Feasibility and Efficacy of Intra-Arterial Administration of Mesenchymal Stem Cells in an Animal Model of Double Toxin-Induced Multiple System Atrophy

Abstract

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease of the central and autonomic nervous system. Because no drug treatment consistently benefits MSA patients, neuroprotective strategy using mesenchymal stem cells (MSCs) has a lot of concern for the management of MSA. In this study, we investigated the safety and efficacy of intra‐arterial administration of MSCs via internal carotid artery (ICA) in an animal model of MSA. The study was composed of feasibility test using a ×10 and ×50 of a standard dose of MSCs (4 × 107 MSCs) and efficacy test using a ×0.2, ×2, and ×20 of the standard dose. An ultrasonic flow meter and magnetic resonance imaging (MRI) showed that no cerebral ischemic lesions with patent ICA blood flow was were observed in animals receiving a ×10 of the standard dose of MSCs. However, no MSA animals receiving a ×50 of the standard dose survived. In efficacy test, animals injected with a ×2 of the standard dose increased nigrostriatal neuronal survival relative to a ×0.2 or ×20 of the standard dose. MSA animals receiving MSCs at ×0.2 and ×2 concentrations of the standard dose exhibited a significant reduction in rotation behavior relative to ×20 of the standard dose of MSCs. Cerebral ischemic lesions on MRI were only observed in MSA animals receiving a ×20 of the standard dose. The present study revealed that if their concentration is appropriate, intra‐arterial injection of MSCs is safe and exerts a neuroprotective effect on striatal and nigral neurons with a coincidental improvement in motor behavior. Stem Cells Translational Medicine 2017;6:1424–1433

Stem Cell Therapies for Progressive Multiple Sclerosis

“…Nevertheless, while IV injection of stem cells may not be the optimal method for direct cell replacement, it has instead the potential to be highly effective for cells which primarily exert their therapeutic effect through long distance paracrine modulation, such as MSCs. Alternatively, intraarterial injection of stem cells has been proposed to prevent the collection of cells in systemic organs and increase the incidence of cells reaching their CNS targets (Walczak et al, 2008;Argibay et al, 2017;Na Kim et al, 2017). However, caution should be taken when using this administration route as it runs the risk of causing microembolisms if the volume and concentration of injected cells are not carefully controlled (Argibay et al, 2017;Na Kim et al, 2017).…”

“…Alternatively, intraarterial injection of stem cells has been proposed to prevent the collection of cells in systemic organs and increase the incidence of cells reaching their CNS targets (Walczak et al, 2008;Argibay et al, 2017;Na Kim et al, 2017). However, caution should be taken when using this administration route as it runs the risk of causing microembolisms if the volume and concentration of injected cells are not carefully controlled (Argibay et al, 2017;Na Kim et al, 2017).…”

Insight Into the Mechanisms and the Challenges on Stem Cell-Based Therapies for Cerebral Ischemic Stroke

“…Regarding intravascular delivery methods, viable stem cells may not pass filtering organs, such as the lungs, liver, and spleen after IV administration. However, some studies promote the use of IA for stem cell administration as the shortest route toward the lesion, with improving cell engraftment and survival (Na Kim et al, 2017 ). The current animal studies or clinical trials did not systematically assess or report adverse events associated with the delivery route chosen.…”

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“…The sporadic neurodegenerative disease multiple system atrophy affects the cells of the central and autonomic nervous system and currently suffers from a lack of effective therapeutic options. For this reason, researchers from the Phil Hyu Lee laboratory (Yonsei University, Seoul, South Korea) sought to assess the effectiveness of MSC‐based neuroprotective therapy in an animal disease model administered through an alternative route . Encouragingly, Kim et al demonstrated the feasibility of intra‐arterial administration of MSCs and an overall improvement in striatal and nigral neuronal viability and motor behavioral performance in affected mice.…”