Sanquin Research and Landsteiner Laboratory, Academic Medical Center, Amsterdam, the Netherlands.
Dept. Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
Haematologica. 2020 Dec 1;105(12):2746-2756. doi: 10.3324/haematol.2018.196329.
Bone marrow endothelium plays an important role in the homing of hematopoietic stem and progenitor cells upon transplantation, but surprisingly little is known on how the bone marrow endothelial cells regulate local permeability and hematopoietic stem and progenitor cells transmigration. We show that temporal loss of vascular endothelial-cadherin function promotes vascular permeability in BM, even upon low-dose irradiation. Loss of vascular endothelial-cadherin function also enhances homing of transplanted hematopoietic stem and progenitor cells to the bone marrow of irradiated mice although engraftment is not increased. Intriguingly, stabilizing junctional vascular endothelial-cadherin in vivo reduced bone marrow permeability, but did not prevent hematopoietic stem and progenitor cells migration into the bone marrow, suggesting that hematopoietic stem and progenitor cells use the transcellular migration route to enter the bone marrow. Indeed, using an in vitro migration assay, we show that human hematopoietic stem and progenitor cells predominantly cross bone marrow endothelium in a transcellular manner in homeostasis by inducing podosome-like structures. Taken together, vascular endothelial-cadherin is crucial for BM vascular homeostasis but dispensable for the homing of hematopoietic stem and progenitor cells. These findings are important in the development of potential therapeutic targets to improve hematopoietic stem and progenitor cell homing strategies.
骨髓内皮细胞在造血干细胞和祖细胞移植后的归巢中起着重要作用，但令人惊讶的是，对于骨髓内皮细胞如何调节局部通透性和造血干细胞和祖细胞的迁移，我们知之甚少。我们发现，血管内皮钙黏蛋白功能的暂时丧失会促进 BM 中的血管通透性，即使在低剂量辐射下也是如此。内皮钙黏蛋白功能的丧失也增强了移植的造血干细胞和祖细胞向辐射小鼠骨髓中的归巢，尽管植入并没有增加。有趣的是，体内稳定连接的血管内皮钙黏蛋白减少了骨髓通透性，但并没有阻止造血干细胞和祖细胞迁移到骨髓中，这表明造血干细胞和祖细胞利用细胞间迁移途径进入骨髓。事实上，我们通过体外迁移实验表明，在稳态下，人造血干细胞和祖细胞主要通过诱导类似足突的结构以细胞间的方式穿过骨髓内皮细胞。总之，血管内皮钙黏蛋白对于 BM 血管的稳态至关重要，但对于造血干细胞和祖细胞的归巢是可有可无的。这些发现对于开发潜在的治疗靶点以改善造血干细胞和祖细胞归巢策略非常重要。
