Fli1 Promotes Vascular Morphogenesis by Regulating Endothelial Potential of Multipotent Myogenic Progenitors.
Fli1 Promotes Vascular Morphogenesis by Regulating Endothelial Potential of Multipotent Myogenic Progenitors.
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Fli1通过调节多能肌源性祖细胞的内皮潜能促进血管形态发生。
DOI：
10.1161/circresaha.121.318986
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发表时间：
2021-10-29
影响因子：
20.1
通讯作者：
Hill JA
中科院分区：
文献类型：
--
作者：
Ferdous A;Singh S;Luo Y;Abedin MJ;Jiang N;Perry CE;Evers BM;Gillette TG;Kyba M;Trojanowska M;Hill JA
胎儿的生长和存活关键取决于血管系统的正常发育和完整性。FLI1(Friend白血病整合1)是ETS家族转录因子家族的成员之一，在妊娠中期的血管形态发生和动态平衡中发挥关键作用，而妊娠中期是其上游调控因子ETV2表达停止的发育阶段。然而，FLI1在血管形态发生中作用的分子机制仍不完全清楚。探讨FLI1调控血管形态发生的分子机制。利用FLI1启动子驱动的谱系特异性LacZ表达、FLI1功能丧失策略和一系列分子技术，我们证明了在多潜能肌源性祖细胞(MPC)中，FLI1的表达不依赖于ETV2，并且FLI1的表达缺失导致体节和肢芽内中胚层的LacZ+细胞显著增加，导致几个关键的内皮和肌源性基因的表达和血管异常的相互调节。相反，在MPC中具有条件FLI1功能获得的胚胎表现出异常的血管生成而缺乏肌肉生成。从机制上讲，在X连锁肌营养不良mdx小鼠的成肌细胞和成年MPC(也称为卫星细胞)中，FLI1活性的升高显著地诱导内皮细胞，但减弱了肌源性基因的表达和分化。重要的是，两个关键的成肌调节因子Myf5或MyoD在表达FLI1的成肌细胞中的异位表达恢复了它们的分化潜能，表明MPC中FLI1和成肌调节因子的水平反向调节它们的内皮和成肌潜能。FLI1通过反向调节MPC中的内皮与肌源性程序来调节内皮潜能，从而调控血管的形态发生。我们的数据揭示了由FLI1调控的血管形态发生的一个重要且先前未知的机制，并强调了微调多能祖细胞中的FLI1活性对于发育和疾病期间适当的血管和肌肉形态发生的生理学意义。
Fetal growth and survival depend critically on proper development and integrity of the vascular system. Fli1 (Friend leukemia integration 1), a member of the Ets family of transcription factors, plays critical roles in vascular morphogenesis and homeostasis at mid-gestation, the developmental stage at which expression of its upstream regulator, Etv2, ceases. However, molecular mechanisms of Fli1 action in vascular morphogenesis remain incompletely understood. To dissect molecular mechanisms of vascular morphogenesis governed by Fli1. Utilizing Fli1 promoter-driven lineage-specific LacZ expression, Fli1 loss-of-function strategies, and a series of molecular techniques, we demonstrate that Fli1 expression in multipotent myogenic progenitor cells (MPCs) occurs independent of Etv2, and loss of Fli1 expression results in a significant increase in LacZ+ cells in mesoderm within somites and limb buds, leading to reciprocal regulation of the expression of several key endothelial and myogenic genes and vascular abnormalities. Conversely, embryos with conditional Fli1 gain-of-function in MPCs manifested aberrant vasculogenesis with lack of myogenesis. Mechanistically, elevated Fli1 activity in myoblasts and in adult MPCs (also called satellite cells) of X-linked muscular dystrophic mdx mice markedly induced endothelial, but attenuated myogenic, gene expression and differentiation. Importantly, ectopic expression of Myf5 or MyoD, two key myogenic regulators, in Fli1-expressing myoblasts restored their differentiation potential, indicating that levels of Fli1 and myogenic regulators in MPCs inversely regulate their endothelial versus myogenic potential. Fli1 governs vascular morphogenesis by regulating endothelial potential by inversely regulating endothelial versus myogenic programs in MPCs. Our data uncover an important and previously unrecognized mechanism of vascular morphogenesis governed by Fli1 and highlight the physiological significance of the fine tuning of Fli1 activity in multipotent progenitors for proper vascular and muscle morphogenesis during development and disease.