Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program.
Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program.
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DOI：
10.1038/s41467-018-03959-6
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发表时间：
2018-04-17
影响因子：
16.6
通讯作者：
Mäkinen T
中科院分区：
文献类型：
--
作者：
Frye M;Taddei A;Dierkes C;Martinez-Corral I;Fielden M;Ortsäter H;Kazenwadel J;Calado DP;Ostergaard P;Salminen M;He L;Harvey NL;Kiefer F;Mäkinen T
组织和血管壁硬化改变了内皮细胞的特性，并导致血管功能障碍。然而，细胞外基质（ECM）硬度是否影响血管发育尚不清楚。在这里，我们表明，基质硬度控制淋巴管形态发生。在小鼠胚胎中的原子力显微镜测量显示，静脉淋巴管内皮细胞（LEC）祖细胞迁移出主静脉后，基底硬度降低，这诱导了形成第一个淋巴管所需的GATA 2依赖性转录程序。转录组分析显示，在软基质上生长的LEC表现出增加的GATA 2表达和参与细胞迁移和淋巴管生成的基因（包括VEGFR 3）的GATA 2依赖性上调。对小鼠模型的分析表明，GATA 2在调节LEC对VEGF-C的反应性和控制LEC迁移和体内发芽中具有细胞自主功能。因此，我们的研究揭示了ECM刚度决定淋巴管内皮细胞在早期淋巴发育过程中的迁移行为的机制。已知机械刺激会影响内皮细胞的行为。Frye等人在此表明，淋巴管内皮祖细胞在发育过程中经历不同程度的基质硬度，并且基质硬度调节GATA 2表达以驱动淋巴管形成。
Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development. Mechanical cues are known to influence endothelial cell behavior. Here Frye et al. show that lymphatic endothelial cell progenitors experience varying degrees of matrix stiffness during development, and that matrix stiffness regulates GATA2 expression to drive lymphatic vessel formation.
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影响因子：
20.1
作者：
Choi D;Park E;Jung E;Seong YJ;Hong M;Lee S;Burford J;Gyarmati G;Peti-Peterdi J;Srikanth S;Gwack Y;Koh CJ;Boriushkin E;Hamik A;Wong AK;Hong YK
通讯作者：
Hong YK
影响因子：
11.8
作者：
Bazigou, Eleni;Xie, Sherry;Chen, Chun;Weston, Anne;Miura, Naoyuki;Sorokin, Lydia;Adams, Ralf;Muro, Andres F.;Sheppard, Dean;Makinen, Taija
通讯作者：
Makinen, Taija
影响因子：
15.9
作者：
Bazigou, Eleni;Lyons, Oliver T. A.;Makinen, Taija
通讯作者：
Makinen, Taija
影响因子：
15.9
作者：
Choi, Dongwon;Park, Eunkyung;Hong, Young-Kwon
通讯作者：
Hong, Young-Kwon
DOI：
10.4161/bioa.29175
发表时间：
2014-01-01
期刊：
Bioarchitecture
影响因子：
--
作者：
Gu, Zhizhan
通讯作者：
Gu, Zhizhan