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Neurogenic and cognitive enhancing effects of human dental pulp stem cells and its secretome in animal model of hippocampal neurodegeneration

Venugopal C, Shobha K, Rai KS, Dhanushkodi A

Brain Res Bull, 2022 Mar;180:46-58.
PMID: 34979238 DOI: 10.1016/j.brainresbull.2021.12.012

Progressive hippocampal neuronal losses, neuroinflammation, declined neurogenesis and impaired hippocampal functions are pathological features of Alzheimer's disease and temporal lobe epilepsy (TLE). Halting neuroinflammation and progressive neurodegeneration in the hippocampus is a major challenge in treating such disease conditions which, if unsuccessful would lead to learning/memory dysfunction and co-morbidities like anxiety/depression. Mesenchymal stem cells (MSCs) therapy provides hope for treating neurodegenerative diseases by either replacing lost neurons by transplantation of MSCs which might differentiate into appropriate neuronal phenotypes or by stimulating the resident neural stem cells for proliferation/differentiation. In this current study, we demonstrate that the intrahippocampal transplantation of ectoderm originated dental pulp stem cells (DPSCs) or intrahippocampal injection of DPSCs condition medium (DPSCs-CM) in a mouse model of hippocampal neurodegeneration could efficiently prevent neurodegeneration, neuroinflammation, enhance hippocampal neurogenesis and spatial learning and memory functions much superior to commonly used bone marrow mesenchymal stem cells (BM-MSCs) or its secretome. Probing the possible mechanisms of neuroprotection revealed that DPSCs/DPSCs-CM treatment upregulated an array of hosts' endogenous neural survival factors expression, reduced pro-apoptotic caspase activity and upregulated the anti-apoptotic factors BCL-2 and phosphorylated PI3K prominently than BM-MSCs/BM-MSCs-CM, suggesting that among MSCs, neural crest originated DPSCs might be a better adult stem cell candidate for treating neurodegenerative diseases.
Neuroprotection by Human Dental Pulp Mesenchymal Stem Cells: From Billions to Nano

Venugopal C, K S, Rai KS, Pinnelli VB, Kutty BM, Dhanushkodi A

Curr Gene Ther, 2018;18(5):307-323.
PMID: 30209999 DOI: 10.2174/1566523218666180913152615

INTRODUCTION: Mesenchymal Stem Cell (MSC) therapy in recent years has gained significant attention. Though the functional outcomes following MSC therapy for neurodegenerative diseases are convincing, various mechanisms for the functional recovery are being debated. Nevertheless, recent studies convincingly demonstrated that recovery following MSC therapy could be reiterated with MSC secretome per se thereby shifting the dogma from cell therapy to cell "based" therapy. In addition to various functional proteins, stem cell secretome also includes extracellular membrane vesicles like exosomes. Exosomes which are of "Nano" size have attracted significant interest as they can pass through the bloodbrain barrier far easily than macro size cells or growth factors. Exosomes act as a cargo between cells to bring about significant alterations in target cells. As the importance of exosomes is getting unveil, it is imperial to carry out a comprehensive study to evaluate the neuroprotective potential of exosomes as compared to conventional co-culture or total condition medium treatments.
OBJECTIVE: Thus, the present study is designed to compare the neuroprotective potential of MSC derived exosomes with MSC-condition medium or neuron-MSC-co-culture system against kainic acid induced excitotoxicity in in vitro condition. The study also aims at comparing the neuroprotective efficacy of exosomes/condition medium/co-culture of two MSC viz., neural crest derived human Dental Pulp Stem Cells (hDPSC) and human Bone-Marrow Mesenchymal Stem Cells (hBM-MSC) to identify the appropriate MSC source for treating neurodegenerative diseases.
RESULT: Our results demonstrated that neuroprotective efficacy of MSC-exosomes is as efficient as MSC-condition medium or neuron-MSC co-culture system and treating degenerating hippocampal neurons with all three MSC based approaches could up-regulate host's endogenous growth factor expressions and prevent apoptosis by activating cell survival PI3K-B-cell lymphoma-2 (Bcl-2) pathway.
CONCLUSION: Thus, the current study highlights the possibilities of treating neurodegenerative diseases with "Nano" size exosomes as opposed to transplanting billions of stem cells which inherit several disadvantages.
Remarkable migration propensity of dental pulp stem cells towards neurodegenerative milieu: An in vitro analysis

Senthilkumar S, Venugopal C, Parveen S, K S, Rai KS, Kutty BM, et al.

Neurotoxicology, 2020 12;81:89-100.
PMID: 32905802 DOI: 10.1016/j.neuro.2020.08.006

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.
Corrigendum to: Neuroprotection by Human Dental Pulp Mesenchymal Stem Cells: From Billions to Nano

Venugopal C, K S, Rai KS, Pinnelli VB, Kutty BM, Dhanushkodi A

Curr Gene Ther, 2023;23(3):243-244.
PMID: 37394956 DOI: 10.2174/156652322303230528200022

In this correction, the Editor in Chief suggested revising the publication of Figures 3 and 8E in the article after the correction in numeric value. Below is the corrected version of the figures [1]. The electronic version of the article can be found in "Neuroprotection by Human Dental Pulp Mesenchymal Stem Cells: From Billions to Nano" in the journal Current Gene Therapy, 2018, 18(5), 307-323. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. The original article can be found online at: https://www.eurekaselect.com/article/93056.