Tumor Prevention in Spinal Cord Stem Cell Treatment

Induced pluripotent stem cells (iPSCs) have great potentials in regenerative medicine in their ability to self-renew and be differentiated or grown into different cell types. One of these applications is to improve motor functions post spinal cord injury. However, because undifferentiated cells' and neural stem/progenitor cells' inherent nature to keep multiplying , one of the biggest challenges in their clinical application is to reduce their tumorigenicity - the ability of these cells to give rise to benign or malignant tumors. Interestingly, a recent article published in Stem Cell Reports titled "Fail-Safe System against Potential Tumorigenicity after Transplantation of iPSC Derivatives" explored the efficacy of a suicide gene (a gene causing the cells to die naturally) introduced into iPSCs to prevent post-transplantation tumor formation in mice.

 

For a brief background, this group integrated the suicide gene called iCaspase9 (iC9) into two human iPSC lines that have previously shown to produce tumors. A small molecule called CID was also used as an inducer/activator for cell suicide. The iCaspase 9 system and CID were then tested in their ability to induce cell death both in cell culture studies and using mouse models.

To show the efficacy of the iCaspase 9 system, Figure 1 showed that with the integration of the suicide iC9 gene and the administration of CID, cell suicide is effectively achieved in the targeted cell lines.

 

Figure 1. Itakura, G., et. al. (2017). Stem Cell Reports.

This is consistent with the results in Figure 2 when the cell lines were transplanted into the injured spinal cords of mice, where they multiply and proliferate until the administration of CID. Interestingly, the hind limb motor function of mice showed improvement after transplantation, but declines after 2-3 weeks post transplantation due to the enlargement of tumor. However, functional recovery was significantly increased after treatment with CID with ablation of the tumor.

 

Figure 2.  Itakura, G., et. al. (2017). Stem Cell Reports.

Stained sections of the spinal cord in Figure 3 and 4 also showed that the transplanted neural stem/progenitor cells formed neural tumors, and these tumors can be ablated upon the activation of the iCaspase 9 system with CID.

 

Figure 3.  Itakura, G., et. al. (2017). Stem Cell Reports.

 

Figure 4.  Itakura, G., et. al. (2017). Stem Cell Reports.


In summary, results from this paper showed that the iCaspase 9 system with the suicide small molecule activator CID is effective in both cell culture studies and in mouse models. Injected CID can also cross the blood-brain-barrier to reach transplanted cells to do its works and ablate tumors in the spinal cord. This makes it an effective system to solve the problem of potential tumor formation in transplanted neural stem/ progenitor cells in the treatment of spinal cord injury. However, the lentiviral vector used to integrate the iC9 gene causes it not suitable for clinical application, as it integrates the gene into the genome. Thus, finding a non-integrating vector would be the next step and can bring the iCaspase 9 system closer to its clinical application.