1. Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
2. Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, Hebei, China.
3. Department of Nuclear Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
4. Preclinical Imaging Laboratory, Turku PET Centre, University of Turku, Turku, Finland.
5. MediCity Research Laboratory, University of Turku, Turku, Finland.
6. Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland.
7. Department of Chemistry, University of Turku, Turku, Finland.
8. Accelerator Laboratory, Turku PET Centre, Åbo Akademi University, Turku, Finland.
9. Turku PET Centre, University of Turku, Turku, Finland.
Rationale: Olfactory ensheathing cell (OEC) transplantation has emerged as a promising therapy for spinal cord injury (SCI) repair. In the present study, we explored the possible mechanisms of OECs transplantation underlying neuroinflammation modulation.
Methods: Spinal cord inflammation after intravenous OEC transplantation was detected in vivo and ex vivo by translocator protein PET tracer [18F]F-DPA. To track transplanted cells, OECs were transduced with enhanced green fluorescent protein (eGFP) and HSV1-39tk using lentiviral vector and were monitored by fluorescence imaging and [18F]FHBG study. Protein microarray analysis and ELISA studies were employed to analyze differential proteins in the injured spinal cord after OEC transplantation. The anti-inflammation function of the upregulated protein was also proved by in vitro gene knocking down experiments and OECs/microglia co-culture experiment.
Results: The inflammation in the spinal cord was decreased after OEC intravenous transplantation. The HSV1-39tk-eGFP-transduced OECs showed no accumulation in major organs and were found at the injury site. After OEC transplantation, in the spinal cord tissues, the interleukin-1 receptor antagonist (IL-1Ra) was highly upregulated while many chemokines, including pro-inflammatory chemokines IL-1α, IL-1β were downregulated. In vitro studies confirmed that lipopolysaccharide (LPS) stimulus triggered OECs to secrete IL-1Ra. OECs significantly suppressed LPS-stimulated microglial activity, whereas IL-1Ra gene knockdown significantly reduced their ability to modulate microglial activity.
Conclusion: The OECs that reached the lesion site were activated by the release of pro-inflammatory cytokines from activated microglia in the lesion site and secreted IL-1Ra to reduce neuroinflammation. Intravenous transplantation of OECs has high therapeutic effectiveness for the treatment of SCI via the secretion of IL-1Ra to reduce neuroinflammation.
Keywords: spinal cord injury, olfactory ensheathing cells, interleukin-1 receptor antagonist (IL-1Ra), neuroinflammation, PET imaging