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Removing Barriers to Regenerative Medicine and Promoting Innovative Applications: the Discovery of Human Endogenous Pluripotent Muse Cells

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Removing Barriers to Regenerative Medicine and Promoting Innovative Applications: the Discovery of Human Endogenous Pluripotent Muse Cells Technology and Innovation, Vol. 21, pp. 143-152, 2020 ISSN 1949-8241 • E-ISSN 1949-825X Printed in the USA. All rights reserved. http://dx.doi.org/10.21300/21.2.2020.143 Copyright © 2020 National Academy of Inventors. www.technologyandinnovation.org REMOVING BARRIERS TO REGENERATIVE MEDICINE AND PROMOTING INNOVATIVE APPLICATIONS: THE DISCOVERY OF HUMAN ENDOGENOUS PLURIPOTENT MUSE CELLS Mari Dezawa Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan Multilineage-differentiating stress-enduring (Muse) cells are naturally existing, non-tumorigenic reparative endogenous stem cells identified by SSEA-3 expression. Muse cells are able to differ- entiate into nearly all cell types in the body, mobilize from the bone marrow to the peripheral blood and distribute to the connective tissue of organs, and contribute to daily minute repair of damaged/lost cells by spontaneous differentiation into tissue-compatible cells. Endogenous Muse cells express receptors for damage signaling by sphingosine-1-phosphate and are thus able to specifically home to sites of damage to regenerate healthy tissue by simultaneous dif- ferentiation into multiple tissue-constituent cells. When the number of endogenous Muse cells is not sufficient, administration of exogenous Muse cells delivers robust functional recovery. Muse cells do not need to be “induced” or genetically manipulated to exhibit pluripotency or to differentiate into various cell types for clinical use. Intravenous drip is the main method of administration, making surgery unnecessary. Furthermore, because Muse cells have an immunomodulatory system similar to the placenta, donor-derived Muse cells can be directly administered to patients without human leukocyte antigen-matching or immunosuppression therapy. Clinical trials for the treatment of myocardial infarction, stroke, and epidermolysis bullosa by intravenous delivery of donor-derived Muse cells are currently being conducted by the Life Science Institute Inc., a member of the Mitsubishi Chemical Holdings Corporation. Overall, Muse cells may safely provide clinically relevant regenerative effects compatible with the ‘body’s natural repair systems’ by a simple, cost-effective strategy—collection of Muse cells, large-scale expansion, and intravenous administration. Key words: Muse cells; Repair; Intravenous injection; Sphingosine-1-phosphate; Differentia- tion; Immunomodulation INTRODUCTION stage-specific embryonic antigen-3 (SSEA-3) as well Multilineage-differentiating stress enduring as pluripotent master genes, including Oct3/4, Nanog, (Muse) cells are endogenous pluripotent reparative and Sox2, and are able to differentiate into cells of all stem cells considered to contribute to tissue homeo- three germ layers from a single cell and to self-renew stasis through daily minute tissue repair and to be (2). They are able to differentiate into mesodermal distinct from other known stem cells (Figure 1) (1). (cardiomyocytes, glomerular cells, osteocytes, adi- Muse cells express the pluripotent surface marker pocytes, and vascular endothelial cells), endodermal _____________________ Accepted: November 1, 2019. Address correspondence to Mari Dezawa, Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. [email protected] +81-22-717-8025 143 144 DEZ AWA (hepatocytes and cholangiocytes), and ectodermal (MSCs) and fibroblasts as several percent of the total (neural cells, melanocytes, and keratinocytes) cells in cells (1). While Muse cells exhibit pluripotent prop- vitro, either spontaneously or by cytokine induction erties similar to embryonic stem (ES) and induced (3-5). They also exhibit triploblastic-lineage differen- pluripotent stem (iPS) cells, they are non-tumori- tiation in vivo with unique characteristics. Without genic, consistent with the fact that they exist in vivo. prior cytokine induction, Muse cells home to the In fact, gene expression levels of factors relevant to damaged tissue and differentiate into the multiple cell cycle progression are similar between Muse cells cell types comprising the damaged tissue with a rapid and somatic cells, and Muse cell telomerase activity, time-course. For example, in a liver damage model, an indicator of tumorigenesis, is low compared with engrafted Muse cells spontaneously differentiate into that of iPS cells and tumorigenic HeLa cells. They hepatocytes, cholangiocytes, sinus endothelial cells, do not form teratomas for up to six months when and Kupffer cells, while in damaged glomeruli, they transplanted into the testis of immunodeficient mice differentiate into podocytes, mesangial cells, and cap- (2,9). On the other hand, their proliferation speed is illary endothelial cells (6,7). ~1.3 days/cell division, similar to or slightly slower than that of fibroblasts, and are thus expandable to Figure 1. Schematic diagram for Muse cell dynamics in the steady state. Muse cells mobilize from the bone marrow to clinical scale (2). the peripheral blood and are distributed to connective tissue Muse cells are characterized as endogenous repar- of organs, where they participate in tissue repair to maintain ative stem cells (Figure 1). Reparative effects of Muse tissue homeostasis. This figure was reproduced from Kushida, cells have been demonstrated following their intrave- Wakao, and Dezawa’s “Muse Cells Are Endogenous Reparative Stem Cells” in Advances in Experimental Medicine and Biology nous or local injection into animal models of acute with permission of Springer, copyright 2018. myocardial infarction, stroke, liver damage, chronic kidney disease, aortic aneurism, and skin ulcers of diabetes mellitus (6,7,10-15). In these models, Muse cells specifically home to the site of damage after administration, replenish the lost/damaged cells by spontaneous differentiation into new tissue-specific cells, and repair the damaged tissue. Clinical data of patients with acute myocardial infarction support this concept (16). Muse Cells Tolerate Extensive Genotoxic Stimuli and Quickly Repair DNA Muse cells have a robust, effective DNA damage checkpoint and DNA repair system for the complete recovery of cells to maintain their reparative func- Muse cells are identified as SSEA-3(+) in tis- tion. Compared with general somatic cells, Muse cells sues. In vivo, they are found in the bone marrow, are more resistant to chemical genotoxic stress, such peripheral blood, and connective tissue of organs as hydrogen peroxide, and physical genotoxic stress, (1). Importantly, they are also found in extra-em- such as UV irradiation (17). The levels of senescence bryonic tissue such as the umbilical cord, which is and apoptosis are lower in Muse cells than in somatic rich in connective tissue (8). The proportion of Muse cells under both types of genotoxic stress because, in cells to mononucleated cells in the bone marrow Muse cells, the DNA damage repair system is prop- is approximately 1:3000 (~0.03%). Muse cells are erly activated following injury, and the damage is also found in the peripheral blood at a proportion of quickly repaired within six hours. This is partly due to approximately 0.01%~0.2% of the mononuclear frac- the prompt increase in non-homologous end joining tion (1). Muse cells are also found in commercially (NHEJ) enzymatic activity in Muse cells. Activation available cultured mesenchymal stem/stromal cells of RAD51 and DNA-PK, which are involved in the MUSE CELLS AS ENDOGENOUS REPARATIVE STEM CELLS 145 homologous recombination and NHEJ repair sys- 2) Muse cells are stress-tolerant and able to sur- tems, respectively, occurs soon after DNA damage vive in the hostile microenvironment of damaged and declines to basal levels within six hours after the tissue. The immunomodulatory effect of Muse cells induction of stress in Muse cells, suggesting that Muse allows intravenously administered allograft cells to cells have a powerful NHEJ system that allows them escape from host immunologic attack, enabling them to survive strong genotoxic stress. to efficiently home to the site of damage and repair the damaged tissue. Therefore, donor-derived Muse Muse Cells Function as Reparative Stem Cells cells can be directly administered to patients with- A series of studies, in which exogenous Muse cells out human leukocyte antigen (HLA)-matching or were administered, unveiled many mechanisms immunosuppression therapy. Allogeneic Muse cells underlying the tissue repair effects of endogenous and remain in the host tissue as functional cells for over exogenous Muse cells. The innate reparative functions six months without immunosuppression. of Muse cells substantiate the feasibility of utilizing 3) After homing, Muse cells replenish new func- Muse cells for clinical applications. tional cells by spontaneous differentiation into tissue-compatible cells (Figure 3). Figure 2. Schematic diagram for Muse cell dynamics and their 4) Exogenously administered Muse cells sur- mechanism under critical situations such as acute myocar- dial infarction. Damaged tissue produces S1P. Following an vive and remain integrated in the host tissue for an increase in the serum S1P level, large numbers of Muse cells extended period as functional cells. Therefore, their are mobilized from the bone marrow to the peripheral blood. pleiotropic effects, including anti-fibrotic, anti-in- Circulating Muse cells accumulate in the damaged tissue via flammatory, anti-apoptotic, and paracrine effects, the S1P-S1PR2
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