Tumorigenic Development of Induced Pluripotent Stem Cells in Ischemic Mouse Brain

Abstract

Induced pluripotent stem (iPS) cells may provide cures for various neurological diseases. However, undifferentiated iPS cells have high tumorigenicity, and evaluation of the cells fates, especially in pathologic condition model, is needed. In this study, we demonstrated the effect of ischemic condition to undifferentiated iPS cells fates in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells were characterized with immunofluorescent staining. The iPS cells (5 × 10 5 ) were injected into ipsilateral striatum and cortex after 24 h of MCAO. Histological analysis was performed from 3 to 28 days after cell transplantation. iPS cells in ischemic brain formed teratoma with higher probability (p < 0.05) and larger volume (p < 0.01) compared with those in intact brain. Among the four transcriptional factors to produce iPS cells, c-Myc, Oct3/4, and Sox2 strongly expressed in iPS-derived tumors in ischemic brain (p < 0.01). Additionally, expression of matrix metalloproteinase-9 (MMP-9) and phosphorylated vascular endothelial growth factor receptor2 (phospho-VEGFR2) were significantly increased in iPS-derived tumors in the ischemic brain (p < 0.05). These results suggest that the transcriptional factors might increase expression of MMP-9 and activate VEGFR2, promoting teratoma formation in the ischemic brain. We strongly propose that the safety of iPS cells should be evaluated not only in normal condition, but also in a pathologic, disease model.

Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: Improving the safety of iPS cell transplantation to myocardium

“…5 However, the risk of tumorigenicity is a major obstacle hindering clinical application of iPS cells. [32][33][34] Zhang et al reported that intramyocardial transplantation of undifferentiated rat iPS cells causes tumorigenesis in the heart. 35 Previous studies demonstrated that the residual undifferentiated iPSD can form teratomas after cell transplantation, and Fu et al 36 reported that even extended periods of cell differentiation do not fully eliminate residual undifferentiated iPS cells.…”

Preclinical Studies for Induced Pluripotent Stem Cell-based Therapeutics

“…There are significant similarities between cancer cells and iPSCs, which include certain molecular properties, the ability to self-renew, rapid unlimited proliferation, high telomerase activity, expression profiles, and epigenetic signatures (78). As one of the criteria for pluripotency, iPSCs are known to form teratomas in immunocompromised recipients after subcutaneous, intratesticular, or intramuscular injection (79,80). The teratoma-forming capability of the differentiated iPSCs derived from different adult tissues varied substantially and correlated with the number of residual pluripotent cells (81).…”

PET Demonstrates Functional Recovery After Transplantation of Induced Pluripotent Stem Cells in a Rat Model of Cerebral Ischemic Injury

“…iPSCs can be generated by transduction of defined transcription factors from adult somatic cells through reprogramming (4) and have been differentiated in vitro into the early neural stem cell stage or the neural lineage, including neurons and glial cells (5)(6)(7). More recently, iPSCs have been applied to a variety of nervous system disease models, including Parkinson disease (8), spinal cord injury (9,10), and stroke (11)(12)(13)(14), and were found to improve neural function (11,13,15). However, to better understand the in vivo behavior and efficacy of iPSCs, a noninvasive, sensitive, and clinically applicable approach for tracking the transplanted iPSCs and monitoring the therapeutic response in living subjects is warranted.…”