Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases

Toru Yamashita, Yoshihiro Kushida, Koji Abe, Mari Dezawa, Toru Yamashita, Yoshihiro Kushida, Koji Abe, Mari Dezawa

Abstract

Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.

Keywords: ALS; MSCs; SSEA-3; encephalitis; ischemia; pluripotent; sphingosine-1-phosphate; stroke.

Conflict of interest statement

Y.K. and M.D. are parties to a co-development and co-research agreement with Life Science Institute, Inc. (LSII: Tokyo, Japan). M.D. has a patent for Muse cells, and the Muse cell isolation method is licensed to LSII. T.Y., Y.K., K.A., and M.D. received a joint research grant from LSII.

Figures

Figure 1
Figure 1
Distribution of Muse cells in the body. Muse cells, detected as SSEA-3(+), distribute in the bone marrow (green signal) [7], peripheral blood (green signal) [4], and connective tissue of various organs, such as the trachea, liver, spleen, pancreas, and skin (brown signal) [8].
Figure 2
Figure 2
Daily reparative activity of endogenous Muse cells. Muse cells in the bone marrow are considered to be constantly mobilized to the peripheral blood and supplied to every organ, where they replace minutely damaged/apoptotic cells by spontaneous differentiation.
Figure 3
Figure 3
Production of sphingosine-1-phosphate by damaged cells. (1) Sphingosine, located in the outer leaflet of the cell membrane, is the substrate of sphingosine-1-phosphate (S1P). (2) When the cell membrane is damaged, (3) sphingosine reacts with enzymes (Enz1, Enz2) and is phosphorylated to become S1P. Released S1P binds to S1P receptor 2, a G-protein coupled receptor, on Muse cells to attract them to the site of damage. This figure was reproduced with permission from Advances in Experimental Medicine and Biology (Springer, copyright 2018 [2]).
Figure 4
Figure 4
Strategy of Muse cell therapy. For example, in acute myocardial infarction, S1P as an alert signal is produced by the infarcted area and delivered to the bone marrow, where endogenous Muse cells are mobilized to the peripheral blood to increase the number of circulating Muse cells. The circulating Muse cells migrate to the infarcted area via the S1P–S1PR2 axis and replace damaged cells by spontaneous differentiation into tissue-appropriate cells to repair the cardiac tissue. When the number of endogenous Muse cells is insufficient, intravenous administration of exogenous Muse cells enhances the reparative activity, leading to successful tissue repair. This figure was reproduced with permission from Advances in Experimental Medicine and Biology (Springer, copyright 2018 [2]).
Figure 5
Figure 5
Strategy for Muse cell clinical trials consists of 3 simple steps. Muse cells, collectable from donor sources such as the bone marrow, adipose tissue, and skin, are expanded to produce Muse cell preparations and directly delivered to patients with acute myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, cerebral palsy, and ALS by intravenous drip without HLA-matching and immunosuppressant treatment.
Figure 6
Figure 6
In vivo dynamics of intravenously injected exogenous Muse cells in animal models. Nano-lantern-labeled human Muse cells were intravenously injected into a rabbit model of acute myocardial infarction (3 days after), a mouse model of lacunar infarction (1 day after), and a mouse model of epidermolysis bullosa (1 week after). Muse cells selectively accumulated in the damaged tissue in all models.
Figure 7
Figure 7
Spontaneous differentiation of homed Muse cells in each damaged tissue. Muse cells after homing to the damaged tissue spontaneously differentiate into tissue-comprising cells.
Figure 8
Figure 8
Effectiveness of human Muse cells in a mouse ALS model. (A) Free radicals and mechanism of action of a free radical scavenger, edaravone. Free radicals, such as hydroxyl radicals (•OH), are produced under pathologic conditions. Hydroxyl radicals are extremely reactive among reactive oxygen species and oxidize biologic components, such as proteins, lipids, sugars, and nucleic acids, causing neuronal cell death. On the other hand, edaravone is thought to mainly detoxify hydroxyl radicals by donating electrons. (B) Schema of intravenous administration therapy with Muse cells for ALS mice. Muse cells administered by tail vein injection migrated to the lumbar spinal cord and survived for a long period of time. (C) In vivo dynamics of Nano-lantern-labeled MSCs and Muse cells. Only Muse cells and not MSCs homed to the cervical (C) and lumbar (L) spinal cord. Both MSCs and Muse cells were detected in the lung and the femur. (D) Clinical analysis of ALS mice treated with vehicle, MSC, and Muse cells (modified from Yamashita et al., 2020 [36]). Mice receiving Muse cells showed significant improvement in the rotarod test, hanging-wire test, and lower limb muscle strength (* p < 0.05 vs. vehicle). The figure is reproduced from Yamashita et al., Sci Rep, 2020 [36].
Figure 9
Figure 9
Strategy of Muse cell treatment in stroke. Muse cells selectively home to the post-infarct area in the brain after intravenous injection and spontaneously differentiate into neuronal and glial cells. Differentiated neuronal cells extend neurites that are incorporated into the pyramidal tract, including pyramidal decussation.

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