Anatomy and Physiology, Department Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
Int J Mol Sci. 2022 Apr 23;23(9):4680. doi: 10.3390/ijms23094680.
The use of human pluripotent stem cells (hPSCs) in regenerative medicine has great potential. However, it is important to exclude that these cells can undergo malignant transformation, which could lead to the development of malignant tumours. This property of hPSCs is currently being tested using the teratoma assay, through which cells are injected into immunodeficient mice. Transplantation of stem cells in immunocompromised recipient animals certainly has a much higher incidence of tumour formation. On the other hand, the results obtained in immunodeficient mice could indicate a risk of tumour formation that is practically not present in the human immunocompetent recipient. The presence of a humanised immune system might be more representative of the human situation; therefore, we investigated if the demonstrated malignant features of chosen and well-characterised stem cell lines could be retrieved and if new features could arise in a humanised mouse model. Hu-CD34NSG (HIS) mice were compared side by side with immunocompromised mice (NSG) after injection of a set of benign (LU07) and malignant (LU07+dox and 2102Ep) cell lines. Analysis of the tumour development, histological composition, pathology evaluation, and malignancy-associated miRNA expression levels, both in tumour and plasma samples, revealed no differences among mouse groups. This indicates that the HIS mouse model is comparable to, but not more sensitive than, the NSG immunodeficient model for studying the malignancy of stem cells. Since in vivo teratoma assay is cumbersome, in vitro methods for the detection of malignancy are urgently needed.
人多能干细胞（hPSCs）在再生医学中的应用具有巨大的潜力。然而，重要的是要排除这些细胞可能发生恶性转化的可能性，因为这可能导致恶性肿瘤的发展。目前，通过畸胎瘤检测来测试 hPSC 的这种特性，即将细胞注射到免疫缺陷小鼠中。在免疫功能低下的受体动物中移植干细胞肯定会导致肿瘤形成的发生率更高。另一方面，在免疫缺陷小鼠中获得的结果可能表明在人类免疫功能正常的受体中实际上不存在的肿瘤形成风险。具有人源化免疫系统的动物可能更能代表人类的情况；因此，我们研究了选择和特征良好的干细胞系的恶性特征是否可以被重现，如果在人源化小鼠模型中是否会出现新的特征。在注射了一组良性（LU07）和恶性（LU07+dox 和 2102Ep）细胞系后，我们将 Hu-CD34NSG（HIS）小鼠与免疫缺陷小鼠（NSG）进行了平行比较。对肿瘤发展、组织学组成、病理评估以及肿瘤和血浆样本中与恶性相关的 miRNA 表达水平进行分析，结果表明各组小鼠之间没有差异。这表明 HIS 小鼠模型与 NSG 免疫缺陷模型相似，但在研究干细胞的恶性方面并不比后者更敏感。由于体内畸胎瘤检测很繁琐，因此迫切需要用于检测恶性的体外方法。
