Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy.
Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy.
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DOI：
10.1161/circresaha.110.239848
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发表时间：
2011-05-27
影响因子：
20.1
通讯作者：
Yoon YS
中科院分区：
文献类型：
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作者：
Jeong JO;Han JW;Kim JM;Cho HJ;Park C;Lee N;Kim DW;Yoon YS
骨髓间充质干细胞具有多能性和培养扩增能力，在心血管细胞治疗中具有广阔的应用前景。本研究的目的是探讨骨髓间充质干细胞是否可以治疗实验性急性心肌梗死（MI）和糖尿病神经病变。我们从小鼠骨髓中分离单核细胞，并以常规方式培养MSC。这些培养的细胞在第四代的流式细胞术分析显示典型的MSC标志物如CD 44和CD 29的表达，但不是造血标志物如c-kit，flk 1和CD 34。为了确定MSC的治疗效果，我们将MSC注射到小鼠左前降支冠状动脉结扎后的梗死周围区域，并作为单独的实验将同一批次的MSC注射到患有糖尿病神经病变的小鼠的后肢肌肉中。在细胞移植后4-8周的随访期间，在MI模型中30%的心脏中观察到生长的肿瘤，在糖尿病神经病变模型中46%的后肢中观察到生长的肿瘤。肿瘤的组织学检查显示细胞增生、多形性核仁、细胞学坏死和α-平滑肌肌动蛋白阳性染色，提示恶性肉瘤伴肌源性分化。这些骨髓间充质干细胞的染色体分析显示，包括融合，断裂，和环形成的多个染色体畸变。遗传上未修饰的MSC即使在早期传代时也会发生染色体异常，并在体内移植时形成恶性肿瘤。这些结果表明，当体外扩增的MSC用于细胞治疗如MI时，需要仔细监测染色体状态。
Bone marrow (BM)-derived mesenchymal stem cells (MSCs) hold great promise for cardiovascular cell therapy owing to their multipotency and culture-expandability. The aim of the study was to investigate whether MSCs can treat experimental acute myocardial infarction (MI) and diabetic neuropathy. We isolated mononuclear cells from mouse BM and cultured MSCs in a conventional manner. Flow cytometry analyses of these cultured cells at passage four showed expression of typical MSC markers such as CD44 and CD29, but not hematopoietic markers such as c-kit, flk1 and CD34. To determine the therapeutic effects of MSCs, we injected MSCs into the periinfarct area after ligation of the left anterior descending coronary arteries of mice, and as separate experiments injected the same batch of MSCs into hindlimb muscles of mice with diabetic neuropathy. During the follow-up at 4–8 weeks after cell transplantation, growing tumors were observed in 30% of hearts in the MI model, and in 46% of hindlimbs in the diabetic neuropathy model. Histologic examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytologic atypia and necrosis, and positive staining for α-smooth muscle actin, indicative of malignant sarcoma with myogenic differentiation. Chromosomal analysis of these MSCs showed multiple chromosomal aberrations including fusion, fragmentation, and ring formation. Genetically unmodified MSCs can undergo chromosomal abnormalities even at early passages and form malignant tumors when transplanted in vivo. These results suggest that careful monitoring of chromosomal status is warranted when in vitro expanded MSCs are used for cell therapy such as for MI.