Reversal of Neuropsychiatric Comorbidities in an Animal Model of Temporal Lobe Epilepsy Following Systemic Administration of Dental Pulp Stem Cells and Bone Marrow Mesenchymal Stem Cells.

INTRODUCTION: We aim to investigate whether timed systemic administration of dental pulp stem cells (DPSCs) or bone marrow mesenchymal stem cells (BM-MSCs) with status epilepticus (SE) induced blood-brain barrier (BBB) damage could facilitate the CNS homing of DPSCs/BM-MSCs and mitigate neurodegeneration, neuroinflammation and neuropsychiatric comorbidities in an animal model of Temporal Lobe epilepsy (TLE). 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.

Remarkable migration propensity of dental pulp stem cells towards neurodegenerative milieu: An in vitro analysis.

Stem cell therapy provides a ray of hope for treating neurodegenerative diseases (ND). Bone marrow mesenchymal stem cells (BM-MSC) were extensively investigated for their role in neuroregeneration. However, drawbacks like painful bone marrow extraction, less proliferation and poor CNS engraftment following systemic injections of BM-MSC prompt us to search for alternate/appropriate source of MSC for treating ND. In this context, dental pulp stem cells (DPSC) could be an alternative to BM-MSC as it possess both mesenchymal and neural characteristic features due to its origin from ectoderm, ease of isolation, higher proliferation index and better neuroprotection. A study on the migration potential of DPSC compared to BM-MSC in a neurodegenerative condition is warranted. Given the neural crest origin, we hypothesize that DPSC possess better migration towards neurodegenerative milieu as compared to BM-MSC. In this prospect, we investigated the migration potential of DPSC in an in vitro neurodegenerative condition. Towards this, transwell, Matrigel and chorioallantoic membrane (CAM) migration assays were carried-out by seeding hippocampal neurons in the lower chamber and treated with 300 µM kainic acid (KA) for 6 h to induce neurodegeneration. Subsequently, the upper chamber of transwell was loaded with DPSC/BM-MSC and their migration potential was assessed following 24 h of incubation. Our results revealed that the migration potential of DPSC/BM-MSC was comparable in non-degenerative condition. However, following injury the migration potential of DPSC towards the degenerating site was significantly higher as compared to BM-MSC. Furthermore, upon exposure of naïve DPSC/BM-MSCs to culture medium derived from neurodegenerative milieu resulted in significant upregulation of homing factors like SDF-1alpha, CXCR-4, VCAM-1, VLA-4, CD44, MMP-2 suggesting that the superior migration potential of DPSC might be due to prompt expression of homing factors in DPSC compared to BM-MSCs.

Dosage and Passage Dependent Neuroprotective Effects of Exosomes Derived from Rat Bone Marrow Mesenchymal Stem Cells: An In Vitro Analysis.

BACKGROUND: Neurodegenerative diseases comprise a group of disorders for which no treatment is available till date. Stem cell based therapy offers great hope and promise. However, stem cell transplantation is associated with certain disadvantages like poor targeted migration, engraftment and survival of the transplanted cells. MATERIAL & METHOD: Exosomes, a type of extracellular membrane vesicle released by all cell types including stem cells, offer an alternative to stem cell transplantation. Exosome carry a wide array of biomolecules and are implicated in exhibiting substantial benefits in the repair/regeneration of the injured tissue. Thus, exosomes offer an alternative therapeutic approach as a substitute of cell transplantation. In order to utilize exosomes for therapeutic purpose, it is essential to evaluate the appropriate passage number and the dosage to avoid possible cytotoxic effects. Here, we isolated exosomes from different passages of rat bone marrow mesenchymal stem cells (BM-MSC) and analysed the neuroprotective potential of BM-MSC exosomes in an in vitro model of excitotoxicity. RESULT: Our results demonstrated that the exosomes isolated from early passage of rat BM-MSC exhibited more efficient neuroprotective potential as opposed to later passages derived exosomes. Furthermore, the neuroprotective efficacy of exosome is dosage dependent. i.e. the lower dosage of exosomes was found to be neuroprotective, whereas higher dosage of exosomes (from later passages) was found to be detrimental to neurons. The early passage derived exosomes protected neurons through anti-apoptotic, anti-necrotic and anti-oxidant mechanisms. CONCLUSION: Our study suggests that adult stem cells derived exosomes could be a potential therapeutic agent to confer neuroprotection in neurodegenerative diseases like Alzheimer's disease.