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.

A Method for Generate a Mouse Model of Stroke: Evaluation of Parameters for Blood Flow, Behavior, and Survival

“…Corner test is used to detect unilateral abnormalities of sensory and motor functions in the stroke model [17]. Corner was made by placing two wooden cardboards (30 cm × 20 cm × 1 cm) at an angle of 30 degree.…”

Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis

“…A recent in vivo study induced in MSCs overexpression of neurogenin 1(Ngn1), a transcriptional regulator that plays a role in initiating neuronal differentiation. It was found that transplantation of MSCs-Ngn1 improved MN survival in SOD1 mice but that transplantation of unprocessed MSCs did not [25]. Although no evidence that MSC-Ngn1 cells had differentiated into neuronal cells was presented, this study did show the increased ability of MSC-Ngn1 cells to migrate to the spinal cord compared to unmodified MSCs.…”

“…In preclinical studies, MSCs administered intravenously into SOD1 mice resulted in cell migration to various peripheral tissues as well as to the brain and spinal cord [25,60-62]. Significant increase in life span and delay of disease progression were observed in two of these studies [60,61], and Uccelli and colleagues [61] suggest reduced microglia activation and reduced oxidative stress as potential mechanisms of repair.…”

Concise Review: Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future

“…G93A-SOD mice receiving intraspinal MSC transplants exhibit favorable effects on neuroinflammation, astrogliosis and microgial activation [37]. Furthermore, induction of neural differentiation of MSCs via neurogenin 1 expression enhances MSC homing to the CNS following intravenous administration in ALS mice and is associated with delayed disease onset and improved motor function [38]. …”