Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, USA.
Stem Cells. 2012 Nov;30(11):2472-86. doi: 10.1002/stem.1198.
Systemically administered adult mesenchymal stem cells (MSCs), which are being explored in clinical trials to treat inflammatory disease, exhibit the critical ability to extravasate at sites of inflammation. We aimed to characterize the basic cellular processes mediating this extravasation and compare them to those involved in leukocyte transmigration. Using high-resolution confocal and dynamic microscopy, we show that, like leukocytes, human bone marrow-derived MSC preferentially adhere to and migrate across tumor necrosis factor-α-activated endothelium in a vascular cell adhesion molecule-1 (VCAM-1) and G-protein-coupled receptor signaling-dependent manner. As several studies have suggested, we observed that a fraction of MSC was integrated into endothelium. In addition, we observed two modes of transmigration not previously observed for MSC: Paracellular (between endothelial cells) and transcellular (directly through individual endothelial cells) diapedesis through discrete gaps and pores in the endothelial monolayer, in association with VCAM-1-enriched "transmigratory cups". Contrasting leukocytes, MSC transmigration was not preceded by significant lateral migration and occurred on the time scale of hours rather than minutes. Interestingly, rather than lamellipodia and invadosomes, MSC exhibited nonapoptotic membrane blebbing activity that was similar to activities previously described for metastatic tumor and embryonic germ cells. Our studies suggest that low avidity binding between endothelium and MSC may grant a permissive environment for MSC blebbing. MSC blebbing was associated with early stages of transmigration, in which blebs could exert forces on underlying endothelial cells indicating potential functioning in breaching the endothelium. Collectively, our data suggest that MSC transmigrate actively into inflamed tissues via both leukocyte-like and novel mechanisms.
系统性给予的成体间充质干细胞（MSCs），目前正在临床试验中探索用于治疗炎症性疾病，其具有在炎症部位渗出的关键能力。我们旨在阐明介导这种渗出的基本细胞过程，并将其与白细胞迁移所涉及的过程进行比较。我们使用高分辨率共聚焦和动态显微镜，显示出与白细胞相似，人骨髓来源的 MSC 优先黏附并穿过肿瘤坏死因子-α激活的内皮细胞，这一过程依赖于血管细胞黏附分子-1（VCAM-1）和 G 蛋白偶联受体信号。正如一些研究表明的，我们观察到一部分 MSC 整合到内皮细胞中。此外，我们观察到两种以前未观察到的 MSC 迁移方式：通过内皮单层中离散的间隙和小孔的细胞旁（在内皮细胞之间）和细胞内（直接穿过单个内皮细胞）穿越，与 VCAM-1 富集的“迁移杯”相关。与白细胞不同，MSC 迁移之前没有明显的侧向迁移，并且发生在数小时而不是数分钟的时间尺度上。有趣的是，MSC 表现出非凋亡性的膜起泡活性，而不是片状伪足和入侵小体，这与先前描述的转移性肿瘤和胚胎生殖细胞的活性相似。我们的研究表明，内皮细胞和 MSC 之间低亲和力的结合可能为 MSC 起泡提供了一个许可的环境。MSC 起泡与迁移的早期阶段相关，在此阶段，起泡可以对下方的内皮细胞施加力，表明其在穿透内皮方面具有潜在的功能。总的来说，我们的数据表明，MSC 通过类似于白细胞的和新颖的机制主动迁移到炎症组织中。
