FIRC Institute of Molecular Oncology Foundation (IFOM), Milan, Italy.
EMBO Mol Med. 2014 Feb;6(2):239-58. doi: 10.1002/emmm.201302520. Epub 2013 Dec 30.
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.
肌肉萎缩症是一种严重的遗传疾病，目前尚无有效的治疗方法。实验性临床治疗包括经动脉内给予血管相关的干细胞，称为中胚层细胞（MABs）。然而，这种方法的一个局限性是移植到病变组织的细胞数量相对较少，至少部分原因是外渗效率不理想，而 MAB 的外渗机制尚不清楚。白细胞通过穿过内皮细胞间的连接和连接蛋白，迁移到炎症组织中，这些连接蛋白指导和控制白细胞的穿胞作用。在这里，我们确定内皮连接蛋白 JAM-A 是 MAB 外渗的关键调节因子。我们表明，JAM-A 基因失活和 JAM-A 阻断抗体强烈增强了 MAB 在萎缩肌肉中的植入。在没有 JAM-A 的情况下，交换因子 EPAC-1 和 2 下调，从而阻止了小 GTPase Rap-1 的激活。结果，连接收紧减少，允许 MAB 穿胞作用。值得注意的是，Rap-1 的药理学抑制增加了 MAB 在萎缩肌肉中的植入，从而显著改善了肌肉功能，为基于干细胞的治疗提供了一种新策略。
