The tumourigenicity of iPS cells and their differentiated derivates

Abstract

Induced pluripotent stem cell (iPSC) provides a promising seeding cell for regenerative medicine. However, iPSC has the potential to form teratomas after transplantation. Therefore, it is necessary to evaluate the tumorigenic risks of iPSC and all its differentiated derivates prior to use in a clinical setting. Here, murine iPSCs were transduced with dual reporter gene consisting of monomeric red fluorescent protein (mRFP) and firefly luciferase (Fluc). Undifferentiated iPSCs, iPSC derivates from induced differentiation (iPSC-derivates), iPSC-derivated cardiomyocyte (iPSC-CMs) were subcutaneously injected into the back of nude mice. Non-invasive bioluminescence imaging (BLI) was longitudinally performed at day 1, 7, 14 and 28 after transplantation to track the survival and proliferation of transplanted cells. At day 28, mice were killed and grafts were explanted to detect teratoma formation. The results demonstrated that transplanted iPSCs, iPSC-derivates and iPSC-CMs survived in receipts. Both iPSCs and iPSC-derivates proliferated dramatically after transplantation, while only slight increase in BLI signals was observed in iPSC-CM transplanted mice. At day 28, teratomas were detected in both iPSCs and iPSC-derivates transplanted mice, but not in iPSC-CM transplanted ones. In vitro study showed the long-term existence of pluripotent cells during iPSC differentiation. Furthermore, when these cells were passaged in feeder layers as undifferentiated iPSCs, they would recover iPSC-like colonies, indicating the cause for differentiated iPSC's tumourigenicity. Our study indicates that exclusion of tumorigenic cells by screening in addition to lineage-specific differentiation is necessary prior to therapeutic use of iPSCs.

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

“…6 However, a crucial hurdle for therapeutic application of iPS cells or iPS derivates (iPSD) is their potential to form tumors in vivo. 7,8 To achieve tumor-free iPS cell treatment, investigators have developed genetic and non-genetic approaches to enrich and purify stem cell-derived CM; 9 however, the procedures are tedious, inefficient, and only partially efficacious.…”

Inhibition of DNA Topoisomerase II Selectively Reduces the Threat of Tumorigenicity Following Induced Pluripotent Stem Cell-Based Myocardial Therapy

“…1C). iPSC-based predifferentiation into the cardiac progenitor population facilitates the loss of tumorigenicity associated with lineage specification [26]. Our model shows that mouse iPSCs were differentiated into early cardiac progenitors, day-7 EBs, using the hanging-drop method for cardiac differentiation and treated with and without the established concentration of etoposide for 24 h [18].…”

“…Pluripotent stem cells have the innate capability for selfrenewal and unique capacity to differentiate into all somatic lineages, providing an ideal source for patient-specific cell-based therapy that circumvents the ethical issues and immune rejection associated with human embryonic stem cell application [26,28,29]. Yet, the property of tumorigenicity remains a main concern for safe hiPSC transplantation [30].…”

“Footprint-Free” Human Induced Pluripotent Stem Cell-Derived Astrocytes for In Vivo Cell-Based Therapy

“…Experimental allotransplantation of undifferentiated ESC and iPSC into the brain or other tissues results in teratoma formation [48][49][50][51][52]. This very serious risk has hindered the use of hiPSC-derived cells from clinical trials.…”