Muse cell

A Muse cell (Multi-lineage differentiating stress enduring cell) is an endogenous non-cancerous pluripotent stem cell.[1][2] They reside in the connective tissue of nearly every organ, bone marrow and peripheral blood.[1][3][4][5] They are collectable from commercially obtainable mesenchymal cells such as human fibroblasts, bone marrow-mesenchymal stem cells and adipose-derived stem cells.[6][7][8] Muse cells are able to generate cells representative of all three germ layers from a single cell both spontaneously and under cytokine induction. Expression of pluripotency genes and triploblastic differentiation are self-renewable over generations. Muse cells do not undergo teratoma formation when transplanted into a host environment in vivo. This can be explained in part by their intrinsically low telomerase activity, eradicating the risk of tumorigenesis through unbridled cell proliferation. They were discovered in 2010 by Mari Dezawa and her research group.[1] Clinical trials for acute myocardial infarction, stroke, epidermolysis bullosa and spinal cord injury are conducted by Life Science Institute, Inc., a group company of Mitsubishi Chemical Holdings company.[9]

Characteristics
  • Stress-tolerant.[10]
  • Do not show tumorigenicity.[11] Resistant to genotoxic stresses due to efficient sensing of DNA damage and activation of DNA repair systems.[12]
  • Can be isolated as cells positive for SSEA-3, a well known human embryonic stem cell marker. Needless to inform that the positive SSEA-3 cells or Muse cells are fresh for maximum one day after sorting and if you sort the same cells after 5 days for instance, you only collect about the same percentage of Muse or positive signal you got before first sorting .[1][3][4][5]
  • Pluripotent stem cells, which can generate various kinds of the cells representative of all three germ layers have the ability to self-renew.[1]
  • Non-tumorigenic. Low telomerase activity.[1][7][13]
  • Accumulate into damaged tissue by intravenous or local injections.[14][15][16]
  • Replenish new functional cells through spontaneous differentiation into tissue-compatible cells.[1][14][15][16]
  • Repair tissue by systemic administration.
  • Comprise ~0.03% of bone marrow transplantation and several % of mesenchymal stem cell transplantation.[1]
  • Have immunosuppressive and immunomodulatory effect.[13]
  • Pluripotent stem cells can be directly obtained from normal human mesenchymal tissues without using artificial manipulations such as gene introduction.

Markers

Muse cells are identified as cells positive for SSEA-3+,[17] a well-known marker for undifferentiated human ES cells.[18] They are also positive for general mesenchymal stem cell markers such as CD105, CD90 and CD29.[1] Therefore, Muse cells are double positive for pluripotent and mesenchymal stem cell markers. Cell isolation by SSEA-3 cell sorting can be done using SSEA-3 antibody. Their size is 13~15 μm in diameter. Muse cells do not express CD34 (markers for hematopoietic stem cells, adipose stem cells, VSELs) and CD117 (hematopoietic stem cells markers), Snai1 and Slug (skin-derived precursors markers), CD271 and Sox10 (neural crest-derived stem cells markers), NG2 and CD146 (perivascular cells) or CD31 and von Willebrand factor (endothelial progenitor markers). This indicates that Muse cells do not belong to previously investigated stem cell types.[1][19]

Differentiation capacity

In vitro

Muse cells can differentiate into:

  1. Ectodermal- (cells positive for nestin, NeuroD, Musashi, neurofilament, MAP-2,[3] melanocyte markers (tyrosinase, MITF, gf100, TRP-1, DCT)[20]),
  2. Mesodermal- (brachyury, Nkx2-5, smooth muscle actin,[1] osteocalcin, oil red-(+) lipid droplets,[3] desmin[1])
  3. Endodermal- (GATA-6, α-fetoprotein, cytokeratin-7,[1] albumin[3]) lineages both spontaneously and under cytokine induction.[1]

Recently, Tsuchiyama et al. showed that human dermal fibroblast-derived Muse cells were efficiently differentiated into melanin-producing functional melanocytes by a cocktail of cytokines.[20] These cells maintained their melanin producing activity even after transplantation into the skin.

In vivo

Muse cells are shown to home into the damage site and spontaneously differentiate into tissue-compatible cells according to the microenvironment to contribute to tissue regeneration when infused into the blood stream.[1] This was shown in human Muse cells infused into animal models with fulminant hepatitis,[1] partial hepatectomy,[14] muscle degeneration,[1] skin injury,[16][1][21] stroke[15] and spinal cord injury.[22]

Non-tumorigenicity

Low telomerase activity

Muse cells are characterized by low telomerase activity, not a strong indicator of tumorigenicity. Hela cells and human fibroblast-derived iPS cells showed high telomerase activity while Muse was at nearly the same level as that in somatic cells such as fibroblasts (these data are shown without running control for the telomerase activity, the comparison is not scientific thought). This indicates the non-tumorigenic nature of Muse cells.[1][7][13]

The expression 'pattern' of genes related to pluripotency in Muse cells was almost the same as that in ES and iPS cells, while the expression 'level' was much higher in ES and iPS cells and that in Muse cells.[3] In contrast, genes related to cell cycle progression and tumorigenicity in Muse cells were at the same level as those in somatic cells, while the same genes were very high in ES and iPS cells. These gene expression pattern and level may explain why Muse cells are pluripotent but without tumorigenic activity.[23]

Transplantation into mouse testes

Unlike ES and iPS cells, transplanted Muse cells in testes of immunodeficient mice -a commonly used experiment to test the tumorigenicity of stem cells- have not been reported to form teratomas, even after six months.[1] Thus, Muse cells are pluripotent but are non-tumorigenic.[17] Similarly, epiblast stem cells cultured under certain conditions also do not form teratomas in testes, even though they show pluripotency in vitro.[24] Thus, pluripotent stem cells do not always show teratoma formation when transplanted in vivo.

Tissue repair

Muse cells act as tissue repairing cells in vivo. When systemically administrated, naive Muse cells (without cytokine treatment or gene introduction) migrate to damaged site, home into the site and spontaneously differentiate into tissue-compatible cells to replenish new functional cells. This phenomenon was observed by the infusion of green fluorescent protein-labeled naive human Muse cells into animal models with fulminant hepatitis,[1] partial hepatectomy,[14] muscle degeneration,[1] skin injury,[16][1][21] stroke[15] and spinal cord injury.[22] Infused Muse cells integrated into each damaged tissue and differentiated into human albumin- and human anti-trypsin-expressing hepatocytes in the liver,[1] human dystrophin-expressing cells in the muscle,[1] neurofilament and MAP-2-expressing neuronal cells in the spinal cord[22] and stroke,[15] and cytokerain14-expressing epidermal cells in the skin,[16][1][21] respectively.

Muse cells have great advantages for regenerative medicine. Without need of cytokine induction or artificial gene manipulation, Muse cells are capable of repairing tissues when directly infused into the blood stream. Hence, the clinical applications of Muse cells appear promising.[6] Precise conditions such as the number and source of Muse cells for each organ regeneration requires further investigation.

Currently, Life Science Institute, Inc. and its parent company, Mitsubishi Chemical Holdings, have established a cell-processing procedure that is compliant with the Japanese Good Manufacturing Practice (GMP) and Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (GCTP) regulation. The Muse cell preparation is currently being tested in nonclinical toxicity studies.[9]

Basic characteristics

Pluripotency, namely pluripotent marker expression, triploblastic differentiation and self-renewability, are recognized in Muse cells directly collected from BM aspirates, indicating that their characteristics are not newly acquired by in vitro manipulation nor are they modified under culture conditions.[1]

Location in vivo

Muse cells are not generated by stress, cytokine induction or exogenous gene transfection. They are preexisting pluripotent stem cells that normally reside in mesenchymal tissues such as the bone marrow,[1] dermis[3] and adipose tissue.[8] In the bone marrow, they represent one out of 3000 mono-nucleated cells. Other than mesenchymal tissues, Muse cells locate in connective tissue of every organ and in the peripheral blood.[1][3][4][5]

Duality

Muse cells behave as mesenchymal cells in adherent environments such as in connective tissue and adherent culture, and switch to pluripotent behavior when they are transferred to a suspension environment such as in the blood stream and suspension culture[25][26]

Formation of clusters similar to embryoid body of ES cells in suspension

In cell suspension, Muse cells begin to proliferate and to form clusters that are very similar to embryoid bodies formed from ES cells in suspension. Muse cell clusters are positive for pluripotency indicators such as alkaline phosphatase reactivities, Nanog, Oct3/4, Sox2 and PAR4. One of remarkable properties of Muse cells is that they are capable of forming clusters from a single cell in suspension. A single Muse cell-derived cluster is shown to spontaneously generate cells representative of all three germ layers on a gelatin-coated dish, proving the pluripotency of Muse cells. It is important to mention that non-Muse population also generates cluster in same condition, but in lower percentage (50 Muse vs 10 non-Muse) [1][7][8]

Proliferation speed

Muse cells proliferate at a speed of ~1.3 day/cell division in adherent culture. This is slightly slower than that of human fibroblasts (~1 day/cell division).[22]

Self-renewal

Muse cells are able to self-renew, maintaining their proliferative activity, pluripotency marker expression and a normal karyotype.[22]

Sources

Muse cells can be collected from bone marrow aspirate, whose collection is a well known procedure done daily in clinics. They can also be isolated from skin fibroblasts obtained via skin biopsy or from adipose tissue obtained by liposuction; a safe and non-invasive procedure often used for cosmetic surgery interventions[8] Easy accessibility

of Muse cells allows them to be auto- or allo-transplanted in regenerative clinical applications. Muse cells are also isolated from commercially available mesenchymal cell cultures, which ensure their availability and accessibility.

  • General Sources. Muse cells can be obtained from:
    • Bone marrow aspirate
    • Adipose tissue and liposuction
    • Dermis
    • Commercially available culture cells such as:
      • Bone marrow-derived mesenchymal stem cells
      • Fibroblasts
      • Adipose-derived stem cells
  • Bone marrow: Bone marrow mononucleated cells contain ~0.03% of SSEA-3/CD105 double positive Muse cells.[1] This ratio corresponds to one out of 3000 mono-nucleated cells.
  • Dermis: Muse cells, detected as SSEA-3-positive cells, are located sparsely in the connective tissues of organs. In the human dermis, Muse cells are located in the connective tissues distributed in the dermis and hypodermis. Their location is not related to particular structures such as blood vessels or dermal papilla.[3]
  • Adipose tissue: Recently, Muse cells have been successfully isolated from adipose tissue and liposuction material. The characteristics of adipose tissue-derived Muse cells were consistent with those of Muse cells isolated from bone marrow aspirate and commercially available fibroblasts. Chazenbalk et al. showed that Muse cells spontaneously differentiated into cells representative of all three germ layers.[7][8]
  • Bone marrow mesenchymal stem cells contain about 1% SSEA-3 positive Muse cells.
  • Human dermal fibroblasts contain around 1 to 5% SSEA-3 positive Muse cells.
  • Adipose-derived stem cells (Lonza Co.) has around 1 to 7% SSEA-3 positive Muse cells.
  • The overall percentage of Muse cells depends on the source of mesenchymal tissue as well as manipulation and number of mesenchymal cells utilized for isolation by cell culture technique.
  • Muse cells in different species: Most of Muse cell research has been done in human samples. Recently, they have been isolated from goat skin fibroblasts. Goat SSEA3+ M-clusters showed stem cell-like morphological characters and normal karyotypes. Also, they were consistently positive for pluripotency markers and alkaline phosphatase staining. Goat Muse cells showed triploblastic differentiation capability both in vivo and in vitro and remained undifferentiated over eight passages in suspension culture.[27]

Collection methods

Muse cells can be collected by several techniques:

  • Cell sorting: By using SSEA-3 single- or SSEA-3/CD105 double-positivity, Muse cells can be isolated from tissues and commercially obtained cultured cells. When Muse cells are to be collected directly from tissue, cells are labeled with both SSEA-3 and CD105. However, in the case of cultured mesenchymal cells, almost all cells in MSCs are positive for mesenchymal markers such as CD105 and CD90. Single labeling with SSEA-3 is sufficient to collect Muse cells. The procedure includes the following steps:
  1. Preparation of mesenchymal cells from either dermal fibroblasts or fresh bone marrow-derived mononuclear cells.
  2. Isolation of Muse cells by FACS as cells positive for SSEA-3.
  3. M-cluster formation in suspension culture using single-cell suspension culture. The surface of the bottom of each culture dish or well must be coated with poly-HEMA to avoid adhesion of the cells.
  • Long-term trypsin (LTT) treatment: For large-scale usage of Muse cells -for transplantation experiments for example- they could be enriched in naive cells by severe cellular stress conditions. The resulting population is called a Muse-Enriched Cell (MEC) population. The best conditions for Muse enrichment have been described as long trypsin incubation for 16 hours in skin fibroblasts and long trypsin incubation for 8 hours in bone marrow mesenchymal stem cells. However, the practical procedure for transplantation or differentiation purposes is the isolation of Muse cells from a bulk culture of skin fibroblasts or bone marrow MSCs as cells positive for SSEA-3.[1]
  • Severe cellular stress treatment (SCST): Muse cells can be isolated from lipoaspired fat by subjection to severe stress conditions that eliminate all other cell types except for Muse cells, which survive as a feature of their capacity for stress endurance. The resulting cell population contains a high number of Muse cells and therefore there is no need for cell sorting. The stress conditions included; long incubation with collagenase, low temperature, serum deprivation, and severe hypoxia for 16 hours. Finally, the digested material is centrifuged and the pellet is re-suspended in PBS and incubated with a red blood cell lysis buffer. Muse cells isolated by this method have been found to be distinct population from adipose stem cells.[8]

Basic difference from other mesenchymal stem cells

There are major differences between Muse cells and non-Muse cells in present within mesenchymal cell population. When mesenchymal cells (sometimes called mesenchymal stem cells) are separated into Muse and non-Muse cells by SSEA-3 cell sorting, the following differences are observed:

  1. Muse cells, SSEA-3(+) form clusters (which are similar to embryoid bodies of ES cells) from a single cell in suspension, while non-Muse cells, SSEA-3(-) do not proliferate successfully in suspension and thus do not form these distinctive clusters.
  2. Basic expression level of pluripotency genes in non-Muse cells is very low or undetectable level compared to Muse cells.[3]
  3. Non-Muse cells do not exhibit tissue reparation when infused into the blood stream. While they do not integrate into the damaged tissue, they may indirectly contribute to tissue regeneration by their production of cytokines, trophic factors and anti-inflammatory factors.

Muse cells as a primary source of iPS cells

In 2009, a study showed that only SSEA-3+ cells generate induced pluripotent stem (iPS) cells in human fibroblasts.[28] In 2011, it was suggested that iPS cells are generated only from Muse cells. When the technique for generation of iPS cells was applied to both Muse and non-Muse cells, iPS cells were successfully generated only from Muse cells. In contrast, non-Muse cells did not show elevation in Sox2 and Nanog, master genes of pluripotent stem cells, even after receiving the four Yamanaka factors. These results support the elite model of iPS cell generation rather than the stochastic model. Divergent from their Muse cell origin, iPS cells showed tumorigenecity. Since Muse cells are originally pluripotent without tumorigenic activity, what the Yamanaka factors newly conferred to Muse cells was not 'pluripotency' but tumorigenic activity. These results collectively suggest that only preexisting cells with promising pluripotency can be programmed into iPS cells.[19][3]

Derived melanocytes

Human dermal fibroblast-derived Muse cells are shown to be a practical source for melanocyte induction. A cytokine induction system consisting of Wnt3a, SCF, ET-3, bFGF, linoleic acid, cholera toxin, L-ascorbic acid, 12-O-tetradecanoylphorbol 13-acetate, insulin, transferrin, selenium, and dexamethasone was applied to both human dermal fibroblast-derived Muse and non-Muse cells. Only Muse cells differentiated into L-DOPA reactive functional melanocytes. A three-dimensional culture model was used to assess Muse cell-derived melanocytes. In that model, the dermis was mimicked by collagen type 1 and normal human dermal fibroblasts, while epidermis was mimicked by keratinocytes and Muse cell-derived melanocytes. Furthermore, Muse cell-derived melanocytes showed melanin production. Moreover, when Muse cell-derived melanocytes was transplanted onto the back skin of severe combined immunodeficient mice, they integrated to the basal layer of the epidermis producing melanin in vivo.[20]

Differentiation ability of Muse cells in vitro

Muse cells from different sources are capable of in vitro differentiation into various cell types.

Melanocytes:

Human dermal fibroblast-derived Muse cells are a practical source for melanocyte induction. Application of a cytokine induction system comprising Wnt3a, SCF, ET-3, basic fibroblast growth factor, linoleic acid, cholera toxin, L-ascorbic acid, 12-O-tetradecanoylphorbol 13-acetate, insulin, transferrin, selenium, and dexamethasone to both human dermal fibroblast-derived Muse and non-Muse cells induces only the Muse cells into L-DOPA–reactive functional melanocytes capable of melanin production in a 3D cultured skin model.[29] The application of a set of cytokines also differentiates dermal-Muse cells into melanocytes.[30]

Keratinocytes

Human adipose tissue-derived Muse cells differentiate into keratinocytes by spontaneous differentiation on a gelatin culture dish[31] or by cytokine induction containing bone morphogenetic protein-4 and all trans retinoic acid.[32][33]

Neuronal Cells:

Human bone marrow- and fibroblast-derived Muse cells spontaneously differentiate into neural lineage cells with a lower proportion on a gelatin culture.[17] Cells expanded from single Muse cell-derived clusters on gelatin-coated culture dishes express the neural markers nestin (1.9%), MAP-2 (3.8%), GFAP (3.4%), and O4 (2.9%), suggesting the ability of Muse cells to differentiate into neural-lineage cells.[15] The cells positive for MAP-2 or GFAP were increased following induction with basic fibroblast growth factor, forskolin, and ciliary neurotrophic factor.[25]

Liver Cells:

Muse cells can spontaneously differentiate in vitro into hepatocyte lineage cells positive for DLK, alpha-fetoprotein, cytokeratin 19, and cytokeratin 18 on gelatin-coated culture dishes.[26] In the presence of insulin-transferrin-selenium, dexamethasone, hepatocyte growth factor, and fibroblast growth factor-4, Muse cells differentiate into alpha-fetoprotein(+), albumin(+) cells.[34]

Glomerular cells:

Muse cells differentiate in vitro into renal lineage-cells with increased expression of developmental renal markers WT1 and EYA1 compared with non-Muse cells after 3 weeks following the application of a cytokine induction cocktail containing all trans retinoic acid, activin A, and bone morphologic protein-7.[35]

Cardiac cells:

Treatment of Muse cells with 5’ -azacytidine in suspension culture; then transferring the cells onto adherent culture and treatment with early cardiac differentiation factors wingless-int (Wnt)-3a, bone morphogenetic proteins (BMP)-2/4, and transforming growth factor (TGF) b 1; further treatment with late cardiac differentiation cytokines including cardiotrophin-1 converted Muse cells into cardiomyocyte-like cells that expressed a -actinin and troponin-I with a striation-like pattern.[36]

Adipocytes & Osteocytes:

Expanded cells from Muse clusters differentiate into adipocytes by the application of 1-methyl-3-isobutylxanthine, dexamethasone, insulin, and indomethacin. These induced adipocytes contain lipid droplets and stain positive for oil red O. In addition, Muse cluster expanded cells differentiate into osteoblasts positive for osteocalcin using dexamethasone, ascorbic acid, and β-glycerophosphate.[25]

In vivo reparative effect of Muse cells

Muse cells from different sources demonstrate reparative effects in animal disease models.

Acute myocardial infarction model

Rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells were intravenously administrated in a rabbit acute myocardial infarction model. In vivo dynamics of Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with ≈14.5% of injected Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells were shown to be mediated through the S1P (sphingosine monophosphate)-S1PR2 axis. After homing, Muse cells spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin-43, and vascular markers, and GCaMP3-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole, suggesting their functionality as working cardiomyocytes. Infarct size was reduced by ≈52%, and the ejection fraction was increased by ≈38% compared with vehicle injection at 2 months, ≈2.5 and ≈2.1 times higher, respectively, than that induced by mesenchymal stem cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression.[37]

Stroke and intracerebral hemorrhage models:

The neural regeneration capability of Muse cells has been demonstrated in several models. In a rat stroke model induced by ischemic-reperfusion of middle cerebral artery occlusion (MCAO), 3 x 104 human dermal-Muse cells topically injected into three sites in the infarct area (each site received 1 x 104 Muse cells) delivered statistically significant functional recovery compared to vehicle and non-Muse fibroblast cell-injected groups after ~2.5 months. The functional recovery was supported by the incorporation of human Muse cells into rat pyramidal and sensory tracts with normalized hind limb somatosensory evoked potentials.[15] Similarly, topically injected human bone marrow-Muse cells integrate into infarct region and replenish new neuronal cells and oligodendrocytes in mouse permanent MCAO and mouse lacunar stroke models.[38] In the mouse lacunar stroke model, human Muse cells-derived neuronal cells integrated into the pyramidal tract, leading to statistically meaningful functional recovery.[38] In a mouse intracerebral hemorrhage model, topically injected human bone marrow-Muse cells spontaneously differentiate into neuronal cells. Mice recovered motor function and spatial learning and memory ability.[39]

Liver cirrhosis and partial hepatectomy models:

Intravenously injected human bone marrow-derived Muse cells are able to repair an immunodeficient mouse (SCID) model of CCL4-induced liver cirrhosis. Human Muse cells spontaneously differentiate in vivo into hepatocytes without fusing with host hepatocytes, and express mature functional markers such as human CYP1A2 (detoxification enzyme) and human Glc-6-Pase (enzyme for glucose metabolism) at 8 weeks after homing.[26] Human bone marrow-derived Muse cells injected intravenously into a partial hepatectomy model in SCID mice differentiate spontaneously into major liver components, namely hepatocytes (74.3% of green fluorescent protein-positive integrated Muse cells), cholangiocytes (17.7%), sinusoidal endothelial cells (2.0%), and Kupffer cells (6.0%) after migrating and homing into the injured liver.[34] Non-Muse bone marrow MSCs are not detected in the liver from the early stage (~ 1 week) to the end-point in either model.[26][34]

Chronic kidney disease model:

Human bone marrow-derived Muse cells injected intravenously repair SCID and BALB/c mouse models of focal segmental glomerulosclerosis without added immunosuppression. Injected human Muse cells preferentially integrate into the damaged glomeruli and spontaneously differentiate into cells expressing markers of podocytes (podocin; ~31%), mesangial cells (megsin; ~13%), and endothelial cells (CD31; ~41%) without fusing with host glomerular cells; attenuate glomerular sclerosis and interstitial fibrosis; and induce the recovery of renal function, including creatinine clearance.[35]

Skin ulcers in diabetes mellitus:

Human adipose tissue-derived Muse-rich cells significantly accelerate wound healing in skin ulcers of a mouse type 1 diabetes model. Subcutaneously injected human Muse cells integrate into the epidermis and dermis and differentiate into keratinocytes, vascular endothelial cells, and other cell types in the dermis. Ulcers treated with human Muse cells heal faster with a thick epidermal layer than those treated with non-Muse cells, with a wound closure duration even shorter than that in wild-type mice.[40]

Aortic aneurism model:

Therapeutic efficacy of intravenous injection of human bone marrow-Muse cells into a SCID mouse aortic aneurysm model was evaluated. At 8 weeks, infusion of human Muse cells attenuated aneurysm dilation, and the aneurysmal size in the Muse group corresponded to approximately 45.6% in the vehicle group. Infused Muse cells were shown to migrate into aneurysmal tissue from the adventitial side and penetrated toward the luminal side. Histologic analysis demonstrated robust preservation of elastic fibers and spontaneous differentiation of Muse cells into endothelial cells and vascular smooth muscle cells.[41]

Muse cells in clinical data

Muse cells are present in the human bone marrow of healthy donors.[42] The number of peripheral blood-Muse cells is drastically elevated in stroke patients 24 h after onset.[42] In acute myocardial infarction patients, peripheral blood-Muse cells significantly increase 24 h after onset, concomitant with an increase in serum sphingosine-1-phosphate, and return to baseline levels with 2~3 weeks. Importantly, patients with an increased peripheral blood-Muse cell number in the acute phase show cardiac function recovery and avoidance of heart failure at 6 months after onset, suggesting the reparative function of endogenous Muse cells.[43]

Regenerative medicine
  • Bone marrow transplantation: Muse cells are a subpopulation of bone marrow cells. They represent a small population of mono-nucleated bone marrow cells (~0.03%).[22] This means that they have already been supplied to patients many times all over the world in bone marrow transplantations; a well-known procedure that has been performed in clinics since 1958.[44]
  • Mesenchymal stem cell transplantation: Muse cells exist within cultured MSCs such as bone marrow mesenchymal stem cells and adipose-derived stem cells. MSC transplantation has been employed for repairing liver, heart, neural tissue, airway, skin, skeletal muscle, and intestine.[45] Therefore, if Muse cells were purified or enriched, the effectiveness of currently performed MSC transplantation is expected to see vast improvements.[4]
  • Because Muse cells do not form teratomas in vivo, they could provide an ideal source of pluripotent stem cells for regenerative medicine and cell-based therapy.

Clinical Trial

See also

References
  1. Kuroda, Y.; Kitada, M.; Wakao, S.; Nishikawa, K.; Tanimura, Y.; Makinoshima, H.; Goda, M.; Akashi, H.; Inutsuka, A.; Niwa, A.; Shigemoto, T.; Nabeshima, Y.; Nakahata, T.; Nabeshima, Y.-i.; Fujiyoshi, Y.; Dezawa, M. (2010). "Unique multipotent cells in adult human mesenchymal cell populations". Proceedings of the National Academy of Sciences. 107 (19): 8639–43. Bibcode:2010PNAS..107.8639K. doi:10.1073/pnas.0911647107. PMC 2889306. PMID 20421459.
  2. https://www.springer.com/us/book/9784431568452
  3. Wakao, S.; Kitada, M.; Kuroda, Y.; Shigemoto, T.; Matsuse, D.; Akashi, H.; Tanimura, Y.; Tsuchiyama, K.; Kikuchi, T.; Goda, M.; Nakahata, T.; Fujiyoshi, Y.; Dezawa, M. (2011). "Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts". Proceedings of the National Academy of Sciences. 108 (24): 9875–80. Bibcode:2011PNAS..108.9875W. doi:10.1073/pnas.1100816108. PMC 3116385. PMID 21628574.
  4. Dezawa, Mari (2016). "Muse Cells Provide the Pluripotency of Mesenchymal Stem Cells: Direct Contribution of Muse Cells to Tissue Regeneration". Cell Transplantation. 25 (5): 849–61. doi:10.3727/096368916X690881. PMID 26884346.
  5. Hori, Emiko; Hayakawa, Yumiko; Hayashi, Tomohide; Hori, Satoshi; Okamoto, Soushi; Shibata, Takashi; Kubo, Michiya; Horie, Yukio; Sasahara, Masakiyo; Kuroda, Satoshi (2016). "Mobilization of Pluripotent Multilineage-Differentiating Stress-Enduring Cells in Ischemic Stroke". Journal of Stroke and Cerebrovascular Diseases. 25 (6): 1473–81. doi:10.1016/j.jstrokecerebrovasdis.2015.12.033. PMID 27019988.
  6. Kuroda, Yasumasa; Wakao, Shohei; Kitada, Masaaki; Murakami, Toru; Nojima, Makoto; Dezawa, Mari (2013). "Isolation, culture and evaluation of multilineage-differentiating stress-enduring (Muse) cells". Nature Protocols. 8 (7): 1391–415. doi:10.1038/nprot.2013.076. PMID 23787896.
  7. Ogura, Fumitaka; Wakao, Shohei; Kuroda, Yasumasa; Tsuchiyama, Kenichiro; Bagheri, Mozhdeh; Heneidi, Saleh; Chazenbalk, Gregorio; Aiba, Setsuya; Dezawa, Mari (2014). "Human Adipose Tissue Possesses a Unique Population of Pluripotent Stem Cells with Nontumorigenic and Low Telomerase Activities: Potential Implications in Regenerative Medicine". Stem Cells and Development. 23 (7): 717–28. doi:10.1089/scd.2013.0473. PMID 24256547.
  8. Heneidi, Saleh; Simerman, Ariel A.; Keller, Erica; Singh, Prapti; Li, Xinmin; Dumesic, Daniel A.; Chazenbalk, Gregorio (2013). "Awakened by Cellular Stress: Isolation and Characterization of a Novel Population of Pluripotent Stem Cells Derived from Human Adipose Tissue". PLOS One. 8 (6): e64752. Bibcode:2013PLoSO...864752H. doi:10.1371/journal.pone.0064752. PMC 3673968. PMID 23755141.
  9. "Initiation of Exploratory Clinical Trial of Muse Cell Product Targeting Acute Myocardial Infarction" (PDF).
  10. Alessio, Nicola; Özcan, Servet; Tatsumi, Kazuki; Murat, Ayşegül; Peluso, Gianfranco; Dezawa, Mari; Galderisi, Umberto (2016). "The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation". Cell Cycle. 16 (1): 1–12. doi:10.1080/15384101.2016.1211215. PMC 5270533. PMID 27463232.
  11. Wakao, S; Kitada, M; Kuroda, Y; Shigemoto, T; Matsuse, D; Akashi, H; Tanimura, Y; Tsuchiyama, K; Kikuchi, T; Goda, M; Nakahata, T; Fujiyoshi, Y; Dezawa, M (2011). "Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts". Proceedings of the National Academy of Sciences. 108 (24): 9875–9880. Bibcode:2011PNAS..108.9875W. doi:10.1073/pnas.1100816108. PMC 3116385. PMID 21628574.
  12. Alessio, N; Squillaro, T; Özcan, S; Di Bernardo, G; Venditti, M; Melone, M; Peluso, G; Galderisi, U (2018). "Stress and stem cells: Adult Muse cells tolerate extensive genotoxic stimuli better than mesenchymal stromal cells". Oncotarget. 9 (27): 19328–19341. doi:10.18632/oncotarget.25039. PMC 5922400. PMID 29721206.
  13. Gimeno, M. L.; Fuertes, F.; Barcala Tabarrozzi, A. E.; Attorressi, A. I.; Cucchiani, R.; Corrales, L.; Oliveira, T. C.; Sogayar, M. C.; Labriola, L.; Dewey, R. A.; Perone, M. J. (2016). "Pluripotent Nontumorigenic Adipose Tissue-Derived Muse Cells Have Immunomodulatory Capacity Mediated by Transforming Growth Factor-β1". Stem Cells Translational Medicine. 6 (1): 161–173. doi:10.5966/sctm.2016-0014. PMC 5442729. PMID 28170177.
  14. Katagiri, H.; Kushida, Y.; Nojima, M.; Kuroda, Y.; Wakao, S.; Ishida, K.; Endo, F.; Kume, K.; Takahara, T.; Nitta, H.; Tsuda, H.; Dezawa, M.; Nishizuka, S. S. (2016). "A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components". American Journal of Transplantation. 16 (2): 468–83. doi:10.1111/ajt.13537. PMID 26663569.
  15. Uchida, Hiroki; Morita, Takahiro; Niizuma, Kuniyasu; Kushida, Yoshihiro; Kuroda, Yasumasa; Wakao, Shohei; Sakata, Hiroyuki; Matsuzaka, Yoshiya; Mushiake, Hajime; Tominaga, Teiji; Borlongan, Cesario V.; Dezawa, Mari (2016). "Transplantation of Unique Subpopulation of Fibroblasts, Muse Cells, Ameliorates Experimental Stroke Possibly via Robust Neuronal Differentiation". Stem Cells. 34 (1): 160–73. doi:10.1002/stem.2206. PMID 26388204.
  16. Kinoshita, K.; Kuno, S.; Ishimine, H.; Aoi, N.; Mineda, K.; Kato, H.; Doi, K.; Kanayama, K.; Feng, J.; Mashiko, T.; Kurisaki, A.; Yoshimura, K. (2015). "Therapeutic Potential of Adipose-Derived SSEA-3-Positive Muse Cells for Treating Diabetic Skin Ulcers". Stem Cells Translational Medicine. 4 (2): 146–55. doi:10.5966/sctm.2014-0181. PMC 4303359. PMID 25561682.
  17. Kuroda, Yasumasa; Kitada, Masaaki; Wakao, Shohei; Nishikawa, Kouki; Tanimura, Yukihiro; Makinoshima, Hideki; Goda, Makoto; Akashi, Hideo; Inutsuka, Ayumu (2010-05-11). "Unique multipotent cells in adult human mesenchymal cell populations". Proceedings of the National Academy of Sciences of the United States of America. 107 (19): 8639–8643. Bibcode:2010PNAS..107.8639K. doi:10.1073/pnas.0911647107. ISSN 1091-6490. PMC 2889306. PMID 20421459.
  18. Thomson, J. A.; Itskovitz-Eldor, Joseph; Shapiro, Sander S.; Waknitz, Michelle A.; Swiergiel, Jennifer J.; Marshall, Vivienne S.; Jones, Jeffrey M. (1998). "Embryonic Stem Cell Lines Derived from Human Blastocysts". Science. 282 (5391): 1145–7. Bibcode:1998Sci...282.1145T. doi:10.1126/science.282.5391.1145. PMID 9804556.
  19. Wakao, Shohei; Kitada, Masaaki; Dezawa, Mari (2013). "The elite and stochastic model for iPS cell generation: Multilineage-differentiating stress enduring (Muse) cells are readily reprogrammable into iPS cells". Cytometry Part A. 83A (1): 18–26. doi:10.1002/cyto.a.22069. PMID 22693162.
  20. Tsuchiyama, Kenichiro; Wakao, Shohei; Kuroda, Yasumasa; Ogura, Fumitaka; Nojima, Makoto; Sawaya, Natsue; Yamasaki, Kenshi; Aiba, Setsuya; Dezawa, Mari (2013). "Functional Melanocytes Are Readily Reprogrammable from Multilineage-Differentiating Stress-Enduring (Muse) Cells, Distinct Stem Cells in Human Fibroblasts". Journal of Investigative Dermatology. 133 (10): 2425–35. doi:10.1038/jid.2013.172. PMID 23563197.
  21. Mineda, K.; Feng, J.; Ishimine, H.; Takada, H.; Doi, K.; Kuno, S.; Kinoshita, K.; Kanayama, K.; Kato, H.; Mashiko, T.; Hashimoto, I.; Nakanishi, H.; Kurisaki, A.; Yoshimura, K. (2015). "Therapeutic Potential of Human Adipose-Derived Stem/Stromal Cell Microspheroids Prepared by Three-Dimensional Culture in Non-Cross-Linked Hyaluronic Acid Gel". Stem Cells Translational Medicine. 4 (12): 1511–22. doi:10.5966/sctm.2015-0037. PMC 4675504. PMID 26494781.
  22. Wakao, Shohei; Kuroda, Yasumasa; Ogura, Fumitaka; Shigemoto, Taeko; Dezawa, Mari (2012). "Regenerative Effects of Mesenchymal Stem Cells: Contribution of Muse Cells, a Novel Pluripotent Stem Cell Type that Resides in Mesenchymal Cells". Cells. 1 (4): 1045–60. doi:10.3390/cells1041045. PMC 3901150. PMID 24710542.
  23. Kitada, Masaaki; Wakao, Shohei; Dezawa, Mari (2012). "Muse cells and induced pluripotent stem cell: Implication of the elite model". Cellular and Molecular Life Sciences. 69 (22): 3739–50. doi:10.1007/s00018-012-0994-5. PMC 3478511. PMID 22527723.
  24. Chou, Yu-Fen; Chen, Hsu-Hsin; Eijpe, Maureen; Yabuuchi, Akiko; Chenoweth, Joshua G.; Tesar, Paul; Lu, Jun; McKay, Ronald D.G.; Geijsen, Niels (2008). "The Growth Factor Environment Defines Distinct Pluripotent Ground States in Novel Blastocyst-Derived Stem Cells". Cell. 135 (3): 449–61. doi:10.1016/j.cell.2008.08.035. PMC 2767270. PMID 18984157.
  25. Wakao, Shohei; Kitada, Masaaki; Kuroda, Yasumasa; Shigemoto, Taeko; Matsuse, Dai; Akashi, Hideo; Tanimura, Yukihiro; Tsuchiyama, Kenichiro; Kikuchi, Tomohiko (2011-06-14). "Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts". Proceedings of the National Academy of Sciences of the United States of America. 108 (24): 9875–9880. Bibcode:2011PNAS..108.9875W. doi:10.1073/pnas.1100816108. ISSN 1091-6490. PMC 3116385. PMID 21628574.
  26. Iseki, Masahiro; Kushida, Yoshihiro; Wakao, Shohei; Akimoto, Takahiro; Mizuma, Masamichi; Motoi, Fuyuhiko; Asada, Ryuta; Shimizu, Shinobu; Unno, Michiaki (2017-05-09). "Muse Cells, Nontumorigenic Pluripotent-Like Stem Cells, Have Liver Regeneration Capacity Through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis". Cell Transplantation. 26 (5): 821–840. doi:10.3727/096368916X693662. ISSN 1555-3892. PMC 5657714. PMID 27938474.
  27. Liu, Jun; Yang, Zhongcai; Qiu, Mingning; Luo, Yan; Pang, Meijun; Wu, Yongyan; Zhang, Yong (2013). "Developmental Potential of Cloned Goat Embryos from an SSEA3+ Subpopulation of Skin Fibroblasts". Cellular Reprogramming. 15 (2): 159–65. doi:10.1089/cell.2012.0073. PMID 23441574.
  28. Byrne, James A.; Nguyen, Ha Nam; Reijo Pera, Renee A. (2009). "Enhanced Generation of Induced Pluripotent Stem Cells from a Subpopulation of Human Fibroblasts". PLOS One. 4 (9): e7118. Bibcode:2009PLoSO...4.7118B. doi:10.1371/journal.pone.0007118. PMC 2744017. PMID 19774082.
  29. Tsuchiyama, Kenichiro; Wakao, Shohei; Kuroda, Yasumasa; Ogura, Fumitaka; Nojima, Makoto; Sawaya, Natsue; Yamasaki, Kenshi; Aiba, Setsuya; Dezawa, Mari (October 2013). "Functional melanocytes are readily reprogrammable from multilineage-differentiating stress-enduring (muse) cells, distinct stem cells in human fibroblasts". The Journal of Investigative Dermatology. 133 (10): 2425–2435. doi:10.1038/jid.2013.172. ISSN 1523-1747. PMID 23563197.
  30. Tian, Ting; Zhang, Ru-Zhi; Yang, Yu-Hua; Liu, Qi; Li, Di; Pan, Xiao-Ru (April 2017). "Muse Cells Derived from Dermal Tissues Can Differentiate into Melanocytes". Cellular Reprogramming. 19 (2): 116–122. doi:10.1089/cell.2016.0032. ISSN 2152-4998. PMID 28170296.
  31. Heneidi, Saleh; Simerman, Ariel A.; Keller, Erica; Singh, Prapti; Li, Xinmin; Dumesic, Daniel A.; Chazenbalk, Gregorio (2013). "Awakened by cellular stress: isolation and characterization of a novel population of pluripotent stem cells derived from human adipose tissue". PLOS One. 8 (6): e64752. Bibcode:2013PLoSO...864752H. doi:10.1371/journal.pone.0064752. ISSN 1932-6203. PMC 3673968. PMID 23755141.
  32. Yamauchi, Takeshi; Yamasaki, Kenshi; Tsuchiyama, Kenichiro; Koike, Saaya; Aiba, Setsuya (June 2017). "A quantitative analysis of multilineage-differentiating stress-enduring (Muse) cells in human adipose tissue and efficacy of melanocytes induction". Journal of Dermatological Science. 86 (3): 198–205. doi:10.1016/j.jdermsci.2017.03.001. ISSN 1873-569X. PMID 28292562.
  33. Yamauchi, Takeshi; Yamasaki, Kenshi; Tsuchiyama, Kenichiro; Koike, Saaya; Aiba, Setsuya (2017-07-20). "The potential of Muse cells for regenerative medicine of skin: procedures to reconstitute skin with Muse cell-derived keratinocytes, fibroblasts, and melanocytes". The Journal of Investigative Dermatology. 137 (12): 2639–2642. doi:10.1016/j.jid.2017.06.021. ISSN 1523-1747. PMID 28736234.
  34. Katagiri, H.; Kushida, Y.; Nojima, M.; Kuroda, Y.; Wakao, S.; Ishida, K.; Endo, F.; Kume, K.; Takahara, T. (February 2016). "A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components". American Journal of Transplantation. 16 (2): 468–483. doi:10.1111/ajt.13537. ISSN 1600-6143. PMID 26663569.
  35. Uchida, Nao; Kushida, Yoshihiro; Kitada, Masaaki; Wakao, Shohei; Kumagai, Naonori; Kuroda, Yasumasa; Kondo, Yoshiaki; Hirohara, Yukari; Kure, Shigeo (2017-07-03). "Beneficial Effects of Systemically Administered Human Muse Cells in Adriamycin Nephropathy". Journal of the American Society of Nephrology. 28 (10): 2946–2960. doi:10.1681/ASN.2016070775. ISSN 1533-3450. PMC 5619953. PMID 28674043.
  36. Amin, Mohamed; Kushida, Yoshihiro; Wakao, Shohei; Kitada, Masaaki; Tatsumi, Kazuki; Dezawa, Mari (2018). "Cardiotrophic Growth Factor–Driven Induction of Human Muse Cells into Cardiomyocyte-Like Phenotype". Cell Transplantation. 27 (2): 285–298. doi:10.1177/0963689717721514. PMC 5898685. PMID 29637816.
  37. Yamada, Yoshihisa; Wakao, Shohei; Kushida, Yoshihiro; Minatoguchi, Shingo; Mikami, Atsushi; Higashi, Kenshi; Baba, Shinya; Shigemoto, Taeko; Kuroda, Yasumasa; Kanamori, Hiromitsu; Amin, Mohamad; Kawasaki, Masanori; Nishigaki, Kazuhiko; Taoka, Masato; Isobe, Toshiaki; Muramatsu, Chisako; Dezawa, Mari; Minatoguchi, Shinya (2018). "S1P–S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction". Circulation Research. 122 (8): 1069–1083. doi:10.1161/CIRCRESAHA.117.311648. PMID 29475983.
  38. Uchida, Hiroki; Niizuma, Kuniyasu; Kushida, Yoshihiro; Wakao, Shohei; Tominaga, Teiji; Borlongan, Cesario V; Dezawa, Mari (2017). "Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model". Stroke. 48 (2): 428–435. doi:10.1161/STROKEAHA.116.014950. PMC 5262965. PMID 27999136.
  39. Shimamura, Norihito; Kakuta, Kiyohide; Wang, Liang; Naraoka, Masato; Uchida, Hiroki; Wakao, Shohei; Dezawa, Mari; Ohkuma, Hiroki (February 2017). "Neuro-regeneration therapy using human Muse cells is highly effective in a mouse intracerebral hemorrhage model". Experimental Brain Research. 235 (2): 565–572. doi:10.1007/s00221-016-4818-y. ISSN 1432-1106. PMID 27817105.
  40. Kinoshita, Kahori; Kuno, Shinichiro; Ishimine, Hisako; Aoi, Noriyuki; Mineda, Kazuhide; Kato, Harunosuke; Doi, Kentaro; Kanayama, Koji; Feng, Jingwei (February 2015). "Therapeutic Potential of Adipose-Derived SSEA-3-Positive Muse Cells for Treating Diabetic Skin Ulcers". Stem Cells Translational Medicine. 4 (2): 146–155. doi:10.5966/sctm.2014-0181. ISSN 2157-6564. PMC 4303359. PMID 25561682.
  41. Hosoyama, Katsuhiro; Wakao, Shohei; Kushida, Yoshihiro; Ogura, Fumitaka; Maeda, Kay; Adachi, Osamu; Kawamoto, Shunsuke; Dezawa, Mari; Saiki, Yoshikatsu (2018). "Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types". The Journal of Thoracic and Cardiovascular Surgery. 155 (6): 2301–2313.e4. doi:10.1016/j.jtcvs.2018.01.098. PMID 29559260.
  42. Hori, Emiko; Hayakawa, Yumiko; Hayashi, Tomohide; Hori, Satoshi; Okamoto, Soushi; Shibata, Takashi; Kubo, Michiya; Horie, Yukio; Sasahara, Masakiyo (June 2016). "Mobilization of Pluripotent Multilineage-Differentiating Stress-Enduring Cells in Ischemic Stroke". Journal of Stroke and Cerebrovascular Diseases. 25 (6): 1473–1481. doi:10.1016/j.jstrokecerebrovasdis.2015.12.033. ISSN 1532-8511. PMID 27019988.
  43. Tanaka, Toshiki; Nishigaki, Kazuhiko; Minatoguchi, Shingo; Nawa, Takahide; Yamada, Yoshihisa; Kanamori, Hiromitsu; Mikami, Atsushi; Ushikoshi, Hiroaki; Kawasaki, Masanori; Dezawa, Mari; Minatoguchi, Shinya (2018). "Mobilized Muse Cells After Acute Myocardial Infarction Predict Cardiac Function and Remodeling in the Chronic Phase". Circulation Journal. 82 (2): 561–571. doi:10.1253/circj.CJ-17-0552. PMID 28931784.
  44. Cosset, Jean Marc (2002). "ESTRO Breur Gold Medal Award Lecture 2001: Irradiation accidents – lessons for oncology?". Radiotherapy and Oncology. 63 (1): 1–10. doi:10.1016/s0167-8140(02)00059-2. PMID 12065098.
  45. Kuroda, Yasumasa; Kitada, Masaaki; Wakao, Shohei; Dezawa, Mari (2011). "Bone Marrow Mesenchymal Cells: How Do They Contribute to Tissue Repair and Are They Really Stem Cells?". Archivum Immunologiae et Therapiae Experimentalis. 59 (5): 369–78. doi:10.1007/s00005-011-0139-9. PMID 21789625.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.