Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine

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.

Neural Differentiation of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells

“…Despite the advantages of ESCs, they are not practical for neurodegenerative diseases due to several problems (6,21). Recently, MSCs have been the focus of intensive investigations because of their relative advantages (22)(23)(24).…”

“…Embryonic stem cells (ESCs), neural stem cells (NSCs), bone marrow (BM)-derived mesenchymal stem cells (MSCs), and adipose-derived adult stem (ADAS) cells have been shown to generate differentiated neural cells both in vitro and in vivo, which can be used as substitute therapies for various neurodegenerative diseases (1)(2)(3)(4)(5). However, despite the differentiation capability of these cells, ethical conflicts, legal restrictions, the invasive procedures required to obtain them, and graftversus-host disease (GVHD) are major challenges in their development for clinical applications that emphasize exploring and evaluating different sources for use in various cell-based therapies (1,6). MSCs have been shown to be ideal candidates for regenerative medicine (7).…”

Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis

“…Stem cells have the potential to protect, repair, and regenerate impaired tissues. Working with embryonic stem cells has many drawbacks, such as genetic mutations, teratomas formation, difficult ethical considerations, and possibility of immune rejection [15]. To overcome these limitations, MSCs have been studied as an alternative source for cell therapy, because they are easy to prepare, have immunologic advantages, and involve no ethical controversy [16].…”

Induced Pluripotency and Oncogenic Transformation Are Related Processes

“…However, Nanog, Sox2, and Oct4 (also known as Pou5f1) are linked to tumorigenesis as well ( [8][9][10] and reviewed in ref. [11]). The degree to which iPSCs can form malignant tumors remains mostly undefined as are the mechanisms involved when tumor formation has been shown to occur [12].…”

“…Also of concern is the compelling similarity that we first noted between the methods used for iPSC production and those used to produce so-called oncogenic foci (OF) [11]. OF formation assays have been used to study oncogenes for decades [23].…”