Distinct Cellular Mechanisms Underlie Smooth Muscle Turnover in Vascular Development and Repair.
Distinct Cellular Mechanisms Underlie Smooth Muscle Turnover in Vascular Development and Repair.
复制标题
血管发育和修复过程中平滑肌更新的基础是独特的细胞机制。
DOI：
10.1161/circresaha.117.312111
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发表时间：
2018-01-19
影响因子：
20.1
通讯作者：
Cossu G
中科院分区：
文献类型：
--
作者：
Roostalu U;Aldeiri B;Albertini A;Humphreys N;Simonsen-Jackson M;Wong JKF;Cossu G
补充数字内容可在文本中找到。血管平滑肌更新对血管修复和心血管疾病的发生发展具有重要意义，但由于缺乏特异的转基因动物模型，阻碍了其体内分析。本研究的目的是表征从胚胎发育的最早阶段到成人动脉修复的血管平滑肌周转的动力学和机制。我们发现，CD 146是瞬时表达的血管平滑肌发育。通过使用CRISPR-Cas9基因组编辑和体外平滑肌分化测定，我们证明了CD 146调节增殖和分化之间的平衡。我们开发了一种三重转基因小鼠模型来绘制NG 2 + CD 146+未成熟平滑肌细胞的命运。一系列脉冲追踪实验表明，主动脉血管平滑肌细胞的起源可以追溯到E10.5时胚胎背主动脉壁中的祖细胞。在胚胎发育过程中出现一个独特的CD 146+平滑肌祖细胞群体，并在出生后维持在动脉分支部位。为了表征不同细胞类型对动脉修复的贡献，我们使用了2种损伤模型。在有限导丝诱导的损伤反应中，现有平滑肌细胞是新生内膜形成的主要贡献者。相反，微吻合导致早期平滑肌死亡和随后的血管壁的增殖外膜细胞，有助于修复的殖民。原始胚胎背主动脉中未成熟平滑肌细胞的广泛增殖建立了构成成人主动脉壁的长寿命平滑肌细胞谱系。平滑肌细胞的离散群体在胚胎中形成，并在出生后维持在动脉分支部位。为了应对动脉损伤，现有的平滑肌细胞会产生新生内膜，但在广泛损伤时，它们会被外膜细胞取代。
Supplemental Digital Content is available in the text. Vascular smooth muscle turnover has important implications for blood vessel repair and for the development of cardiovascular diseases, yet lack of specific transgenic animal models has prevented it’s in vivo analysis. The objective of this study was to characterize the dynamics and mechanisms of vascular smooth muscle turnover from the earliest stages of embryonic development to arterial repair in the adult. We show that CD146 is transiently expressed in vascular smooth muscle development. By using CRISPR-Cas9 genome editing and in vitro smooth muscle differentiation assay, we demonstrate that CD146 regulates the balance between proliferation and differentiation. We developed a triple-transgenic mouse model to map the fate of NG2+CD146+ immature smooth muscle cells. A series of pulse-chase experiments revealed that the origin of aortic vascular smooth muscle cells can be traced back to progenitor cells that reside in the wall of the dorsal aorta of the embryo at E10.5. A distinct population of CD146+ smooth muscle progenitor cells emerges during embryonic development and is maintained postnatally at arterial branch sites. To characterize the contribution of different cell types to arterial repair, we used 2 injury models. In limited wire-induced injury response, existing smooth muscle cells are the primary contributors to neointima formation. In contrast, microanastomosis leads to early smooth muscle death and subsequent colonization of the vascular wall by proliferative adventitial cells that contribute to the repair. Extensive proliferation of immature smooth muscle cells in the primitive embryonic dorsal aorta establishes the long-lived lineages of smooth muscle cells that make up the wall of the adult aorta. A discrete population of smooth muscle cells forms in the embryo and is postnatally sustained at arterial branch sites. In response to arterial injuries, existing smooth muscle cells give rise to neointima, but on extensive damage, they are replaced by adventitial cells.