Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells.
Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells.
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DOI：
10.1161/circresaha.111.259507
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发表时间：
2012-03-02
影响因子：
20.1
通讯作者：
Rota M
中科院分区：
文献类型：
--
作者：
Ferreira-Martins J;Ogórek B;Cappetta D;Matsuda A;Signore S;D'Amario D;Kostyla J;Steadman E;Ide-Iwata N;Sanada F;Iaffaldano G;Ottolenghi S;Hosoda T;Leri A;Kajstura J;Anversa P;Rota M
胚胎和胎儿心肌的生长以心肌细胞数量的急剧增加为特征，但心肌细胞区室的扩张是由驻留心脏干细胞（CSCs）的激活和定向分化决定，还是由未成熟心肌细胞的分裂决定，或者两者兼而有之，目前尚不清楚。
在这项研究中，我们测试了产前心脏发育是否受心脏干细胞的激活和分化控制，以及小鼠心脏中c - kit阳性心脏干细胞的分裂是否由自发的钙离子振荡触发。
我们报道胚胎 - 胎儿期c - kit阳性心脏干细胞在体外和体内具有自我更新、克隆形成和多能性。c - kit阳性心脏干细胞的生长和定向分化负责发育中心脏的心肌细胞后代的产生。通过数学模型计算的值与在胚胎第9天、第14天、第19天以及出生后1天对心肌细胞数量的直接测量值之间的紧密对应强烈表明，胚胎心脏的器官发生依赖于由驻留心脏干细胞调控的细胞分化层级模型。c - kit阳性心脏干细胞的生长促进作用由细胞内钙离子的自发振荡触发，这种振荡由IP3受体激活介导，它决定了干细胞不对称分裂和心肌细胞谱系的特化。
由心脏干细胞分化产生的心肌细胞形成是发育过程中心脏生长的主要决定因素。小鼠中c - kit阳性心脏干细胞的分裂由自发的钙离子峰值促进，它决定了干细胞复制的模式以及在产前所有阶段直至出生后1天心肌细胞后代的产生。
Embryonic and fetal myocardial growth is characterized by a dramatic increase in myocyte number, but whether the expansion of the myocyte compartment is dictated by activation and commitment of resident cardiac stem cells (CSCs), division of immature myocytes or both is currently unknown. In this study, we tested whether prenatal cardiac development is controlled by activation and differentiation of CSCs and whether division of c-kit-positive CSCs in the mouse heart is triggered by spontaneous Ca2+ oscillations. We report that embryonic-fetal c-kit-positive CSCs are self-renewing, clonogenic and multipotent in vitro and in vivo. The growth and commitment of c-kit-positive CSCs is responsible for the generation of the myocyte progeny of the developing heart. The close correspondence between values computed by mathematical modeling and direct measurements of myocyte number at E9, E14, E19 and one day after birth strongly suggests that the organogenesis of the embryonic heart is dependent on a hierarchical model of cell differentiation regulated by resident CSCs. The growth promoting effects of c-kit-positive CSCs are triggered by spontaneous oscillations in intracellular Ca2+, mediated by IP3 receptor activation, which condition asymmetric stem cell division and myocyte lineage specification. Myocyte formation derived from CSC differentiation is the major determinant of cardiac growth during development. Division of c-kit-positive CSCs in the mouse is promoted by spontaneous Ca2+ spikes, which dictate the pattern of stem cell replication and the generation of a myocyte progeny at all phases of prenatal life and up to one day after birth.