Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury.
Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury.
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心脏中激活的c-Kit受体促进损伤后的心脏修复和再生。
DOI：
10.1038/cddis.2016.205
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发表时间：
2016-07-28
影响因子：
9
通讯作者：
Pellegrini M
中科院分区：
文献类型：
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作者：
Di Siena S;Gimmelli R;Nori SL;Barbagallo F;Campolo F;Dolci S;Rossi P;Venneri MA;Giannetta E;Gianfrilli D;Feigenbaum L;Lenzi A;Naro F;Cianflone E;Mancuso T;Torella D;Isidori AM;Pellegrini M
内源性c-Kit受体激活在心肌细胞内稳态和修复中的作用在很大程度上尚不清楚。建立了c-Kit基因激活区突变(TgD814Y)的转基因小鼠。C-KitTgD814Y受体在胚胎发育和出生后的心脏中表达，与内源性基因的表达时间和表达模式相似，但不在造血室表达，从而可以研究心脏特有的表型。C-KitTgD814Y突变使c-Kit受体信号的下游分子ERK1/2和AKT的磷酸化增加，从而在转基因小鼠的心肌组织和细胞中产生了结构性的活性c-Kit受体。在成年转基因心脏中，心脏的形态、大小和c-Kit+心肌细胞总数与wt小鼠没有差异。然而，当c-KitTgD814Y小鼠受到冷冻损伤(CI)造成的跨壁坏死性心脏损伤时，所有转基因小鼠都存活了下来，而wt小鼠只有一半存活。在脑梗塞后的亚急性期，转基因小鼠和wt小鼠表现出类似的心脏损伤。然而，在CI后第9天，转基因小鼠坏死区周围的c-Kit+CD31+内皮祖细胞数量增加。在随后的随访中，与wt小鼠相比，转基因小鼠的纤维化面积持续减少，毛细血管密度增加，心肌细胞补充率增加(通过BrdU掺入建立)。从转基因c-−TgD814Y小鼠体内分离的CD45Kitc-Kit+心肌干细胞与从Wt中分离的细胞相比，表现出更强的内皮和心肌细胞分化潜能。c-Kit受体的结构性激活与小鼠损伤后心肌和血管再生修复潜力的增加有关，从而显著提高了存活率。
The role of endogenous c-Kit receptor activation on cardiac cell homeostasis and repair remains largely unexplored. Transgenic mice carrying an activating point mutation (TgD814Y) in the kinase domain of the c-Kit gene were generated. c-KitTgD814Y receptor was expressed in the heart during embryonic development and postnatal life, in a similar timing and expression pattern to that of the endogenous gene, but not in the hematopoietic compartment allowing the study of a cardiac-specific phenotype. c-KitTgD814Y mutation produced a constitutive active c-Kit receptor in cardiac tissue and cells from transgenic mice as demonstrated by the increased phosphorylation of ERK1/2 and AKT, which are the main downstream molecular effectors of c-Kit receptor signaling. In adult transgenic hearts, cardiac morphology, size and total c-Kit+ cardiac cell number was not different compared with wt mice. However, when c-KitTgD814Y mice were subjected to transmural necrotic heart damage by cryoinjury (CI), all transgenic survived, compared with half of wt mice. In the sub-acute phase after CI, transgenic and wt mice showed similar heart damage. However, 9 days after CI, transgenic mice exhibited an increased number of c-Kit+CD31+ endothelial progenitor cells surrounding the necrotic area. At later follow-up, a consistent reduction of fibrotic area, increased capillary density and increased cardiomyocyte replenishment rate (as established by BrdU incorporation) were observed in transgenic compared with wt mice. Consistently, CD45−c-Kit+ cardiac stem cells isolated from transgenic c-KitTgD814Y mice showed an enhanced endothelial and cardiomyocyte differentiation potential compared with cells isolated from the wt. Constitutive activation of c-Kit receptor in mice is associated with an increased cardiac myogenic and vasculogenic reparative potential after injury, with a significant improvement of survival.