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Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor
Kota Kojima1,2, Hiroyuki Miyoshi1, Narihito Nagoshi2
1Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
Abstract:
Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270.
Insights
Tumorigenesis poses a risk in stem cell therapy for spinal cord injury (SCI). This study introduces a suicide gene system to eliminate undifferentiated cells, preventing tumor formation and preserving motor function recovery.
Area of Science:
- Regenerative Medicine
- Neuroscience
- Cancer Biology
Background:
- Tumorigenesis is a significant challenge in human stem/progenitor cell transplantation for spinal cord injury (SCI).
- Undifferentiated transplanted cells increase the risk of tumor formation, leading to motor function deterioration after initial improvement.
- Developing strategies to mitigate this risk is crucial for advancing stem cell therapies.
Purpose of the Study:
- To investigate the efficacy of a suicide gene system for preventing and treating tumorigenesis in human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) transplanted for SCI.
- To determine if selective ablation of immature proliferating cells can prevent tumor formation without compromising therapeutic benefits.
Main Methods:
- Introduction of the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into hiPSC-NS/PCs using lentiviral vectors.
- In vitro assessment of the HSVtk system's ability to ablate immature cells while preserving mature neurons.
- In vivo transplantation into the injured spinal cords of immune-deficient mice to evaluate tumor prevention and functional recovery.
Main Results:
- The HSVtk system effectively ablated immature, proliferative neural cells in vitro and in vivo.
- Transplantation of HSVtk-modified hiPSC-NS/PCs prevented tumor formation in the injured spinal cord.
- Selective ablation of proliferating cells protected motor function recovery, demonstrating a dual benefit of preventing tumors and maintaining therapeutic gains.
Conclusions:
- Suicide gene systems, specifically the HSVtk approach, show promise in opposing tumorigenesis during stem cell therapy for SCI.
- This strategy offers a method to prevent and treat tumor formation post-transplantation without sacrificing the functional improvements achieved by stem cells.
- The findings support the potential of engineered stem cells for safer and more effective SCI treatment.
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