Tumorigenic and Differentiation Potentials of Embryonic Stem Cells Depend on TGFβFamily Signaling: Lessons from Teratocarcinoma Cells Stimulated to Differentiate with Retinoic Acid

Abstract

A significant challenge for the development of safe pluripotent stem cell-based therapies is the incomplete in vitro differentiation of the pluripotent stem cells and the presence of residual undifferentiated cells initiating teratoma development after transplantation in recipients. To understand the mechanisms of incomplete differentiation, a comparative study of retinoic acid-induced differentiation of mouse embryonic stem (ES) and teratocarcinoma (EC) cells was conducted. The present study identified differences in proliferative activity, differentiation, and tumorigenic potentials between ES and EC cells. Higher expression of Nanog and Mvh, as well as Activin A and BMP4, was found in undifferentiated ES cells than in EC cells. However, the expression levels of Activin A and BMP4 increased more sharply in the EC cells during retinoic acid-induced differentiation. Stimulation of the Activin/Nodal and BMP signaling cascades and inhibition of the MEK/ERK and PI3K/Act signaling pathways resulted in a significant decrease in the number of Oct4-expressing ES cells and a loss of tumorigenicity, similar to retinoic acid-stimulated EC cells. Thus, this study demonstrates that a differentiation strategy that modulates prodifferentiation and antiproliferative signaling in ES cells may be effective for eliminating tumorigenic cells and may represent a valuable tool for the development of safe stem cell therapeutics.

Expression dynamics of Mage family genes during self-renewal and differentiation of mouse pluripotent stem and teratocarcinoma cells

“…The differentiation potential of the pluripotent stem cells, ESCs R1 and EGCs-10, and teratocarcinoma cells, ECCs F9 and ECCs P19, was significantly different during spontaneous in vitro differentiation and after transplantation into Nude mice [46–48]. However, during RA-induced differentiation, the ESCs, EGCs and ECCs exhibited similar, nearly two-fold decreases in the number of cells in the S-phase of the cell cycle (30–40%) and the number of Oct4-expressing cells (50–60%) (Figure 2A–2C).…”

Biocompatible Gold Nanoparticles Ameliorate Retinoic Acid-Induced Cell Death and Induce Differentiation in F9 Teratocarcinoma Stem Cells

“…The authors concluded that the tested AuNPs did not markedly alter the in vitro differentiation potentials of hESCs [ 88 ]. Gordeeva and Khaydukov [ 91 ] explored the mechanisms of incomplete differentiation in a comparative study of RA-induced differentiation of mouse ESCs and teratocarcinoma (EC) cells. Higher expression of Nanog , Mvh , Activin A , and BMP4 were evident in undifferentiated ESCs compared to EC cells.…”

Tracking and Quantification of Magnetically Labeled Stem Cells Using Magnetic Resonance Imaging

“…[ 103,105,107 ] Successful clinical use of hPSC therapies is likely to require that most, if not all, neural cells of interest be differentiated beyond the hPSC stage since residual hPSCs could produce teratoma tumors if transplanted into the patient. [ 108 ] This is a serious safety issue for hPSC-based therapies. Since our hPSC derived lines of hNP cells are devoid of pluripotent cells and recent successful animal models of stroke indicate a benefi t, we, as well as others, are motivated to conduct further translational research.…”