Abstract
Mesenchymal stromal cells (MSC) are used extensively in clinical trials; however, the possibility that MSCs have a potential for malignant transformation was raised. We examined the genomic stability versus the tumor-forming capacity of multiple mouse MSCs. Murine MSCs have been shown to be less stable and more prone to malignant transformation than their human counterparts. A large series of independently isolated MSC populations exhibited low tumorigenic potential under syngeneic conditions, which increased in immunocompromised animals. Unexpectedly, higher ploidy correlated with reduced tumor-forming capacity. Furthermore, in both cultured MSCs and primary hepatocytes, polyploidization was associated with a dramatic decrease in the expression of the long noncoding RNA H19. Direct knockdown of H19 expression in diploid cells resulted in acquisition of polyploid cell traits. Moreover, artificial tetraploidization of diploid cancer cells led to a reduction of H19 levels, as well as to an attenuation of the tumorigenic potential. Polyploidy might therefore serve as a protective mechanism aimed at reducing malignant transformation through the involvement of the H19 regulatory long noncoding RNA.
Highlights
Bone marrow stromal cells were first thought to serve as a tissue scaffold for hemopoietic cells [1]
The tumorigenic potential of the various mesenchymal stromal/ stem cells (MSC) populations and clones was evaluated and is summarized in Fig. 2C (The tumorigenicity of individual cells is shown in Supplementary Tables S4 and S5.) We found that the tumorigenicity of MSCs decreased significantly with increased ploidy
Our study shows that tumor formation by mouse MSCs is a relatively rare event
Summary
Bone marrow stromal cells were first thought to serve as a tissue scaffold for hemopoietic cells [1] Further studies revealed their regulatory role in protecting hemopoietic stem cells from extinction through overdifferentiation [2]. MSCs have potential cell therapy uses [3,4,5]; the possible susceptibility of MSCs to malignant transformation puts their application in question. It appears that culturing of murine MSCs results in the accumulation of chromosomal aberrations, such as aneuploidy and polyploidy, which may lead to the acquisition of tumorigenic properties [6, 7]. Human MSCs generally undergo growth arrest after a few passages in culture, necessitating
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