Elucidating the Morphogenic and Signaling Roles of Defined Growth Factors Controlling Human Endothelial Cell Lumen Formation Versus Sprouting Behavior.
Elucidating the Morphogenic and Signaling Roles of Defined Growth Factors Controlling Human Endothelial Cell Lumen Formation Versus Sprouting Behavior.
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阐明控制人内皮细胞管腔形成与发芽行为的特定生长因子的形态发生和信号传导作用。
DOI：
10.1016/j.ajpath.2023.08.009
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Davis,GeorgeE
中科院分区：
文献类型：
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作者：
Lin,PriscaK;Koller,GretchenM;Davis,GeorgeE
五种生长因子 [即胰岛素、成纤维细胞生长因子-2 (FGF-2)、干细胞因子、IL-3 和基质衍生因子 1α] 的组合是人内皮细胞 (EC) 经历管形态发生所必需的，该过程需要管腔形成和萌芽行为。本研究通过将因素分为 4 个不同的组来调查为什么需要这些因素：仅胰岛素、胰岛素和 FGF-2、无 FGF-2（所有因素但不含 FGF-2）和所有因素。研究发现，仅使用胰岛素的条件无法支持 EC 形态发生或存活，胰岛素和 FGF-2 条件主要支持 EC 管腔形成，而无 FGF-2 条件则支持 EC 萌芽行为。相比之下，全因素条件更强烈地刺激 EC 管腔形成和发芽行为，信号分析显示多种前形态发生信号的长期刺激与前退信号的抑制相结合。 Jak 激酶的药理学抑制更选择性地阻断 EC 出芽行为，而 Raf、磷脂酰肌醇 3-激酶和 Akt 激酶的抑制则显示出选择性阻断管腔形成。抑制 Src 家族激酶和 Notch 会导致发芽增加，同时导致管腔形成减少，而抑制 Pak、Mek 和雷帕霉素激酶的哺乳动物靶标会阻止发芽和管腔形成。这些发现揭示了组装人类内皮细胞毛细管网络所需的特定因子的新的下游生物和信号传导活性。
Five growth factors [ie, insulin, fibroblast growth factor-2 (FGF-2), stem cell factor, IL-3, and stromal-derived factor 1α] in combination are necessary for human endothelial cells (ECs) to undergo tube morphogenesis, a process requiring both lumen formation and sprouting behavior. This study investigated why these factors are required by subdividing the factors into 4 separate groups: insulin-only, insulin and FGF-2, no FGF-2 (all factors but without FGF-2), and all factors. The study found that the insulin-only condition failed to support EC morphogenesis or survival, the insulin and FGF-2 condition supported primarily EC lumen formation, and the no FGF-2 condition supported EC sprouting behavior. By comparison, the all-factors condition more strongly stimulated both EC lumen formation and sprouting behavior, and signaling analysis revealed prolonged stimulation of multiple promorphogenic signals coupled with inhibition of proregressive signals. Pharmacologic inhibition of Jak kinases more selectively blocked EC sprouting behavior, whereas inhibition of Raf, phosphatidylinositol 3-kinase, and Akt kinases showed selective blockade of lumen formation. Inhibition of Src family kinases and Notch led to increased sprouting coupled to decreased lumen formation, whereas inhibition of Pak, Mek, and mammalian target of rapamycin kinases blocked both sprouting and lumen formation. These findings reveal novel downstream biological and signaling activities of defined factors that are required for the assembly of human EC-lined capillary tube networks.