Division of Cardiovascular Research, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Circ Res. 2011 May 27;108(11):1340-7. doi: 10.1161/CIRCRESAHA.110.239848. Epub 2011 Apr 14.
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 4 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 peri-infarct 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 to 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. Histological examination of the tumors revealed hypercelluarity, pleomorphic nucleoli, cytological 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.
骨髓（BM）来源的间充质干细胞（MSCs）由于其多能性和培养扩增能力，在心血管细胞治疗中具有很大的应用前景。
本研究旨在探讨 MSCs 是否可以治疗实验性急性心肌梗死（MI）和糖尿病性神经病。
我们从鼠 BM 中分离出单核细胞，并以常规方式培养 MSCs。对这些培养的第 4 代细胞进行流式细胞术分析，显示出典型的 MSC 标志物的表达，如 CD44 和 CD29，但不表达造血标志物，如 c-kit、flk1 和 CD34。为了确定 MSCs 的治疗效果，我们在结扎小鼠左前降支冠状动脉后将 MSCs 注射到梗死区周围，作为单独的实验，我们将同一批 MSCs 注射到糖尿病性神经病小鼠的后肢肌肉中。在细胞移植后 4 至 8 周的随访期间，在 MI 模型中，30%的心脏中观察到肿瘤生长，在糖尿病性神经病模型中，46%的后肢中观察到肿瘤生长。对肿瘤进行组织学检查，发现细胞过度生长、多形性核仁、细胞学异型性和坏死，并对α-平滑肌肌动蛋白呈阳性染色，提示具有肌源性分化的恶性肉瘤。对这些 MSCs 进行染色体分析显示，包括融合、碎裂和环状形成在内的多种染色体异常。
即使在早期传代时，未经基因修饰的 MSCs 也可能发生染色体异常，并在体内移植后形成恶性肿瘤。这些结果表明，当体外扩增的 MSCs 用于细胞治疗（如 MI）时，有必要对其染色体状态进行仔细监测。
