Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis

Toru Yamashita,Mari Dezawa,Yoshio Omote,Shohei Wakao,Yoshihiro Kushida,Emi Nomura,Koji Abe,Mami Takemoto,Koh Tadokoro,Nozomi Hishikawa,Yasuyuki Ohta

doi:10.1038/s41598-020-74216-4

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 104 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss
The present study is the first report to demonstrate that multiple IV administration of Multilineage-differentiating stress-enduring (Muse) cells improved clinical scores in the rotarod, hanging-wire and muscle strength of lower limbs in the ALS model G93A Tg mice
IV-injected Muse cells homed to the lumbar spinal cord, lung and bone (Fig. 2a,b)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 104 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. Such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent-like stem cells collectable as cells positive for the pluripotent stem cell surface marker, stage-specific embryonic antigen (SSEA)-3 They are normally located in the bone marrow, peripheral blood, and connective tissues of organs and are non-tumorigenic[10,11,12,13]. Muse cells are unique for several reasons: they recognize damaged tissue and selectively accumulate at the site of damage by intravenous injection because they express sphingosine-1-phosphate (S1P)

Methods

Results

Conclusion