Cardiotrophic Growth Factor–Driven Induction of Human Muse Cells Into Cardiomyocyte-Like Phenotype

Amin, Mohamed N.; Kushida, Yoshihiro; Wakao, Shohei; Kitada, Masaaki; Tatsumi, Kazuki; Dezawa, Mari

doi:10.1177/0963689717721514

Cited by 24 publications

(35 citation statements)

References 66 publications

(72 reference statements)

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“…Muse cells are stress-tolerant, have high activity to repair damaged DNA, exhibit low telomerase activity, and do not form teratomas when transplanted in vivo 3 – 7 . They are identified as cells positive for stage-specific embryonic antigen (SSEA)-3, a pluripotent surface marker, in the PB, BM, and organ connective tissues 4 , 8 – 10 .…”

Section: Introductionmentioning

confidence: 99%

A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood

et al. 2020

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Peripheral blood (PB) contains several types of stem/progenitor cells, including hematopoietic stem and endothelial progenitor cells. We identified a population positive for both the pluripotent surface marker SSEA-3 and leukocyte common antigen CD45 that comprises 0.04% ± 0.003% of the mononuclear cells in human PB. The average size of the SSEA-3(+)/CD45(+) cells was 10.1 ± 0.3 µm and ∼22% were positive for CD105, a mesenchymal marker; ∼85% were positive for CD19, a B cell marker; and ∼94% were positive for HLA-DR, a major histocompatibility complex class II molecule relevant to antigen presentation. These SSEA-3(+)/CD45(+) cells expressed the pluripotency markers Nanog, Oct3/4, and Sox2, as well as sphingosine-1-phosphate (S1P) receptor 2, and migrated toward S1P, although their adherence and proliferative activities in vitro were low. They expressed NeuN at 7 d, Pax7 and desmin at 7 d, and alpha-fetoprotein and cytokeratin-19 at 3 d when supplied to mouse damaged tissues of the brain, skeletal muscle and liver, respectively, suggesting the ability to spontaneously differentiate into triploblastic lineages compatible to the tissue microenvironment. Multilineage-differentiating stress enduring (Muse) cells, identified as SSEA-3(+) in tissues such as the bone marrow and organ connective tissues, express pluripotency markers, migrate to sites of damage via the S1P-S1P receptor 2 system, and differentiate spontaneously into tissue-compatible cells after homing to the damaged tissue where they participate in tissue repair. After the onset of acute myocardial infarction and stroke, patients are reported to have an increase in the number of SSEA-3(+) cells in the PB. The SSEA-3(+)/CD45(+) cells in the PB showed similarity to tissue-Muse cells, although with difference in surface marker expression and cellular properties. Thus, these findings suggest that human PB contains a subset of cells that are distinct from known stem/progenitor cells, and that CD45(+)-mononuclear cells in the PB comprise a novel subpopulation of cells that express pluripotency markers.

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Section: Introductionmentioning

confidence: 99%

A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood

et al. 2020

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“…Although HUC-derived SSEA3þ and CD105þ cells form neural spheres (ectodermal), we did not observe induction into endodermal or mesodermal cells. However, past studies have shown that HUC-derived SSEA3þ and CD105þ cells can differentiate into the three lineages [63][64][65][66][67] .…”

Section: Discussionmentioning

confidence: 97%

Quantitative Analysis of SSEA3+ Cells from Human Umbilical Cord after Magnetic Sorting

Leng

Sun

Huang³

et al. 2019

Cell Transplant

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Multilineage-differentiating stress-enduring (Muse) cells are a population of pluripotent stage-specific embryonic antigen 3 (SSEA3)+ mesenchymal stem cells first described by Mari Dezawa in 2010. Although some investigators have reported SSEA3+ mesenchymal cells in umbilical cord tissues, none have quantitatively compared SSEA3+ cells isolated from Wharton’s jelly (WJ) and the cord lining (CL) of human umbilical cords (HUCs). We separated WJ and the CL from HUCs, cultured mesenchymal stromal cells (MSCs) isolated from these two tissues with collagenase, and quantified the percentage of SSEA3+ cells over three passages. The first passage had 5.0% ± 4.3% and 5.3% ± 5.1% SSEA3+ cells from WJ and the CL, respectively, but the percentage of SSEA3+ cells decreased significantly ( P < 0.05) between P0 and P2 in the CL group and between P0 and P1 in the WJ group. Magnetic-activated cell sorting (MACS) markedly enriched SSEA3+ cells to 91.4% ± 3.2%. Upon culture of the sorted population, we found that the SSEA3+ percentage ranged from 62.5% to 76.0% in P2–P5 and then declined to 42.0%–54.7% between P6 and P9. At P10, the cultures contained 37.4% SSEA3+ cells. After P10, we resorted the cells and achieved 89.4% SSEA3+ cells in culture. The procedure for MACS-based enrichment of SSEA3+ cells, followed by expansion in culture and a re-enrichment step, allows the isolation of many millions of SSEA3+ cells in relatively pure culture. When cultured, the sorted SSEA3+ cells differentiated into embryoid spheres and survived 4 weeks after transplant into a contused Sprague-Dawley rat spinal cord. The transplanted SSEA3+ cells migrated into the injury area from four injection points around the contusion site and did not produce any tumors. The umbilical cord is an excellent source of fetal Muse cells, and our method allows the practical and efficient isolation and expansion of relatively pure populations of SSEA3+ Muse cells that can be matched by human leukocyte antigen for transplantation in human trials.

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“…Such triploblastic differentiation from a single cell can be reproduced over generations, indicating self-renewability. In addition to their spontaneous differentiation, Muse cells also differentiate in vitro at a high rate (~80–95%) into various target cell types, such as hepatic-, cardiac- and neural-lineage cells, as well as into adipocytes, osteocytes, keratinocytes, and melanocytes, when certain sets of cytokines are supplied in a step-wise manner [ 22 , 23 , 24 ]. Because of these two core characteristics, triploblastic differentiation and self-renewability at a single cell level, Muse cells are considered pluripotent stem cells.…”

Section: Basic Characteristics Of Muse Cellsmentioning

confidence: 99%

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

Yamashita

Kushida

Abe

et al. 2021

Cells

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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.

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Cardiotrophic Growth Factor–Driven Induction of Human Muse Cells Into Cardiomyocyte-Like Phenotype

Cited by 24 publications

References 66 publications

A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood

A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood

Quantitative Analysis of SSEA3+ Cells from Human Umbilical Cord after Magnetic Sorting

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

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