Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells.
Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells.
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DOI：
10.1007/s00395-015-0488-3
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发表时间：
2015-05
影响因子：
9.5
通讯作者：
Sussman MA
中科院分区：
文献类型：
--
作者：
Gude N;Joyo E;Toko H;Quijada P;Villanueva M;Hariharan N;Sacchi V;Truffa S;Joyo A;Voelkers M;Alvarez R;Sussman MA
应用自体祖细胞治疗心力衰竭的I期临床试验已经取得了令人鼓舞的结果;然而，功能的改善是适度的，这表明需要增强心脏干细胞的修复能力。Notch信号传导在心脏发育中起着至关重要的作用，指导肌细胞和血管分化的细胞命运决定。Notch通路保留在成体心脏干细胞龛中，其中Notch信号的水平和持续时间影响心脏祖细胞的增殖和分化。在这项研究中，Notch信号在体外促进心脏祖细胞的生长、存活和分化为平滑肌谱系。表达他莫昔芬调节的细胞内Notchl（CPCeK）的心脏祖细胞比对照细胞显著更大并且增殖更慢，表现出升高的mTORCl和Akt信号传导，并且对氧化应激具有抗性。血管平滑肌和心肌细胞标志物增加CPCeK，并进一步增强后，配体介导的诱导Notch信号。指示生长、存活和分化的旁分泌信号随着Notch活性而增加，而衰老标记物减少。相对于接受对照细胞的心脏，将CPCeK连续转移到梗死小鼠心肌中增强了心脏功能的保护并减少了梗死面积。CPCeK治疗的心脏中更大的毛细血管密度和血管平滑肌组织的比例表明血管化改善。最后，我们报告了一个以前未描述的信号传导机制，Notch激活刺激CPC的生长，生存和分化，通过mTORCl和旁分泌因子的表达。总之，这些发现表明，调节Notch激活增强了CPC在心脏病治疗中的修复能力。
Phase I clinical trials applying autologous progenitor cells to treat heart failure have yielded promising results; however, improvement in function is modest, indicating a need to enhance cardiac stem cell reparative capacity. Notch signaling plays a crucial role in cardiac development, guiding cell fate decisions that underlie myocyte and vessel differentiation. The Notch pathway is retained in the adult cardiac stem cell niche, where level and duration of Notch signal influence proliferation and differentiation of cardiac progenitors. In this study, Notch signaling promotes growth, survival and differentiation of cardiac progenitor cells into smooth muscle lineages in vitro. Cardiac progenitor cells expressing tamoxifen-regulated intracellular Notchl (CPCeK) are significantly larger and proliferate more slowly than control cells, exhibit elevated mTORCl and Akt signaling, and are resistant to oxidative stress. Vascular smooth muscle and cardiomyocyte markers increase in CPCeK and are augmented further upon ligand-mediated induction of Notch signal. Paracrine signals indicative of growth, survival and differentiation increase with Notch activity, while markers of senescence are decreased. Adoptive transfer of CPCeK into infarcted mouse myocardium enhances preservation of cardiac function and reduces infarct size relative to hearts receiving control cells. Greater capillary density and proportion of vascular smooth muscle tissue in CPCeK-treated hearts indicate improved vascularization. Finally, we report a previously undescribed signaling mechanism whereby Notch activation stimulates CPC growth, survival and differentiation via mTORCl and paracrine factor expression. Taken together, these findings suggest that regulated Notch activation potentiates the reparative capacity of CPCs in the treatment of cardiac disease.
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影响因子：
46.9
作者：
Chen, Vincent C.;Stull, Robert;Joo, Daniel;Cheng, Xin;Keller, Gordon
通讯作者：
Keller, Gordon
影响因子：
9.5
作者：
Hong KU;Li QH;Guo Y;Patton NS;Moktar A;Bhatnagar A;Bolli R
通讯作者：
Bolli R
影响因子：
4.8
作者：
Buas, Matthew F.;Kabak, Shara;Kadesch, Tom
通讯作者：
Kadesch, Tom
DOI：
10.1073/pnas.0709663105
发表时间：
2008-02-12
影响因子：
11.1
作者：
High, Frances A.;Lu, Min Min;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.
Notch 激活静止心肌细胞的细胞周期重入和进展。
DOI：
10.1083/jcb.200806104
发表时间：
2008-10-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Campa VM;Gutiérrez-Lanza R;Cerignoli F;Díaz-Trelles R;Nelson B;Tsuji T;Barcova M;Jiang W;Mercola M
通讯作者：
Mercola M