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

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.

Adipose Tissue: Understanding the Heterogeneity of Stem Cells for Regenerative Medicine

“…In addition, Muse cells are inherently pluripotent-like and are capable of cell homing damaged tissue following intravenous injection. Due to these unique properties, Muse cells have been explored as a potential therapy to treat acute myocardial infarction, stroke, chronic kidney disease, liver diseases, and neurologic diseases [81,82].…”

Application prospects of multilineage differentiating stress-enduring (Muse) cells in the treatment of skin diseases

“…13 If the number is insufficient for repair, or if the endogenous Muse cells have low reparative activity due to underlying diseases, exogenous Muse cells can be supplied via intravenous infusion. 29 This is the basic concept of Muse cell therapy. 23…”

Intravenously engrafted human multilineage‐differentiating stress‐enduring (Muse) cells rescue erectile function after rat cavernous nerve injury

“…Multilineage-differentiating stress-enduring (Muse) cells are endogenous, reparative, pluripotent stem cells positive for pluripotent surface marker stage-specific embryonic antigen (SSEA)-3, and they are distributed in the BM, peripheral blood, and organ connective tissues [11,12]. Muse cells are able to self-renew and differentiate into cells representative of all three germ layers from a single cell and are stress tolerant [11].…”

“…Additionally, because Muse cells are able to selectively home to damage sites by sensing one of the general tissue damage signals, sphingosine-1-phosphate (S1P), via S1P receptor 2 rather than being trapped in the lung capillary, intravenous drip is the main route for treatment; surgery is not required to deliver cells to the target tissue [13]. After homing to the damaged tissue, Muse cells replenish damaged/lost cells by spontaneous differentiation into the cell types that comprise the tissue and remain in the tissue as differentiated cells for an extended period of time; thus, they do not require gene introduction or cytokine treatment to be rendered pluripotent and to induce differentiation [12][13][14][15][16]. Most importantly, human leucocyte antigen (HLA)-matching, and long-term immunosuppressant treatment are unnecessary for the use of donor-derived Muse cells due to a specific immune privilege system, which is partly explained by the expression of HLA-G, relevant to immune tolerance in the placenta [13].…”