FGFR-1 is required by epicardium-derived cells for myocardial invasion and correct coronary vascular lineage differentiation.
FGFR-1 is required by epicardium-derived cells for myocardial invasion and correct coronary vascular lineage differentiation.
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DOI：
10.1016/j.ydbio.2009.01.023
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发表时间：
2009-04-01
影响因子：
2.7
通讯作者：
Mikawa, Takashi
中科院分区：
文献类型：
--
作者：
Pennisi, David J.;Mikawa, Takashi
冠状动脉血管形成的关键步骤包括心外膜细胞经历上皮 - 间充质转化（EMT）成为心外膜下细胞；心肌的侵入；以及冠状动脉谱系的分化。然而，控制这些过程的因素尚未完全了解。在胚胎发生过程中，心外膜和冠状动脉血管前体通过心外膜原（PE）迁移到无血管的心管。在此，我们表明在鹌鹑胚胎中，成纤维细胞生长因子受体（FGFR）-1在PE和心外膜衍生细胞（包括血管内皮前体）中以时空受限的方式表达，并且在EMT后在心外膜细胞中上调。我们使用复制缺陷型逆转录病毒载体在PE中过表达或敲低FGFR - 1。FGFR - 1过表达导致心外膜EMT增加。然而，FGFR - 1的敲低并不抑制心外膜EMT，但极大地损害了PE后代侵入心肌的能力。然而，后者可能有助于心外膜下血管的内皮和平滑肌。正确的FGFR - 1水平对于正确的冠状动脉谱系分化也很重要，在E12时，FGFR - 1过表达的PE后代中内皮细胞的比例增加，而反义FGFR - 1病毒感染的PE后代中平滑肌细胞的比例降低。最后，在心脏外植体系统中，心外膜细胞中FGFR - 1信号的持续激活导致从心外膜的分层增加、心外膜下的侵入以及心肌的侵入。这些数据揭示了FGFR - 1信号在心外膜生物学和冠状动脉血管谱系分化中的新作用，并指出了潜在的新治疗途径。
Critical steps in coronary vascular formation include the epithelial–mesenchyme transition (EMT) that epicardial cells undergo to become sub-epicardial; the invasion of the myocardium; and the differentiation of coronary lineages. However, the factors controlling these processes are not completely understood. Epicardial and coronary vascular precursors migrate to the avascular heart tube during embryogenesis via the proepicardium (PE). Here, we show that in the quail embryo fibroblast growth factor receptor (FGFR)-1 is expressed in a spatially and temporally restricted manner in the PE and epicardium-derived cells, including vascular endothelial precursors, and is up-regulated in epicardial cells after EMT. We used replication-defective retroviral vectors to over-express or knock-down FGFR-1 in the PE. FGFR-1 over-expression resulted in increased epicardial EMT. Knock-down of FGFR-1, however, did not inhibit epicardial EMT but greatly compromised the ability of PE progeny to invade the myocardium. The latter could, however, contribute to endothelia and smooth muscle of sub-epicardial vessels. Correct FGFR-1 levels were also important for correct coronary lineage differentiation with, at E12, an increase in the proportion of endothelial cells amongst FGFR-1 over-expressing PE progeny and a decrease in the proportion of smooth muscle cells in antisense FGFR-1 virus-infected PE progeny. Finally, in a heart explant system, constitutive activation of FGFR-1 signaling in epicardial cells resulted in increased delamination from the epicardium, invasion of the sub-epicardium, and invasion of the myocardium. These data reveal novel roles for FGFR-1 signaling in epicardial biology and coronary vascular lineage differentiation, and point to potential new therapeutic avenues.
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影响因子：
2.7
作者：
De langhe, Stijn P.;Carraro, Gianni;Bellusci, Saverio
通讯作者：
Bellusci, Saverio
影响因子：
2.5
作者：
MIKAWA, T;BORISOV, A;FISCHMAN, DA
通讯作者：
FISCHMAN, DA
影响因子：
20.1
作者：
Fernandez, B;Buehler, A;Zimmermann, R
通讯作者：
Zimmermann, R
影响因子：
--
作者：
HIRUMA, T;HIRAKOW, R
通讯作者：
HIRAKOW, R
影响因子：
--
作者：
HOOD, LC;ROSENQUIST, TH
通讯作者：
ROSENQUIST, TH