Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine

Department of Cell Biology and Human Anatomy & Stem Cell Program, University of California Davis School of Medicine, Sacramento, CA, USA.
Stem Cells (Impact Factor: 6.52). 05/2009; 27(5):1050-6. DOI: 10.1002/stem.37
Source: PubMed


Many of the earliest stem cell studies were conducted on cells isolated from tumors rather than from embryos. Of particular interest was research on embryonic carcinoma cells (EC), a type of stem cell derived from teratocarcinoma. The EC research laid the foundation for the later discovery of and subsequent work on embryonic stem cells (ESC). Both ESC isolated from the mouse (mESC) and then later from humans (hESC) shared not only pluripotency with their EC cousins, but also robust tumorigenicity as each readily form teratoma. Surprisingly, decades after the discovery of mESC, the question of what drives ESC to form tumors remains largely an open one. This gap in the field is particularly serious as stem cell tumorigenicity represents the key obstacle to the safe use of stem cell-based regenerative medicine therapies. Although some adult stem cell therapies appear to be safe, they have only a very narrow range of uses in human disease. Our understanding of the tumorigenicity of human induced pluripotent stem cells (IPSC), perhaps the most promising modality for future patient-specific regenerative medicine therapies, is rudimentary. However, IPSC are predicted to possess tumorigenic potential equal to or greater than that of ESC. Here, the links between pluripotency and tumorigenicity are explored. New methods for more accurately testing the tumorigenic potential of IPSC and of other stem cells applicable to regenerative medicine are proposed. Finally, the most promising emerging approaches for overcoming the challenges of stem cell tumorigenicity are highlighted.

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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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    • "Adult stem cells are present in somatic tissues, e.g., bone marrow or adipose tissue, and play a vital role to repair and replenish dying somatic cells and damaged tissues [27]. Despite their immense potential in tissue engineering applications, ESCs and iPSCs have been found to differentiate into tumor cells [28], severely limiting scopes of their clinical trials in humans. This makes mesenchymal stem cells (a type of adult stem cells) a viable and practical alternative to use in stem cell research, as there is no literature report till date that hMSCs express cancer genes under any circumstances [11] [27]. "
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    ABSTRACT: Physicochemical features of a cell nanoenvironment exert important influence on stem cell behavior and include the influence of matrix elasticity and topography on differentiation processes. The presence of growth factors such as TGF-β and BMPs on these matrices provides chemical cues and thus plays vital role in directing eventual stem cell fate. Engineering of functional biomimetic scaffolds that present programmed spatio-temporal physical and chemical signals to stem cells holds great promise in stem cell therapy. Progress in this field requires tacit understanding of the mechanistic aspects of cell-environment nanointeractions, so that they can be manipulated and exploited for the design of sophisticated next generation biomaterials. In this review, we report and discuss the evolution of these processes and pathways in the context of matrix adhesion as they might relate to stemness and stem cell differentiation. Super-resolution microscopy and single-molecule methods for in vitro nano-manipulation are helping to identify and characterize the molecules and mechanics of structural transitions within stem cells and matrices. All these advances facilitate research toward understanding of stem cell niche and consequently to developing new class of biomaterials helping the “used biomaterials” for applications in tissue engineering and regenerative medicine.
    Biomaterials 07/2014; 35(20):5278–5293. DOI:10.1016/j.biomaterials.2014.03.044 · 8.56 Impact Factor
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    • "Nonetheless, the teratoma risk associated with contaminating PSCs in differentiated cell populations still remains. This problem is further aggravated by the intrinsic propensity for some PSC derivatives to undergo dedifferentiation in situ [4], [11]. Even if ensuing data from clinical trials supports the efficacy and safety of the PSC-based therapies, the teratoma risk might have to be continuously monitored when PSC-based therapies are routinely applied in a clinical setting. "
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    ABSTRACT: A major concern in Pluripotent Stem Cell (PSC)-derived cell replacement therapy is the risk of teratoma formation from contaminating undifferentiated cells. Removal of undifferentiated cells from differentiated cultures is an essential step before PSC-based cell therapies can be safely deployed in a clinical setting. We report a group of novel small molecules that are cytotoxic to PSCs. Our data indicates that these molecules are specific and potent in their activity allowing rapid eradication of undifferentiated cells. Experiments utilizing mixed PSC and primary human neuronal and cardiomyocyte cultures demonstrate that up to a 6-fold enrichment for specialized cells can be obtained without adversely affecting cell viability and function. Several structural variants were synthesized to identify key functional groups and to improve specificity and efficacy. Comparative microarray analysis and ensuing RNA knockdown studies revealed involvement of the PERK/ATF4/DDIT3 ER stress pathway. Surprisingly, cell death following ER stress induction was associated with a concomitant decrease in endogenous ROS levels in PSCs. Undifferentiated cells treated with these molecules preceding transplantation fail to form teratomas in SCID mice. Furthermore, these molecules remain non-toxic and non-teratogenic to zebrafish embryos suggesting that they may be safely used in vivo.
    PLoS ONE 03/2014; 9(3):e85039. DOI:10.1371/journal.pone.0085039 · 3.23 Impact Factor
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