Human trophoblast stem cell-differentiated syncytiotrophoblasts as a model for hypoxia-enhanced secretion of the anti-angiogenic factor sFLT1.

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Tadashi Sasagawa, Masabumi Shibuya
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引用次数: 0

Abstract

Preeclampsia (PE) is a major disease in the field of obstetrics. Onset and progression of PE are associated with abnormally high serum levels of soluble fms-like tyrosine kinase-1 (sFLT1), an anti-angiogenic factor primarily secreted by syncytiotrophoblasts (STBs) present in the placenta. Although a cell-based assay using primary human trophoblasts has been developed to identify compounds that inhibit sFLT1 secretion, routine application of this assay is limited owing to the complexity of isolating these cells from the placenta and their inability to be passaged. Recently, human trophoblast stem cell (hTSC) lines that can differentiate into STBs and extravillous trophoblasts have been established. Their high proliferative ability allows for obtaining sufficient STBs for drug screening. In the present study, we investigated whether hTSC-differentiated STBs (dSTBs) exhibit enhanced secretion of sFLT1 under hypoxic conditions, similar to primary trophoblasts. Hypoxic stimulation significantly increased sFLT1 secretion by the dSTBs. This response was markedly inhibited by small interfering RNAs targeting the hypoxia-inducible factor (HIF)-2α and HIF-1β, as well as by the HIF-2α inhibitor, belzutifan. These findings suggest that the dSTBs described above are a practical and scalable alternative to primary trophoblasts for drug screening in PE treatment.

人滋养细胞干细胞分化的合胞滋养细胞作为缺氧增强抗血管生成因子sFLT1分泌的模型。
先兆子痫(PE)是产科领域的主要疾病。PE的发病和进展与血清中可溶性纤维样酪氨酸激酶-1 (sFLT1)水平异常升高有关,sFLT1是一种主要由胎盘中的合胞滋养细胞(STBs)分泌的抗血管生成因子。尽管已经开发了一种基于细胞的检测方法,使用原代人滋养细胞来鉴定抑制sFLT1分泌的化合物,但由于从胎盘中分离这些细胞的复杂性以及它们无法传代,这种检测方法的常规应用受到限制。近年来,人类滋养细胞干细胞(hTSC)细胞系已经建立,可以分化为stb和外膜滋养细胞。它们的高增殖能力允许获得足够的性传播感染病毒进行药物筛选。在本研究中,我们研究了htsc分化的STBs (dSTBs)在缺氧条件下是否表现出与原代滋养细胞相似的sFLT1分泌增强。低氧刺激显著增加dstb的sFLT1分泌。这种反应被靶向缺氧诱导因子(HIF)-2α和HIF-1β的小干扰rna以及HIF-2α抑制剂贝尔祖替芬明显抑制。这些发现表明,上述dstb是一种实用且可扩展的替代原代滋养细胞用于PE治疗药物筛选的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
期刊介绍: Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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