Inhibition of DNA topoisomerase II selectively reduces the threat of tumorigenicity following induced pluripotent stem cell-based myocardial therapy.

Abstract

The advent of induced pluripotent stem cell (iPSC) technology creates new opportunities for transplant-based therapeutic strategies. The potential for clinical translation is currently hindered by the risk of dysregulated cell growth. Pluripotent stem cells reprogrammed by three-factor (Sox2, Klf, and Oct4) and four-factor (Sox2, Klf, Oct4, and c-Myc) strategies result in the capacity for teratogenic growth from residual pluripotent progeny upon in vivo transplantation. However, these pluripotent stem cells also have a stage-specific hypersensitivity to DNA-damaging agents that may allow separation of lineage-specific therapeutic subpopulation of cells. We aimed to demonstrate the selective effect of DNA topoisomerase II inhibitor, etoposide, in eliminating pluripotent cells in the early cardiac progenitor population thus decreasing the effect of teratoma formation. Immunodeficient murine hearts were infarcted and received implantation of a therapeutic dose of cardiac progenitors derived from partially differentiated iPSCs. Etoposide-treated cell implantation reduced mass formation in the intracardiac and extracardiac chest cavity compared with the same dose of iPSC-derived cardiac progenitors in the control untreated group. In vivo bioluminescence imaging confirmed the localization and engraftment of transplanted cells in the myocardium postinjection in both groups. Comparatively, the equivalent cell population without etoposide treatment demonstrated a greater incidence and size of teratoma formation. Hence, pretreatment with genotoxic etoposide significantly lowered the threat of teratogenicity by purging the contaminating pluripotent cells, establishing an adjunctive therapy to further harness the clinical value of iPSC-derived cardiac regeneration.

• Authors: Saranya P Wyles, Satsuki Yamada, Saji Oommen, Joseph J Maleszewski, Rosanna Beraldi, Almudena Martinez-Fernandez, Andre Terzic, Timothy J Nelson
• Journal: Stem cells and development (Stem Cells Dev) Vol. 23 Issue 19 Pg. 2274-82 (Oct 01 2014) ISSN: 1557-8534 [Electronic] United States
• PMID: 25036735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Topoisomerases, Type II

Topics

• Animals
• Carcinogenesis (metabolism)
• Cell Differentiation (genetics, physiology)
• Cell- and Tissue-Based Therapy (methods)
• Cells, Cultured
• Cellular Reprogramming (genetics)
• DNA Topoisomerases, Type II (metabolism)
• Induced Pluripotent Stem Cells (cytology, transplantation)
• Mice
• Myocardium (metabolism, pathology)
• Regeneration (physiology)
• Stem Cell Transplantation (methods)