Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood?
Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood?
复制标题
DOI：
10.1002/stem.1111
复制
发表时间：
2012-07-01
期刊：
影响因子：
5.2
通讯作者：
Le Blanc, Katarina
中科院分区：
文献类型：
--
作者：
Moll, Guido;Rasmusson-Duprez, Ida;Le Blanc, Katarina
多能间充质基质细胞（MSC）在许多临床试验中进行了测试。已经提出了关于这些治疗性细胞在全身输注后的命运和功能的问题。因此，我们询问培养扩增的人MSC是否引起先天性免疫攻击，称为即时血液介导的炎症反应（IBMIR），先前已显示其损害全身输注的胰岛细胞和肝细胞的存活和功能。我们发现，MSC表达的止血调节剂类似于内皮细胞产生的止血调节剂，但在其表面上显示出更高量的促血栓形成组织/基质因子，这在血液暴露后触发了IBMIR，其特征在于形成血液活化标志物。这个过程取决于细胞剂量，MSC供体的选择，特别是细胞传代次数。短期扩增的骨髓间充质干细胞在体外仅引发了微弱的血液反应，而延长培养和与活化淋巴细胞共培养增加了其促血栓形成特性。在对患者进行全身输注后，我们发现血液活化标志物的形成增加，但在目前应用的剂量为1.0-3.0 x 10（6）个细胞/kg时，没有形成纤溶亢进标志物D-二聚体或急性期反应物。培养扩增的MSC在体外和体内触发IBMIR。IBMIR的诱导是剂量依赖性的，并且在长时间的离体扩增后增加。目前应用的低传代临床级MSC的剂量仅引起轻微的全身效应，但更高的细胞剂量，特别是更高传代细胞应小心处理。这种有害的反应会损害这些治疗性细胞的存活、植入和功能。干细胞2012;30：1565-1574
Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture-expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell-passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0-3.0 x 10(6) cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low-passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells. STEM CELLS 2012;30:1565-1574