要[14]。在人ESC中，维持多能干细胞处于致敏状态所需的成纤维细胞生长因子（FGF）充当Nodal/激活素信号传导的感受态因子[15]，[16]，[17]，[18]。在小鼠睾丸发育过程中也观察到FGF和Nodal信号传导之间的类似关系，其中FGF 9在11.5 dpc时上调胎儿生殖细胞中的Cripto表达，在6-7 dpp时上调Kit阳性精原细胞中的Cripto表达[19]，[20]。先前对人ESC的研究观察到在无FGF条件下维持的Tra-1-60阳性ESC中CRIPTO表达较低，并且还显示重组Cripto不能替代FGF来阻断人ESC的分化[16]。因此，FGF信号传导参与Nodal-Cripto途径以维持人ESC和iPSC的多能性。
Pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are infinitely proliferative cells that have the ability to differentiate into somatic lineage cells. Numerous studies on pluripotent stem cells have greatly contributed to the development of the fields of regenerative medicine, developmental biology, and etiology. Pluripotency is supported by the involvement of well-established molecular bases, including core transcription factors, epigenetic factors, and signal transduction pathways [1],[2],[3],[4]. These molecular mechanisms, however, can be provoked during tumorigenesis as well, as tumor cells and pluripotent stem cells share various characteristics, including proliferative and metabolic capabilities [5],[6],[7],[8],[9].The Nodal-Cripto pathway is one of the common molecular basis for the self-renewal of pluripotent stem cells and tumor cells. Nodal activates type 1 and 2 activin receptors to regulate transcription via phosphorylation of Smad2/3 [3],[10]. Since Nodal and activins can induce the expression of the same set of genes through the common receptor, the induced genes are also called Nodal/Activin targets. As the target genes include Nodal itself and its inhibitor Lefty, both positive and negative feedbacks can be activated by Nodal action [11],[12]. One of the differences between Nodal and activins, with regards to the mechanism of receptor activation, is the role of Cripto (also termed Tdgf1). Nodal requires Cripto as a co-receptor to activate the signal transduction pathway, while Cripto antagonizes activins [13]. Cripto is essential for maintaining pluripotency of stem cells in the primed state in mice and humans [14]. In human ESCs, fibroblast growth factors (FGF), which are required for maintaining pluripotent stem cells in the primed state, act as a competence factor for Nodal/Activin signaling [15],[16],[17],[18]. A similar relationship between FGF and Nodal signaling has also been observed during mouse testis development, in which FGF9 upregulates Cripto expression in fetal germ cells at 11.5 dpc and in Kit-positive spermatogonia at 6–7 dpp [19],[20]. A previous study on human ESCs observed lower CRIPTO expression in Tra-1-60-positive ESCs maintained under FGF-free conditions, and also showed that recombinant Cripto could not substitute FGF to block the differentiation of human ESCs [16]. Therefore, FGF signaling is involved in the Nodal-Cripto pathway to maintain the pluripotency of human ESCs and iPSCs.