Human Embryonic Stem Cells Are Prone to Generate Primitive, Undifferentiated Tumors in Engrafted Human Fetal Tissues in Severe Combined Immunodeficient Mice

Division of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010 3000, USA.
Stem Cells and Development (Impact Factor: 3.73). 01/2008; 16(6):893-902. DOI: 10.1089/scd.2007.0070
Source: PubMed


Embryonic stem (ES) cells are uniquely endowed with the capacity of self-renewal and the potential to give rise to all possible cell types. Their differentiation potential has raised hope that these cells could be used as a renewable source for cell transplantation in severe degenerative diseases. However, progress in this direction is still limited. Using two human embryonic stem (ES) cell lines, H1 and HSF-6, and three types of human fetal tissues--thymus, lung and pancreas-we investigated whether engrafted human fetal tissues in severe combined immunodeficient mice (SCID) mice could provide a physiologically-relevant microenvironment for human ES cells to differentiate into mature cells of corresponding tissues. Surprisingly, we observed an aggressive growth of tumors when human ES cells were injected into engrafted human fetal tissues in SCID mice. These tumors displayed histological characteristics of primitive, undifferentiated tumors rather than differentiated teratomas. Additionally, these tumors exhibited a normal karyotype and did not express the characteristic antigens of embryonic carcinomas. We also found differences among human fetal tissue types in their abilities to support the growth of these primitive tumors. Our study supports and validates a previously reported phenomenon in mouse that tumorigenesis of ES cells is host dependent. Our study is also the first report to demonstrate that human ES cells are prone to generate primitive, undifferentiated tumors in human fetal tissue grafts in SCID mice and raises a potential safety concern for using human ES cell-derived cell products in humans.

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    • "Studies have shown that mouse embryonic stem cells (MESCs) would form teratocarcinomas when injected into immunodeficient mice [70]. Also, when injected into human embryonic stem cells (hESCs) in severe combined immunodeficient mice, hESCs could generate primitive, undifferentiated tumors [71]. On the contrary, Sieber-Blum found that epidermal neural crest stem cell grafted into the adult spinal cord does not form tumors [72]. "
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    ABSTRACT: Schwann cell (SC) transplantation as a cell-based therapy can enhance peripheral and central nerve repair experimentally, but it is limited by the donor site morbidity for clinical application. We investigated weather respiratory mucosa stem cells (REMSCs), a kind of ectomesenchymal stem cells (EMSCs), isolated from rat nasal septum can differentiate into functional Schwann-like cells (SC-like cells). REMSCs proliferated quickly in vitro and expressed the neural crest markers (nestin, vimentin, SOX10, and CD44). Treated with a mixture of glial growth factors for 7 days, REMSCs differentiated into SC-like cells. The differentiated REMSCs (dREMSCs) exhibited a spindle-like morphology similar to SC cells. Immunocytochemical staining and Western blotting indicated that SC-like cells expressed the glial markers (GFAP, S100 β , Galc, and P75) and CNPase. When cocultured with dREMSCs for 5 days, PC12 cells differentiated into mature neuron-like cells with long neurites. More importantly, dREMSCs could form myelin structures with the neurites of PC12 cells at 21 days in vitro . Our data indicated that REMSCs, a kind of EMSCs, could differentiate into SC-like cells and have the ability to promote the differentiation of PC12 cells and form myelin in vitro .
    Stem cell International 09/2015; 2015(5):328957. DOI:10.1155/2015/328957 · 2.81 Impact Factor
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    • "Stem cell therapy has been proposed as a potential candidate for treating neurological diseases by inducing pluripotent stem cells into differentiated neurons (Alvarez et al. 2010; Yoo et al. 2013); however, many unaddressed risks remain in this context. A high risk of tumorigenesis transformed from the transplantation of differentiated neurons remains an obstacle to the clinical usage of stem cell therapies (Shih et al. 2007; Knoepfler 2009). To seek another approach for cell-based therapies, we suggested the differentiated fibroblasts as an alternative choice (Chen et al. 2012). "
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    ABSTRACT: Background Erythropoietin (EPO) has potent neuroprotective effects. The short-term delivery of high-dose EPO seemed to improve patients’ neuromuscular functions; however, excessive EPO resulted in systematically high hematocrit and thrombotic risk. In our study, we established a cellular material for future in vivo studies of neurodegenerative diseases based on EPO provided regionally at a nontoxic level.MethodsA mouse EPO cDNA was subcloned into the pCMS-EGFP vector and transfected into NIH/3T3 fibroblasts to design a biological provider that can regionally release EPO for the treatment of neurological diseases. After G418 selection, a stable EPO-overexpressing cell line, EPO-3T3-EGFP, was established. To further confirm the neuroprotective abilities of secreted EPO from EPO-3T3-EGFP cells, a cell model of neurodegeneration, PC12-INT-EGFP, was applied.ResultsThe expression level of EPO was highly elevated in EPO-3T3-EGFP cells, and an abundant amount of EPO secreted from EPO-3T3-EGFP cells was detected in the extracellular milieu. After supplementation with conditioned medium prepared from EPO-3T3-EGFP cells, the survival rate of PC12-INT-EGFP cells was significantly enhanced. Surprisingly, a fraction of aggregated cytoskeletal EGFP-tagged α-internexin in PC12-INT-EGFP cells was disaggregated and transported into neurites dynamically. The immunocytochemical distribution of IF proteins, including NF-M, phosphorylated-NF-M, and the α-INT-EGFP fusion protein, were less aggregated in the perikaryal region and transported into neurites after the EPO treatment.Conclusion The established EPO-overexpressing NIH/3T3 cell line, EPO-3T3-EGFP, may provide a material for future studies of cell-based therapies for neurodegenerative diseases via the secretion of EPO on a short-term, high-dose, regional basis.
    Brain and Behavior 06/2015; 5(8). DOI:10.1002/brb3.356 · 2.24 Impact Factor
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    • "The activity of totipotency factors Oct-4, SSEA-3 Tra-1-60 and Tra-1-81 was assessed by immunofluorescence staining (Wang and Matise, 2013), while the expression of totipotency factors C-MYC, KLF-4, OCT-4 and SOX-2 was assessed by RT-PCR. The totipotency of ESCs in vivo was determined by analyzing teratomas in severe combined immunodeficiency disease (SCID) mice (Shih et al., 2007). "
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    Genetics and Molecular Biology 03/2014; 37(1):127-34. DOI:10.1590/S1415-47572014000100019 · 1.20 Impact Factor
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