Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis

Research in recent years has extensively investigated the therapeutic efficacy of mesenchymal stromal cells in regenerative medicine for many neurodegenerative diseases at preclinical and clinical stages. However, the success rate of stem cell therapy remains less at translational phase. Lack of relevant animal models that potentially simulate the molecular etiology of human pathological symptoms might be a reason behind such poor clinical outcomes associated with stem cell therapy. Apparently, self‐renewal and differentiation ability of mesenchymal stem cells may help to study the early developmental signaling pathways connected with the diseases, such as Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), etc., at in vitro level. Cannabidiol, a non‐psychotrophic cannabinoid, has been demonstrated as a potent anti‐inflammatory and neuroprotective agent in neurological preclinical models. In the present study, we investigated the modulatory role of cannabidiol on genes associated with ALS using human gingiva‐derived mesenchymal stromal cells (hGMSCs) as an in vitro model system. Next generation transcriptomic sequencing analysis demonstrated considerable modifications in the expression of genes connected with ALS pathology, oxidative stress, mitochondrial dysfunction, and excitotoxicity in hGMSCs treated with cannabidiol. Our results suggest the efficacy of cannabidiol to delineate the unknown molecular pathways, which may underlie ALS pathology at an early stage using hGMSCs as a compelling in vitro system. J. Cell. Biochem. 118: 819–828, 2017. © 2016 Wiley Periodicals, Inc.

[1]  M. Sanz,et al.  Comparison of periodontal ligament and gingiva-derived mesenchymal stem cells for regenerative therapies , 2017, Clinical Oral Investigations.

[2]  E. Huang,et al.  Modeling ALS and FTD with iPSC-derived neurons , 2017, Brain Research.

[3]  S. Fulle,et al.  Human periodontal ligament stem cells cultured onto cortico-cancellous scaffold drive bone regenerative process. , 2016, European cells & materials.

[4]  Aditi,et al.  An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms. , 2016, Advances in biological regulation.

[5]  P. Pagella,et al.  Innovative Dental Stem Cell-Based Research Approaches: The Future of Dentistry , 2016, Stem cells international.

[6]  L. Walker,et al.  Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents , 2016, Pharmacotherapy.

[7]  Haiyan Lu,et al.  Current Therapy of Drugs in Amyotrophic Lateral Sclerosis , 2016, Current neuropharmacology.

[8]  A. Nishimura,et al.  The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine , 2016, Stem cells international.

[9]  N. Benvenisty,et al.  Pluripotent stem cells in disease modelling and drug discovery , 2016, Nature Reviews Molecular Cell Biology.

[10]  H. Larjava,et al.  Characterisation of human gingival neural crest-derived stem cells in monolayer and neurosphere cultures. , 2016, European cells & materials.

[11]  F. Guimarães,et al.  Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice , 2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[12]  E. Mazzon,et al.  Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis , 2016, Stem Cell Research & Therapy.

[13]  E. Mazzon,et al.  Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis. , 2015, European review for medical and pharmacological sciences.

[14]  S. Miscia,et al.  Human Periodontal Stem Cells Release Specialized Proresolving Mediators and Carry Immunomodulatory and Prohealing Properties Regulated by Lipoxins , 2015, Stem cells translational medicine.

[15]  Sara Zarei,et al.  A comprehensive review of amyotrophic lateral sclerosis , 2015, Surgical neurology international.

[16]  K. Shakesheff,et al.  Dental pulp stem cells: function, isolation and applications in regenerative medicine , 2015, Journal of tissue engineering and regenerative medicine.

[17]  H. Koo,et al.  Strategies to improve the immunosuppressive properties of human mesenchymal stem cells , 2015, Stem Cell Research & Therapy.

[18]  J. Krieger,et al.  Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration , 2015, Front. Cell. Neurosci..

[19]  S. Burstein Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. , 2015, Bioorganic & medicinal chemistry.

[20]  G. D’Antona,et al.  Natural compounds used as therapies targeting to amyotrophic lateral sclerosis. , 2015, Current pharmaceutical biotechnology.

[21]  Seahyoung Lee,et al.  Cell Adhesion and Long-Term Survival of Transplanted Mesenchymal Stem Cells: A Prerequisite for Cell Therapy , 2015, Oxidative medicine and cellular longevity.

[22]  Denis Gris,et al.  Nlrx1 regulates neuronal cell death , 2014, Molecular Brain.

[23]  Daniela C. Zarnescu,et al.  Futsch/MAP1B mRNA Is a Translational Target of TDP-43 and Is Neuroprotective in a Drosophila Model of Amyotrophic Lateral Sclerosis , 2014, The Journal of Neuroscience.

[24]  Ji-xian Wang,et al.  Melatonin Pretreatment Improves the Survival and Function of Transplanted Mesenchymal Stem Cells after Focal Cerebral Ischemia , 2014, Cell transplantation.

[25]  J. Fernández-Ruiz,et al.  Changes in Endocannabinoid Receptors and Enzymes in the Spinal Cord of SOD1G93A Transgenic Mice and Evaluation of a Sativex®‐like Combination of Phytocannabinoids: Interest for Future Therapies in Amyotrophic Lateral Sclerosis , 2014, CNS neuroscience & therapeutics.

[26]  L. Pallanck,et al.  A Drosophila model of mitochondrial disease caused by a complex I mutation that uncouples proton pumping from electron transfer , 2014, Disease Models & Mechanisms.

[27]  Peter Reinhardt,et al.  Investigating human disease using stem cell models , 2014, Nature Reviews Genetics.

[28]  R. Morimoto,et al.  Proteasome Activation is a Mechanism for Pyrazolone Small Molecules Displaying Therapeutic Potential in Amyotrophic Lateral Sclerosis , 2014, ACS chemical neuroscience.

[29]  R. Ramer,et al.  Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. , 2014, Biochemical pharmacology.

[30]  Adriano Chiò,et al.  State of play in amyotrophic lateral sclerosis genetics , 2013, Nature Neuroscience.

[31]  C. di Ilio,et al.  Proteome of Human Stem Cells from Periodontal Ligament and Dental Pulp , 2013, PloS one.

[32]  Seok-Goo Cho,et al.  Clinical applications of mesenchymal stem cells , 2013, The Korean journal of internal medicine.

[33]  Eiki Takahashi,et al.  Analysis of ischemic neuronal injury in Cav2.1 channel α1 subunit mutant mice. , 2013, Biochemical and biophysical research communications.

[34]  C. Blackstone,et al.  N-terminal cleavage of the mitochondrial fusion GTPase OPA1 occurs via a caspase-independent mechanism in cerebellar granule neurons exposed to oxidative or nitrosative stress , 2013, Brain Research.

[35]  J. Martínez-Orgado,et al.  Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? , 2013, British journal of clinical pharmacology.

[36]  M. Kuźma-Kozakiewicz Pathogenesis of amyotrophic lateral sclerosis , 2011 .

[37]  John G. Laffey,et al.  Faculty Opinions recommendation of Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2011 .

[38]  A. Holmgren,et al.  Vertebrate-specific glutaredoxin is essential for brain development , 2011, Proceedings of the National Academy of Sciences.

[39]  I. Lewis,et al.  Potential therapeutic applications of mesenchymal stromal cells , 2011, Pathology.

[40]  J. Hur,et al.  Stem cell technology for neurodegenerative diseases , 2011, Annals of neurology.

[41]  G. Carter,et al.  Cannabis and Amyotrophic Lateral Sclerosis: Hypothetical and Practical Applications, and a Call for Clinical Trials , 2010, The American journal of hospice & palliative care.

[42]  L. Petrocellis,et al.  Cannabimovone, a Cannabinoid with a Rearranged Terpenoid Skeleton from Hemp , 2010 .

[43]  S. Gronthos,et al.  Mesenchymal Stem Cells Derived from Dental Tissues vs. Those from Other Sources: Their Biology and Role in Regenerative Medicine , 2009, Journal of dental research.

[44]  H. Lee,et al.  The Anti‐Inflammatory and Anti‐Angiogenic Role of Mesenchymal Stem Cells in Corneal Wound Healing Following Chemical Injury , 2008, Stem cells.

[45]  A. Nauta,et al.  Immunomodulatory properties of mesenchymal stromal cells. , 2007, Blood.

[46]  R. Tuan,et al.  Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation , 2007, Arthritis research & therapy.

[47]  Armand Keating,et al.  Mesenchymal stromal cells , 2006, Stem Cell Biology and Regenerative Medicine.

[48]  S. McAllister,et al.  Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid , 2004, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[49]  N. Maraldi,et al.  Assessment of an efficient xeno-free culture system of human periodontal ligament stem cells. , 2015, Tissue engineering. Part C, Methods.

[50]  N. Bersinger,et al.  Human placental stem cells: biomedical potential and clinical relevance. , 2011, Journal of stem cells.

[51]  R. Tuan,et al.  Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation , 2007 .

[52]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.