Reduction of N-Glycolylneuraminic Acid Xenoantigen on Human Adipose Tissue-Derived Stromal Cells/Mesenchymal Stem Cells Leads to Safer and More Useful Cell Sources for Various Stem Cell Therapies
Reduction of N-Glycolylneuraminic Acid Xenoantigen on Human Adipose Tissue-Derived Stromal Cells/Mesenchymal Stem Cells Leads to Safer and More Useful Cell Sources for Various Stem Cell Therapies
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DOI：
10.1089/ten.tea.2009.0386
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发表时间：
2010-04-01
影响因子：
4.1
通讯作者：
Matsuyama, Akifumi
中科院分区：
文献类型：
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作者：
Komoda, Hiroshi;Okura, Hanayuki;Matsuyama, Akifumi
脂肪组织是体干细胞治疗的一个有吸引力的来源。目前，人脂肪组织来源的基质细胞/间充质干细胞（hADSC/MSC）与胎牛血清（FBS）一起培养。然而，最近，不仅在小鼠饲养细胞上培养的人胚胎干细胞系，而且与FBS一起培养的骨髓来源的人MSC被报道表达N-羟乙酰神经氨酸（Neu 5Gc）异种抗原。人血清含有高滴度的天然预形成的抗Neu 5Gc抗体。我们研究了Neu 5Gc在与FBS一起培养的hADSCs/MSCs上的存在以及Neu 5Gc介导的人免疫应答。我们的数据表明，与FBS一起培养的hADSCs/MSCs表达Neu 5Gc，并且人天然预形成的抗体可以与hADSCs/MSCs结合。然而，hADSC/MSC表达补体调节蛋白，如CD 46、CD 55和CD 59，并且在很大程度上对补体介导的细胞毒性具有抗性。FBS可通过抗体依赖性细胞介导的细胞毒作用损伤hADSCs/MSCs。此外，人单核细胞衍生的巨噬细胞可以吞噬与FBS一起培养的hADSC/MSC，并且这种吞噬活性在人血清存在下增加。将hADSCs/MSCs与热灭活的人血清共同培养1周，可显著降低hADSCs/MSCs上的Neu 5Gc，并阻止Neu 5Gc介导的免疫反应，如与人天然预制抗体的结合、抗体依赖性细胞介导的细胞毒性和吞噬作用。热灭活人血清培养的hADSCs/MSCs的成脂、成骨分化潜能不低于胎牛血清培养的hADSCs/MSCs。对于基于hADSC/MSC的干细胞疗法，应清除暴露于FBS后在其细胞表面上呈递Neu 5Gc的hADSC/MSC以从异种排斥中拯救。
Adipose tissue is an attractive source for somatic stem cell therapy. Currently, human adipose tissue-derived stromal cells/mesenchymal stem cells (hADSCs/MSCs) are cultured with fetal bovine serum (FBS). Recently, however, not only human embryonic stem cell lines cultured on mouse feeder cells but also bone marrow-derived human MSCs cultured with FBS were reported to express N-glycolylneuraminic acid (Neu5Gc) xenoantigen. Human serum contains high titers of natural preformed antibodies against Neu5Gc. We studied the presence of Neu5Gc on hADSCs/MSCs cultured with FBS and human immune response mediated by Neu5Gc. Our data indicated that hADSCs/MSCs cultured with FBS expressed Neu5Gc and that human natural preformed antibodies could bind to hADSCs/MSCs. However, hADSCs/MSCs express complement regulatory proteins such as CD46, CD55, and CD59 and are largely resistant to complement-mediated cytotoxicity. hADSCs/MSCs cultured with FBS could be injured by antibody-dependent cell-mediated cytotoxicity mechanism. Further, human monocyte-derived macrophages could phagocytose hADSCs/MSCs cultured with FBS and this phagocytic activity was increased in the presence of human serum. Culturing hADSCs/MSCs with heat-inactivated human serum for a week could markedly reduce Neu5Gc on hADSCs/MSCs and prevent immune responses mediated by Neu5Gc, such as binding of human natural preformed antibodies, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Adipogenic and osteogenic differentiation potentials of hADSCs/MSCs cultured with heat-inactivated human serum were not less than that of those cultured with FBS. For stem cell therapies based on hADSCs/MSCs, hADSCs/MSCs that presented Neu5Gc on their cell surfaces after exposure to FBS should be cleaned up to be rescued from xenogeneic rejection.