PET Imaging Of Dynamic Metabolic Changes After Induced Pluripotent Stem Cells Combined With A Traditional Chinese Medicine In The Treatment Of Ischemic Stroke

ObjectiveThe study aimed to use serial 18F-FDG PET imaging to investigate the dynamic metabolic changes after a combined therapeutic approach of induced pluripotent stem cells (iPSCs) and a traditional Chinese medicine (Danhong Injection, DHI) in a rat model of cerebral ischemia-reperfusion injury.MethodsTwenty-four male rats were randomly assigned to 1 of the 4 groups: phosphate-buffered saline (PBS) control, traditional Chinese medicine (DHI), induced pluripotent stem cells (iPSCs), iPSCs combined with DHI (iPSCs+DHI). The rat model of focal cerebral ischemia-reperfusion was established with middle cerebral artery suture occlusion method, followed by suture withdrawal after 90 min. From Day 1 after cerebral ischemia, the rats of the DHI and the combined treatment groups were intraperitoneally injected with DHI daily for 4 weeks. At Day 3 post-ischemia, a volume of 20 uL suspended iPSCs (l*106 cells) or PBS was stereotactically injected into the right lateral ventricle. Serial 18F-FDG small-animal PET imaging and behavioral tests were performed weekly after stem cell transplantation. Bioluminescent imaging was used to monitor the fate of grafted iPSCs in vivo. Autoradiographic imaging and immunohistochemical analyses were conducted at Week 4 after the final PET imaging.ResultsCompared with the PBS control group, higher 18F-FDG accumulations in the right cerebral infarct area were observed in iPSCs+DHI and iPSCs treatment groups at 2-4 wk (P< 0.01) and in the DHI group at 3-4 wk (P< 0.05) after stem cell transplantation. Furthermore, the 18F-FDG uptake in the iPSCs+DHI group was significantly higher than that of iPSCs or DHI group at Week 4 (P< 0.05). The iPSCs+DHI group firstly presented neural functional recovery compared with the PBS group at Week 2{P< 0.05) and the neurologic scores in the iPSCs+DHI group were significantly higher than those of the iPSCs group at Week 4 (P< 0.05). Bioluminescent imaging detected signals in all iPSCs grafted animals from Day 3 to Week 2. At Week 1, the BLI signals were strongest and were stronger in the combined treatment group compared with the iPSCs group (P< 0.05). Immunohistochemical and immunofluorescent analyses revealed that transplanted iPSCs survived and migrated to brain ischemic regions and differentiated into mature nerve cells and angiogenic cells. Immunohistochemical evaluation also found that DHI promoted endogenous neurogenesis and angiogenesis.Conclusion!8F-FDG PET demonstrated metabolic and functional recovery after treatments of iPSCs or combined with DHI in the rat model of cerebral ischemia-reperfusion injury. The combined treatment seemed to be a better therapeutic approach than iPSCs alone.