In vivo monitoring of remnant undifferentiated neural cells following human induced pluripotent stem cell-derived neural stem/progenitor cells transplantation

Abstract

Transplantation of human‐induced pluripotent stem cell‐derived neural stem/progenitor cells (hiPSC‐NS/PCs) is a promising treatment for a variety of neuropathological conditions. Although previous reports have indicated the effectiveness of hiPSC‐NS/PCs transplantation into the injured spinal cord of rodents and nonhuman primates, long‐term observation of hiPSC‐NS/PCs post‐transplantation suggested some “unsafe” differentiation‐resistant properties, resulting in disordered overgrowth. These findings suggest that, even if “safe” NS/PCs are transplanted into the human central nervous system (CNS), the dynamics of cellular differentiation of stem cells should be noninvasively tracked to ensure safety. Positron emission tomography (PET) provides molecular‐functional information and helps to detect specific disease conditions. The current study was conducted to visualize Nestin (an NS/PC marker)‐positive undifferentiated neural cells in the CNS of immune‐deficient (nonobese diabetic‐severe combined immune‐deficient) mice after hiPSC‐NS/PCs transplantation with PET, using 18 kDa translocator protein (TSPO) ligands as labels. TSPO was recently found to be expressed in rodent NS/PCs, and its expression decreased with the progression of neuronal differentiation. We hypothesized that TSPO would also be present in hiPSC‐NS/PCs and expressed strongly in residual immature neural cells after transplantation. The results showed high levels of TSPO expression in immature hiPSC‐NS/PCs‐derived cells, and decreased TSPO expression as neural differentiation progressed in vitro. Furthermore, PET with [18F] FEDAC (a TSPO radioligand) was able to visualize the remnant undifferentiated hiPSC‐NS/PCs‐derived cells consisting of TSPO and Nestin+ cells in vivo. These findings suggest that PET with [18F] FEDAC could play a key role in the safe clinical application of CNS repair in regenerative medicine.

First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: Study protocol

“…In the preclinical study with mice, abnormal growth of the transplant was estimated from the eighth week after transplantation by deterioration of motor function and could be confirmed histologically by the 12th week [ 32 ]. Moreover, abnormal cell growth can be detected by positron emission tomography (PET) imaging by day 28 at the earliest [ 33 ]. Based on these results from animal studies, the time interval between the first and second transplantation is set to a minimum of 12 weeks.…”

Regenerative therapy for spinal cord injury using iPSC technology

“…The remnant undifferentiated NPCs showed a high expression of the 18-kDa translocator protein (TSPO), also known as the peripheral-type benzodiazepine receptor. Because the TSPO-selective radioligand [ 18 F] FEDAC is available as a clinically relevant nuclide, we proposed that the remaining NPCs after transplantation could be detected using positron emission tomography (PET) imaging [17]. When non-tumorigenic iPSC-NPCs were transplanted into central nervous system (CNS) tissue, the cells did not show uptake of the [ 18 F] FEDAC in PET imaging.…”

Tumorigenic and Immunogenic Properties of Induced Pluripotent Stem Cells: a Promising Cancer Vaccine

“…Researchers created an in vitro selective system to ablate immature proliferating cells by introducing suicide genes into the cells [37]. In addition, by identifying and labeling undifferentiated cell markers, researchers are able to monitor remnant immature cells in vivo [38]. Moreover, recent clinical studies showed that the rejection of grafts have not been observed in patients for at least short-term period without using immunosuppression methods (Table 1).…”