BACKGROUND: Cognitive impairments, altered emotional responsiveness, depression, and anxiety are the common neuropsychiatric co-morbidities observed in TLE patients. Mesenchymal stem cells (MSCs) transplantation has gained immense attention in treating TLE, as ~30% of patients do not respond to anti-epileptic drugs. While MSCs are known to cross the BBB, better CNS homing and therapeutic effects could be achieved when the systemic administration of MSC is timed with BBB damage following SE.
OBJECTIVES: The objectives of the present study are to investigate the effects of systemic administration of DPSCs/BM-MSCs timed with BBB damage on CNS homing of DPSCs/BM-MSCs, neurodegeneration, neuroinflammation and neuropsychiatric comorbidities in an animal model of TLE.
METHODOLOGY: We first assessed the BBB leakage following kainic acid-induced SE and timed the intravenous administration of DPSCs/BM-MSCs to understand the CNS homing/engraftment potential of DPSCs/BM-MSCs and their potential to mitigate neurodegeneration, neuroinflammation and neuropsychiatric comorbidities.
RESULTS: Our results revealed that systemic administration of DPSCs/BM-MSCs attenuated neurodegeneration, neuroinflammation, and ameliorated neuropsychiatric comorbidities. Three months following intravenous administration of DPSCs/BM-MSCs, we observed a negligible number of engrafted cells in the corpus callosum, sub-granular zone, and sub-ventricular zone.
CONCLUSION: Thus, it is evident that functional recovery is still achievable despite poor engraftment of MSCs into CNS following systemic administration.
Methods: Sprague-Dawley (SD) rats were divided into three groups: a no-treatment control group (n = 6), balanced salt solution (BSS) treatment group (n = 6), and hUC-MSCs treatment group (n = 6). Visual functions were assessed by flash visual evoked potential (fVEP) at baseline, Week 3, and Week 6 after optic nerve crush injury. Right eyes were enucleated after 6 weeks for histology.
Results: The fVEP showed shortened latency delay and increased amplitude in the hUC-MSCs treated group compared with control and BSS groups. Higher cellular density was detected in the hUC-MSC treated group compared with the BSS and control groups. Co-localized expression of STEM 121 and anti-S100B antibody was observed in areas of higher nuclear density, both in the central and peripheral regions.
Conclusion: Peribulbar transplantation of hUC-MSCs demonstrated cellular integration that can potentially preserve the optic nerve function with a significant shorter latency delay in fVEP and higher nuclear density on histology, and immunohistochemical studies observed cell migration particularly to the peripheral regions of the optic nerve.
METHODS AND RESULTS: The characterized GO-coated coverslip served as a substrate for culturing WJ-MSCs. In addition to investigating the impact of GO on cell proliferation and differentiation, we conducted a gene expression study using PCR array, while epigenetic control was assessed through bisulfite sequencing and Western blot analysis. Our findings indicate that the presence of GO maintained the proliferation and survival of WJ-MSCs. In the absence of induction, GO led to minor lipid and glycosaminoglycan deposition in WJ-MSCs. This was evidenced by the sustained expression of pluripotency and lineage-specific genes, demethylation at the OCT4 promoter, and a decrease in H3K9 methylation. In osteo-induced condition, the occurrence of osteogenesis appeared to be guided by BMP/TGF and ERK pathway activation, accompanied by the upregulation of osteogenic-related genes and downregulation of DNMT3b.
CONCLUSIONS: GO in osteo-induced condition create a favorable microenvironment that promotes the osteogenesis of WJ-MSCs by influencing genetic and epigenetic controls. This helps in advancing our knowledge on the use of GO as priming platform and WJ-MSCs an alternate source for bone repair and regeneration.