The tumorigenicity of human embryonic and induced pluripotent stem cells

Abstract

The unique abilities of human pluripotent stem cells to self-renew and to differentiate into cells of the three germ layers make them an invaluable tool for the future of regenerative medicine. However, the same properties also make them tumorigenic, and therefore hinder their clinical application. Hence, the tumorigenicity of human embryonic stem cells (HESCs) has been extensively studied. Until recently, it was assumed that human induced pluripotent stem cells (HiPSCs) would behave like their embryonic counterparts in respect to their tumorigenicity. However, a rapidly accumulating body of evidence suggests that there are important genetic and epigenetic differences between these two cell types, which seem to influence their tumorigenicity.

Emerging innovation towards safety in the clinical application of ESCs and iPSCs

“…Pluripotent tumour forming potential can be divided into two categories: malignant transformation of differentiated PSCs, and benign teratoma formation from residual undifferentiated PSCs. 14,15 The former should be also investigated for safety. For example, CD30, which is a biomarker for transformed human ESCs, is correlated with karyotype abnormalities such as partial duplication of chromosome.…”

Human-induced pluripotent stem cells as a source of hepatocyte-like cells: new kids on the block

“…Of relevance, the use of these vectors is at risk to produce insertional mutations and genetic alterations able to interfere with normal functions of cells derived from iPS cells and to favor reactivation of reprogramming factors at later stages. Indeed, residual transgene expression has been reported to affect differentiation into specific lineages [2] or even result in tumorigenesis [8][9][10]. At present, the oncogenic potential of iPS cells represents a major concern for clinical application [9] since these cells, much as ES cells, can readily form teratomas when injected into immunodeficient mice.…”

“…Indeed, residual transgene expression has been reported to affect differentiation into specific lineages [2] or even result in tumorigenesis [8][9][10]. At present, the oncogenic potential of iPS cells represents a major concern for clinical application [9] since these cells, much as ES cells, can readily form teratomas when injected into immunodeficient mice. This may rely, for both iPS and ES cells, on the presence of residual diploid pluripotent cells that have not undergone differentiation in the population of transplanted human ES or iPS cells [9].…”

“…At present, the oncogenic potential of iPS cells represents a major concern for clinical application [9] since these cells, much as ES cells, can readily form teratomas when injected into immunodeficient mice. This may rely, for both iPS and ES cells, on the presence of residual diploid pluripotent cells that have not undergone differentiation in the population of transplanted human ES or iPS cells [9]. Moreover, tumor formation in iPS cell chimeric mice has been attributed to the expression of c-Myc in iPS cell-derived somatic cells, irrespective of the type of the original somatic cell employed [9][10][11][12][13].…”

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

“…Billions of dollars have been spent over the last two decades in an effort to safely harness the regenerative capacity of embryonic stem cells [158]. However, the underlying safety concern for teratoma formation by ESCs and iPSCs has been among the most significant roadblocks to their appearance in the clinic [159]. In this regard, investigations into adult pluripotent stem cell populations have yielded several potentially overlapping populations of cells which meet many of the criteria for pluripotency.…”