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

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 T2 values over time in lesioned regions, whereas T2 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. ► NTF+ cell transplantation attenuates the neurotoxicity induced by QA injection. ► HD-derived MSCs possess normal mesenchymal capacity and can be induced to differentiate into NTF+ cells. ► HD-derived NTF+ cells alleviate neural symptoms associated with QA-induced striatal lesions. ► MRI demonstrates in vivo the efficacy of NTF+ cells as treatment for QA toxicity.