title: Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells. Our results suggest that preconditioning stem cells with the mood stabilizers lithium and VPA before transplantation may serve as an effective strategy for enhancing the therapeutic efficacy of stem cell-based therapies.
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gabriel.linares@med.usc.edu.
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Linares
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: chiuc@csr.nih.gov.
authors.forename: Chi-Tso
authors.initials: CT
authors.lastname: Chiu
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lscheui@udel.edu.
authors.forename: Lisa
authors.initials: L
authors.lastname: Scheuing
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lengy@mail.nih.gov.
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: hsiao-mei.liao@fda.hhs.gov.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Liao
authors.affiliation: Flow Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: maricD@ninds.nih.gov.
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.affiliation: Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: chuang@mail.nih.gov.
authors.forename: De-Maw
authors.initials: DM
authors.lastname: Chuang
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000601:surgery*; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D016207:Cytokines; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D000071058:Huntingtin Protein; D018121:Receptors, Cytokine; D014635:Valproic Acid; D019009:Proto-Oncogene Proteins c-kit; D010751:Phosphopyruvate Hydratase; D018021:Lithium Chloride
keywords: Huntington's disease; Intranasal delivery; Lithium; Mesenchymal stem cells; Mood stabilizers; Preconditioning; Stem cell therapy; Valproic acid