Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: A potential therapy for Huntington's disease

O. Sadan, N. Shemesh, R. Barzilay, M. Dadon-Nahum, T. Blumenfeld-Katzir, Y. Assaf, M. Yeshurun, R. Djaldetti, Y. Cohen, E. Melamed, D. Offen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF + cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF + cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF + cells transplanted into rat brains after QA injection survive transplantation (19% after 6weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF + cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF + cells and exert efficacious effects similarly to NTF + cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T 2 values over time in lesioned regions, whereas T 2 values decrease in equivalent regions of QA-injected rats treated with NTF + cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.

Original languageEnglish
Pages (from-to)417-427
Number of pages11
JournalExperimental Neurology
Volume234
Issue number2
DOIs
StatePublished - Apr 2012

Funding

FundersFunder number
Beverly Sackler Center for Biophysics
Herczeg Institute on Aging
Israeli National Psychobiology Institute
Tel-Aviv University
Hereditary Disease Foundation
Israel Science Foundation
Tel Aviv University

    Keywords

    • Huntington's disease
    • In vivo MRI
    • Mesenchymal stem cells
    • Neurotrophic factors
    • Quinilinic acid

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