NOTCH1 is critical for fibroblast-mediated induction of cardiomyocyte specialization into ventricular conduction system-like cells in vitro.
NOTCH1 is critical for fibroblast-mediated induction of cardiomyocyte specialization into ventricular conduction system-like cells in vitro.
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NOTCH 1在体外成纤维细胞介导的诱导心肌细胞特化为心室传导系统样细胞中至关重要。
DOI：
10.1038/s41598-020-73159-0
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发表时间：
2020-09-30
影响因子：
4.6
通讯作者：
Krieger JE
中科院分区：
文献类型：
--
作者：
Ribeiro da Silva A;Neri EA;Turaça LT;Dariolli R;Fonseca-Alaniz MH;Santos-Miranda A;Roman-Campos D;Venturini G;Krieger JE
心脏成纤维细胞存在于整个心肌中，并在心室传导系统（VCF）周围的微环境中富集。几种形式的心律失常与心肌细胞异常有关，但目前尚不清楚心肌细胞畸形是心肌细胞自主的还是与不同细胞类型之间的串扰有关。我们推断成纤维细胞影响心肌细胞的特化。我们建立了新生大鼠心肌细胞的二维和三维培养模型，以评估心脏成纤维细胞对心肌细胞的影响。与心脏成纤维细胞相邻的心肌细胞显示，钙离子标记物（NAV 1.5和CONTACTIN 2）的表达和钙瞬变持续时间增加了两倍，显示出浦肯野样特征。成纤维细胞条件培养基（FCM）足以激活VCS相关基因（Irx3，Scn5a，Connexin 40），并诱导动作电位延长，Purkinge表型的标志。FCM介导的反应似乎是空间依赖性的，因为用FCM处理的心肌细胞类器官主要在其外表面上具有增加的连接蛋白40和NAV 1.5的表达。最后，心肌细胞和成纤维细胞中的NOTCH 1激活是连接蛋白40上调所必需的（代表心肌细胞表型）。总之，我们提供的证据表明，心脏成纤维细胞通过NOTCH1信号影响心肌细胞分化为VCS样细胞在体外。
Cardiac fibroblasts are present throughout the myocardium and are enriched in the microenvironment surrounding the ventricular conduction system (VCS). Several forms of arrhythmias are linked to VCS abnormalities, but it is still unclear whether VCS malformations are cardiomyocyte autonomous or could be linked to crosstalk between different cell types. We reasoned that fibroblasts influence cardiomyocyte specialization in VCS cells. We developed 2D and 3D culture models of neonatal rat cardiac cells to assess the influence of cardiac fibroblasts on cardiomyocytes. Cardiomyocytes adjacent to cardiac fibroblasts showed a two-fold increase in expression of VCS markers (NAV1.5 and CONTACTIN 2) and calcium transient duration, displaying a Purkinje-like profile. Fibroblast-conditioned media (fCM) was sufficient to activate VCS-related genes (Irx3, Scn5a, Connexin 40) and to induce action potential prolongation, a hallmark of Purkinge phenotype. fCM-mediated response seemed to be spatially-dependent as cardiomyocyte organoids treated with fCM had increased expression of connexin 40 and NAV1.5 primarily on its outer surface. Finally, NOTCH1 activation in both cardiomyocytes and fibroblasts was required for connexin 40 up-regulation (a proxy of VCS phenotype). Altogether, we provide evidence that cardiac fibroblasts influence cardiomyocyte specialization into VCS-like cells via NOTCH1 signaling in vitro.
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影响因子：
1.6
作者：
Mohan RA;Boukens BJ;Christoffels VM
通讯作者：
Christoffels VM
影响因子：
20.1
作者：
Kang G;Giovannone SF;Liu N;Liu FY;Zhang J;Priori SG;Fishman GI
通讯作者：
Fishman GI
影响因子：
6.1
作者：
Ben Caref, E.;Boutjdir, Mohamed;El-Sherif, Nabil
通讯作者：
El-Sherif, Nabil
影响因子：
5.5
作者：
Chatelier, Aurelien;Mercier, Aurelie;Faivre, Jean Francois
通讯作者：
Faivre, Jean Francois
DOI：
10.1016/j.bbrc.2017.01.003
发表时间：
2017-01-29
影响因子：
3.1
作者：
Carneiro, Ana Paula;Fonseca-Alaniz, Miriam Helena;Krieger, Jose Eduardo
通讯作者：
Krieger, Jose Eduardo