Dissecting the Oncogenic and Tumorigenic Potential of Differentiated Human Induced Pluripotent Stem Cells and Human Embryonic Stem Cells

Departments of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5454, USA.
Cancer Research (Impact Factor: 9.33). 06/2011; 71(14):5030-9. DOI: 10.1158/0008-5472.CAN-10-4402
Source: PubMed


Pluripotent stem cells, both human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), can give rise to multiple cell types and hence have tremendous potential for regenerative therapies. However, the tumorigenic potential of these cells remains a great concern, as reflected in the formation of teratomas by transplanted pluripotent cells. In clinical practice, most pluripotent cells will be differentiated into useful therapeutic cell types such as neuronal, cardiac, or endothelial cells prior to human transplantation, drastically reducing their tumorigenic potential. Our work investigated the extent to which these differentiated stem cell derivatives are truly devoid of oncogenic potential. In this study, we analyzed the gene expression patterns from three sets of hiPSC- and hESC-derivatives and the corresponding primary cells, and compared their transcriptomes with those of five different types of cancer. Our analysis revealed a significant gene expression overlap of the hiPSC- and hESC-derivatives with cancer, whereas the corresponding primary cells showed minimum overlap. Real-time quantitative PCR analysis of a set of cancer-related genes (selected on the basis of rigorous functional and pathway analyses) confirmed our results. Overall, our findings suggested that pluripotent stem cell derivatives may still bear oncogenic properties even after differentiation, and additional stringent functional assays to purify these cells should be done before they can be used for regenerative therapy.

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    • "To date, the cell-derived trophic support has been successfully used in disease treatments by cord blood, bone marrow, adipose, etc., SC transplantation [42–46]. However, the use of undifferentiated SCs in clinical trials might be hampered by the pitfalls of neoplasia or tumorigenesis [47–49]. The application of committed precursors in order to acquire desired phenotype(s) and to retain certain properties of SCs at the same time seems to be the reasonable solution. "
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    ABSTRACT: Oligodendrocyte progenitor cells (OPCs) are the focus of intense research for the purpose of cell replacement therapies in acquired or inherited neurodegenerative disorders, accompanied by ongoing hypo/demyelination. Recently, it has been postulated that these glia-committed cells exhibit certain properties of neural stem cells. Advances in stem cell biology have shown that their therapeutic effect could be attributed to their ability to secret numerous active compounds which modify the local microenvironment making it more susceptible to restorative processes. To verify this hypothesis, we set up an ex vivo co-culture system of OPCs isolated from neonatal rat brain with organotypic hippocampal slices (OHC) injured by oxygen-glucose deprivation (OGD). The presence of OPCs in such co-cultures resulted in a significant neuroprotective effect manifesting itself as a decrease in cell death rate and as an extension of newly formed cells in ischemically impaired hippocampal slices. A microarray analysis of broad spectrum of trophic factors and cytokines expressed by OPCs was performed for the purpose of finding the factor(s) contributing to the observed effect. Three of them-BDNF, IL-10 and SCF-were selected for the subsequent functional assays. Our data revealed that BDNF released by OPCs is the potent factor that stimulates cell proliferation and survival in OHC subjected to OGD injury. At the same time, it was observed that IL-10 attenuates inflammatory processes by promoting the formation of the cells associated with the immunological response. Those neuroprotective qualities of oligodendroglia-biased progenitors significantly contribute to anticipating a successful cell replacement therapy.
    Molecular Neurobiology 10/2013; 49(2). DOI:10.1007/s12035-013-8549-9 · 5.14 Impact Factor
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    • "The multilineage differentiation potential of hBSCs and the lack of tumor formation in recipient animals suggest the potential use of hBSCs as a therapeutic alternative to hESCs and hiPSCs, the use of which is hindered by ethical and safety issues [36, 44, 45]. Because of its ethical, noninvasive and plentiful nature, breastmilk offers a novel resource of patient-specific stem cells for applications in regenerative medicine. "
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    ABSTRACT: The mammary gland undergoes significant remodeling during pregnancy and lactation, which is fuelled by controlled mammary stem cell (MaSC) proliferation. The scarcity of human lactating breast tissue specimens and the low numbers and quiescent state of MaSCs in the resting breast have hindered understanding of both normal MaSC dynamics and the molecular determinants that drive their aberrant self-renewal in breast cancer. Here, we demonstrate that human breastmilk contains stem cells (hBSCs) with multilineage properties. Breastmilk cells from different donors displayed variable expression of pluripotency genes normally found in human embryonic stem cells (hESCs). These genes included the transcription factors (TFs) OCT4, SOX2, NANOG, known to constitute the core self-renewal circuitry of hESCs. When cultured in the presence of mouse embryonic feeder fibroblasts, a population of hBSCs exhibited an encapsulated ESC-like colony morphology and phenotype and could be passaged in secondary and tertiary clonogenic cultures. While self-renewal TFs were found silenced in the normal resting epithelium, they were dramatically upregulated in breastmilk cells cultured in 3D spheroid conditions. Furthermore, hBSCs differentiated in vitro into cell lineages from all three germ layers. These findings provide evidence that breastmilk represents a novel and noninvasive source of patient-specific stem cells with multilineage potential and establish a method for expansion of these cells in culture. They also highlight the potential of these cells to be used as novel models to understand adult stem cell plasticity and breast cancer, with potential use in bioengineering and tissue regeneration. STEM Cells2012;30:2164-2174.
    Stem Cells 10/2012; 30(10):2164-74. DOI:10.1002/stem.1188 · 6.52 Impact Factor
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    • "There are concerns with iPSCs regarding the use of the protooncogene c-myc, and insertion mutagenesis due to the use of retroviral sequences. There are also concerns regarding the tumourigenic potential of differentiated PSCs [31]. Additionally, there are issues surrounding the genetic and epigenetic integrity of the iPSCs and also the true nature of their immunogenic status. "
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    ABSTRACT: Ischaemia-related diseases such as peripheral artery disease and coronary heart disease constitute a major issue in medicine as they affect millions of individuals each year and represent a considerable economic burden to healthcare systems. If the underlying ischaemia is not sufficiently resolved it can lead to tissue damage, with subsequent cell death. Treating such diseases remains difficult and several strategies have been used to stimulate the growth of blood vessels and promote regeneration of ischaemic tissues, such as the use of recombinant proteins and gene therapy. Although these approaches remain promising, they have limitations and results from clinical trials using these methods have had limited success. Recently, there has been growing interest in the therapeutic potential of using a cell-based approach to treat vasodegenerative disorders. In vascular medicine, various stem cells and adult progenitors have been highlighted as having a vasoreparative role in ischaemic tissues. This review will examine the clinical potential of several stem and progenitor cells that may be utilised to regenerate defunct or damaged vasculature and restore blood flow to the ischaemic tissue. In particular, we focus on the therapeutic potential of endothelial progenitor cells as an exciting new option for the treatment of ischaemic diseases.
    Stem Cell Research & Therapy 08/2012; 3(4):31. DOI:10.1186/scrt122 · 3.37 Impact Factor
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