Neural Induction With Neurogenin 1 Enhances the Therapeutic Potential of Mesenchymal Stem Cells in an Amyotrophic Lateral Sclerosis Mouse Model

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages, whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15-17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.This work was partly supported by Brain Research Center of the 21st Century Frontier Research Program (2011K000262) and the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Education, Science and Technology (2010-0020406) to HSK and by Basic Science Research Program through NRF funded by the Ministry of Education, Science and Technology (2010-0023676) to SSK. Conflicts of Interest: The authors declare no financial or other competing interests