Targeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles.
Targeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles.
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DOI：
10.1002/emmm.201302520
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发表时间：
2014-02
影响因子：
11.1
通讯作者：
Dejana, Elisabetta
中科院分区：
文献类型：
--
作者：
Giannotta, Monica;Benedetti, Sara;Tedesco, Francesco Saverio;Corada, Monica;Trani, Marianna;D'Antuono, Rocco;Millet, Queensta;Orsenigo, Fabrizio;Galvez, Beatriz G.;Cossu, Giulio;Dejana, Elisabetta
肌营养不良是严重的遗传性疾病，目前尚无有效的治疗方法。实验性临床治疗包括动脉内给予血管相关干细胞，称为成中血管细胞（MAB）。然而，这种方法的局限性之一是植入患病组织的细胞数量相对较低，这至少部分是由于外渗的次优效率，其MAB的机制是未知的。白细胞通过穿过内皮细胞-细胞连接迁移到炎症组织中，连接蛋白指导和控制白细胞渗出。在这里，我们确定了内皮连接蛋白JAM-A作为MAB外渗的关键调节因子。我们发现，JAM-A基因失活和JAM-A阻断抗体强烈增强MAB在营养不良肌肉中的植入。在缺乏JAM-A的情况下，交换因子EPAC-1和2被下调，这阻止了小GTdR Rap-1的激活。因此，连接收紧减少，允许MAB渗出。值得注意的是，Rap-1的药理学抑制增加了MAB在营养不良肌肉中的植入，这导致肌肉功能的显著改善，为基于干细胞的治疗提供了新的策略。
Muscular dystrophies are severe genetic diseases for which no efficacious therapies exist. Experimental clinical treatments include intra-arterial administration of vessel-associated stem cells, called mesoangioblasts (MABs). However, one of the limitations of this approach is the relatively low number of cells that engraft the diseased tissue, due, at least in part, to the sub-optimal efficiency of extravasation, whose mechanisms for MAB are unknown. Leukocytes emigrate into the inflamed tissues by crossing endothelial cell-to-cell junctions and junctional proteins direct and control leukocyte diapedesis. Here, we identify the endothelial junctional protein JAM-A as a key regulator of MAB extravasation. We show that JAM-A gene inactivation and JAM-A blocking antibodies strongly enhance MAB engraftment in dystrophic muscle. In the absence of JAM-A, the exchange factors EPAC-1 and 2 are down-regulated, which prevents the activation of the small GTPase Rap-1. As a consequence, junction tightening is reduced, allowing MAB diapedesis. Notably, pharmacological inhibition of Rap-1 increases MAB engraftment in dystrophic muscle, which results into a significant improvement of muscle function offering a novel strategy for stem cell-based therapies.
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影响因子：
9
作者：
通讯作者：
--
VEGF诱导的增殖的接触抑制需要血管内皮钙粘着蛋白，β-catenin和磷酸酶DEP-1/CD148。
影响因子：
7.8
作者：
Lampugnani, MG;Zanetti, A;Corada, M;Takahashi, T;Balconi, G;Breviario, F;Orsenigo, F;Cattelino, A;Kemler, R;Daniel, TO;Dejana, E
通讯作者：
Dejana, E
影响因子：
7.8
作者：
De Angelis, L;Berghella, L;Coletta, M;Lattanzi, L;Zanchi, M;Cusella-De Angelis, MG;Ponzetto, C;Cossu, G
通讯作者：
Cossu, G
DOI：
10.1084/jem.190.9.1351
发表时间：
1999-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Del Maschio A;De Luigi A;Martin-Padura I;Brockhaus M;Bartfai T;Fruscella P;Adorini L;Martino G;Furlan R;De Simoni MG;Dejana E
通讯作者：
Dejana E
影响因子：
21.3
作者：
Dellavalle, Arianna;Sampaolesi, Maurilio;Cossu, Giulio
通讯作者：
Cossu, Giulio