Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation
Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation
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DOI：
10.1089/scd.2012.0486
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发表时间：
2013-05-01
影响因子：
4
通讯作者：
Ohneda, Osamu
中科院分区：
文献类型：
--
作者：
Akimoto, Keiko;Kimura, Kenichi;Ohneda, Osamu
间充质干细胞（Mesenchymal stem cells, MSCs）具有自我更新和多能分化的能力，被认为是多种细胞治疗中最可靠的干细胞来源之一。近年来，利用间充质干细胞进行细胞治疗已被研究为一种新的治疗方法，用于治疗难治性进展和预后不良的癌症。来自不同组织的间充质干细胞具有不同的特性。然而，MSC的不同性质对其在抗癌治疗中的应用的影响尚未得到充分的研究。在本研究中，为了表征不同来源的间充质干细胞的抗癌治疗应用，我们建立了两种不同类型的人间充质干细胞：脐带血来源的间充质干细胞（UCB-MSCs）和脂肪组织来源的间充质干细胞（AT-MSCs）。我们将这些间充质干细胞与原发性多形性胶质母细胞瘤（GBM）细胞共培养，分析不同来源的间充质干细胞如何抑制GBM的生长。我们发现UCB-MSCs抑制GBM生长并引起细胞凋亡，而AT-MSCs促进GBM生长。末端脱氧核苷酸转移酶介导的生物素化UTP镍端标记实验清楚地表明UCB-MSCs通过肿瘤坏死因子相关的凋亡诱导配体（TRAIL）促进GBM的凋亡。TRAIL在UCB-MSCs中的表达高于AT-MSCs。AT-MSCs中血管生成因子（血管内皮生长因子、血管生成素1、血小板衍生生长因子和胰岛素样生长因子）和基质衍生因子-1 （SDF-1/CXCL12）的mRNA表达水平较高，AT-MSCs与GBM共移植时形成高度血管化的肿瘤。重要的是，CXCL12抑制了GBM中凋亡通路的TRAIL激活，这表明at - mscs可能通过至少两种不同的机制——促进血管生成和抑制细胞凋亡——支持GBM在体内的发展。AT-MSCs和UCB-MSCs对GBM的相反作用清楚地表明，为了临床应用的安全性，在选择干细胞来源时必须考虑差异。
Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCB-MSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when AT-MSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms-promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCB-MSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source for safety in clinical application.