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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: 7.7). 05/2009; 27(5):1050-6. DOI: 10.1002/stem.37
Source: PubMed

ABSTRACT 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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    • "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 · 8.31 Impact Factor
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    • "MSCs can be self-donated (Hare et al., 2012), have exhibited lower risk of teratomas (Knoepfler, 2009), and are not subject to the same ethical issues (Zomorodian and Baghaban Eslaminejad, 2012). Bone marrow stromal cells (BMSCs), a subset of which has been shown to be stem cells (also known as bone marrow-derived mesenchymal stem cells) are currently in clinical trials for graft versus host disease (GVHD), and are widely studied for both tissue repair and immune therapies. "
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    ABSTRACT: Inconsistencies among in vitro and in vivo experiments using adult mesenchymal stem cells (MSCs) confound development of therapeutic, regenerative medicine applications, and in vitro expansion is typically required to achieve sufficient cell numbers for basic research or clinical trials. Though heterogeneity in both morphology and differentiation capacity of culture-expanded cells is noted, sources and consequences are not well understood. Here, we endeavored to observe the onset of population heterogeneity by conducting long-term continuous in vitro observation of human adult bone marrow stromal cell (BMSC) populations, a subset of which has been shown to be stem cells (also known as bone marrow-derived MSCs). Semi-automated identification and tracking of cell division and migration enabled construction of cell lineage maps that incorporated cell morphology. We found that all BMSCs steadily grew larger over time; this growth was interrupted only when a cell divided, producing two equally sized, morphologically similar daughter cells. However, a finite probability existed that one or both of these daughters then continued to increase in size without dividing, apparently exiting the cell cycle. Thus, larger BMSCs are those cells that have exited the normal cell cycle. These results hold important implications for MSC in vitro culture expansion and biophysical sorting strategies.
    Stem Cell Research 09/2013; 11(3):1365-1377. DOI:10.1016/j.scr.2013.09.004 · 3.91 Impact Factor
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    • "Additionally M-MSCs have reduced immunogenicity due to their minimal expression of surface MHC ІІ proteins and the lack of T cell stimulatory proteins like CD80 and CD86 [12]. Another important reason for the early success of M-MSCs based therapies is that MSCs have low tumorigenic potential and are safer than therapies based on ESCs or iPSCs which display robust tumori‐ genicity [13]. "
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    ABSTRACT: Four key milestones have to be realized for the ideal customized stem cell therapy to be successful. First, stem cells utilized in these therapies have to be genetically stable and epigenetically regulated to ensure the safety of stem cells employed in any future therapies. This is essential to ensure that patients undergoing stem cell therapy are not exposed to increased risks of tumorigenesis and other mutagenic diseases. Second, stem cells should be able to evade the innate immune response of patients, possibly via the secretion of immunosuppressive molecules that inhibit immune responses or by displaying host cellular recognition markers. The survival of transplanted stem cells is crucial for the design of an effective therapy. Additionally the ability of transplanted stem cells to evade immune detection and inflammatory responses will prevent undesired symptoms such as graft-versus-host-disease in patients. Third, stem cells employed in these therapies should be location specific. These stem cells should possess specific homing cell surface markers that will allow them to locate and migrate to specific localities. This will ensure that stem cells used in therapies will only accumulate in diseased tissues for targeted therapeutic effect, and not in other healthy regions where detrimental non-specific interactions might occur. Finally, the stem cells used in these therapies should be functionally specific and disease relevant.
    Pluripotent Stem Cells, 1 edited by Nibedita Lenka, 08/2013: chapter 17: pages 375-396; InTech., ISBN: 978-953-51-1192-4
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