A Transformed Cell Population Derived From Cultured Mesenchymal Stem Cells Has no Functional Effect After Transplantation Into the Injured Heart
A Transformed Cell Population Derived From Cultured Mesenchymal Stem Cells Has no Functional Effect After Transplantation Into the Injured Heart
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DOI：
10.3727/096368909788534906
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Steinhoff, Gustav
中科院分区：
文献类型：
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作者：
Furlani, Dario;Li, Wenzhong;Steinhoff, Gustav
骨髓间充质干细胞（MSCs）是一种具有自我更新和分化潜能的多能细胞。越来越多的临床和临床前证据表明，MSC是再生医学治疗的一种有前途的细胞来源。然而，在人类和小鼠中已经报道了来自长期培养的MSC的不期望的永生化、自发转化和致瘤潜力。我们报道了从年轻供体中分离的大鼠MSCs在早期传代培养中可以发生转化。我们的目的是表征转化的人口，并确定他们的治疗效果后，心内移植在梗死心肌。根据标准方案从刘易斯大鼠的骨髓中分离MSC并在标准条件下培养。通过流式细胞术评估生长细胞的表型。在大鼠急性心肌梗死后，通过心内注射递送细胞。采用压力-容积环评价心功能。6周后观察脑梗死面积及病理学变化。早在第3代时，就在培养物中检测到异常菌落。注意到它们表现为与典型的MSC明显不同的形态，典型的MSC从正常的细长纺锤形变为紧凑的异常形态。它们表现出快速的细胞增殖。一些亚克隆失去了细胞分裂的接触抑制，形成多层聚集体。检测到染色体不稳定性。它们缺乏表面标志物CD 29、CD 44、CD 90和CD 117。细胞移植后6周，梗死面积和心功能无明显改善。我们的研究强调需要建立生物安全标准来调节培养扩增的MSC以实现充分的临床治疗益处。
Bone marrow-derived mesenchymal stein cells (MSCs) are multipotent cells characterized by their self-renewal and differentiation potential. Accumulating clinical and preclinical evidence indicate MSCs are a promising cell source for regenerative medical therapies. However, undesirable immortalization, spontaneous transformation, and tumorigenic potential from long-term cultured MSCs have been reported in human and mouse. We report rat MSCs isolated from young donors could undergo transformation in early passage culture. We aimed to characterize the transformed population and determine their therapeutic effects after intracardiac transplantation in the infarcted myocardium. MSCs were isolated from bone marrow of Lewis rats according to standard protocols and cultured under standard conditions. Phenotype of growing cells was assessed by flow cytometry. Following acute myocardial infarction in rats, cells were delivered by intracardiac injection. Cardiac functions were assessed by pressure-volume loops. Infarction size and pathologic effects were evaluated after 6 weeks. The abnormal colonies were detected in culture as early at passage 3. They were noted to appear as distinctly different morphology from typical MSCs, which changed from a normal elongated spindle shape to a compact abnormal morphology. They exhibited rapid cell proliferation. Some subclones lost contact inhibition of cell division and formed multilayer aggregates. Chromosomal instability was detected. They were devoid of surface markers CD29, CD44, CD90, and CD117. Furthermore, there was no significant improvement on infarction size and cardiac function 6 weeks after cell transplantation. Our study highlights the need for establishment of biosafety criteria in regulating culture-expanded MSCs to achieve the full clinical therapeutic benefits.