Muse cell: Difference between revisions
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A M'''use cell''' ('''mu'''lti-lineage differentiating '''s'''tress '''e'''nduring cell) is a endogenous non-tumorigenic [[pluripotent stem cell]] discovered by Mari Dezawa and her research group<ref name=":1">{{ |
A M'''use cell''' ('''mu'''lti-lineage differentiating '''s'''tress '''e'''nduring cell) is a endogenous non-tumorigenic [[pluripotent stem cell]] discovered by Mari Dezawa and her research group<ref name=":1">{{cite journal |doi=10.1073/pnas.0911647107 }}</ref> They reside in the connective tissue of nearly every organ, bone marrow and peripheral blood.<ref name=":1"/><ref name=":2">{{cite journal |doi=10.1073/pnas.1100816108 }}</ref><ref name=":3">{{cite journal |doi=10.3727/096368916X690881 }}</ref><ref name=":4">{{cite journal |doi=10.1016/j.jstrokecerebrovasdis.2015.12.033 }}</ref> They are collectable from commercially obtainable mesenchymal cells such as human [[fibroblast]]s, bone marrow-mesenchymal stem cells and adipose-derived stem cells.<ref>{{cite journal |doi=10.1038/nprot.2013.076 }}</ref><ref name=":5">{{cite journal |doi=10.1089/scd.2013.0473 }}</ref><ref name=":6">{{cite journal |doi=10.1371/journal.pone.0064752 }}</ref> 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. |
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== Characteristics == |
== Characteristics == |
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* Stress-tolerant.<ref>{{cite journal |doi=10.1080/15384101.2016.1211215 }}</ref> |
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* Stress-tolerant.<ref>{{Cite journal|last=Alessio|first=Nicola|last2=Özcan|first2=Servet|last3=Tatsumi|first3=Kazuki|last4=Murat|first4=Ayşegül|last5=Peluso|first5=Gianfranco|last6=Dezawa|first6=Mari|last7=Galderisi|first7=Umberto|date=2016-07-27|title=The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation|url=https://www.ncbi.nlm.nih.gov/pubmed/?term=allessio,+gardelisi,+dezawa|journal=Cell Cycle (Georgetown, Tex.)|pages=0|doi=10.1080/15384101.2016.1211215|issn=1551-4005|pmid=27463232}}</ref> |
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* Can be isolated as cells positive for [[SSEA-3]], a well known human [[embryonic stem cell]] marker.<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /> |
* Can be isolated as cells positive for [[SSEA-3]], a well known human [[embryonic stem cell]] marker.<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /> |
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* Pluripotent stem cells, which can generate various kinds of the cells representative of all three germ layers have the ability to self-renew.<ref name=":1"/> |
* Pluripotent stem cells, which can generate various kinds of the cells representative of all three germ layers have the ability to self-renew.<ref name=":1"/> |
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* Non-tumorigenic. Low [[telomerase]] activity.<ref name=":1"/><ref name=":5" /><ref name=":7">{{ |
* Non-tumorigenic. Low [[telomerase]] activity.<ref name=":1"/><ref name=":5" /><ref name=":7">{{cite journal |doi=10.5966/sctm.2016-0014 }}</ref> |
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* Accumulate into damaged tissue by intravenous or local injections.<ref name=":8">{{cite journal |doi=10.1111/ajt.13537 }}</ref><ref name=":9">{{cite journal |doi=10.1002/stem.2206 }}</ref><ref name=":10">{{cite journal |doi=10.5966/sctm.2014-0181 }}</ref> |
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* Accumulate into damaged tissue by intravenous or local injections.<ref name=":8">{{Cite journal|last=Katagiri|first=H.|last2=Kushida|first2=Y.|last3=Nojima|first3=M.|last4=Kuroda|first4=Y.|last5=Wakao|first5=S.|last6=Ishida|first6=K.|last7=Endo|first7=F.|last8=Kume|first8=K.|last9=Takahara|first9=T.|date=2016-02-01|title=A Distinct Subpopulation of Bone Marrow Mesenchymal Stem Cells, Muse Cells, Directly Commit to the Replacement of Liver Components|url=https://www.ncbi.nlm.nih.gov/pubmed/?term=katagiri,+nishizuka,+dezawa|journal=American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons|volume=16|issue=2|pages=468–483|doi=10.1111/ajt.13537|issn=1600-6143|pmid=26663569}}</ref><ref name=":9">{{Cite journal|last=Uchida|first=Hiroki|last2=Morita|first2=Takahiro|last3=Niizuma|first3=Kuniyasu|last4=Kushida|first4=Yoshihiro|last5=Kuroda|first5=Yasumasa|last6=Wakao|first6=Shohei|last7=Sakata|first7=Hiroyuki|last8=Matsuzaka|first8=Yoshiya|last9=Mushiake|first9=Hajime|date=2016-01-01|title=Transplantation of Unique Subpopulation of Fibroblasts, Muse Cells, Ameliorates Experimental Stroke Possibly via Robust Neuronal Differentiation|url=https://www.ncbi.nlm.nih.gov/pubmed/26388204|journal=Stem Cells (Dayton, Ohio)|volume=34|issue=1|pages=160–173|doi=10.1002/stem.2206|issn=1549-4918|pmid=26388204}}</ref><ref name=":10">{{Cite journal|last=Kinoshita|first=Kahori|last2=Kuno|first2=Shinichiro|last3=Ishimine|first3=Hisako|last4=Aoi|first4=Noriyuki|last5=Mineda|first5=Kazuhide|last6=Kato|first6=Harunosuke|last7=Doi|first7=Kentaro|last8=Kanayama|first8=Koji|last9=Feng|first9=Jingwei|date=2015-02-01|title=Therapeutic Potential of Adipose-Derived SSEA-3-Positive Muse Cells for Treating Diabetic Skin Ulcers|journal=Stem Cells Translational Medicine|volume=4|issue=2|pages=146–155|doi=10.5966/sctm.2014-0181|issn=2157-6564|pmc=4303359|pmid=25561682}}</ref> |
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* Replenish new functional cells through spontaneous differentiation into tissue-compatible cells.<ref name=":1"/><ref name=":8" /><ref name=":9" /><ref name=":10" /> |
* Replenish new functional cells through spontaneous differentiation into tissue-compatible cells.<ref name=":1"/><ref name=":8" /><ref name=":9" /><ref name=":10" /> |
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* Repair tissue by systemic administration. |
* Repair tissue by systemic administration. |
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== Markers == |
== Markers == |
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Muse cells are identified as cells positive for [[SSEA-3]]+, a well |
Muse cells are identified as cells positive for [[SSEA-3]]+,{{fact}} a well-known marker for undifferentiated human ES cells.<ref>{{cite journal |doi=10.1126/science.282.5391.1145 }}</ref> They are also positive for general mesenchymal stem cell markers such as [[CD105]], [[CD90]] and [[CD29]].<ref name="Kuroda">{{cite journal |doi=10.1073/pnas.0911647107 }}</ref> 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 cell]]s, [[adipose cell|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]] ([[Vasculature|perivascular cells]]) or [[CD31]] and [[von Willebrand factor]] ([[endothelial progenitor cell|endothelial progenitor]] markers). This indicates that Muse cells do not belong to previously investigated stem cell types.<ref name=":1"/><ref name=Wakaocyto>{{cite journal |doi=10.1002/cyto.a.22069 }}</ref> |
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== Differentiation capacity == |
== Differentiation capacity == |
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===In vitro=== |
===In vitro=== |
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Muse cells can differentiate into: |
Muse cells can differentiate into: |
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# Ectodermal- (cells positive for [[nestin (protein)|nestin]], [[NeuroD]], [[Musashi (protein)|Musashi]], [[neurofilament]], [[MAP-2]],<ref name=WakaoPNAS>{{cite journal |
# Ectodermal- (cells positive for [[nestin (protein)|nestin]], [[NeuroD]], [[Musashi (protein)|Musashi]], [[neurofilament]], [[MAP-2]],<ref name=WakaoPNAS>{{cite journal |doi=10.1073/pnas.1100816108 }}</ref> [[melanocyte]] markers ([[tyrosinase]], [[MITF]], [[gf100]], [[TRP-1]], [[Dopachrome tautomerase|DCT]]) <ref name=Tsuchiyama>{{cite journal |doi=10.1038/jid.2013.172 }}</ref>), |
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# Mesodermal- ([[brachyury]], [[Nkx2-5]], [[smooth muscle]] [[actin]],<ref name=Kuroda /> [[osteocalcin]], oil red-(+) lipid droplets,<ref name=WakaoPNAS /> [[desmin]] <ref name=Kuroda />) |
# Mesodermal- ([[brachyury]], [[Nkx2-5]], [[smooth muscle]] [[actin]],<ref name=Kuroda /> [[osteocalcin]], oil red-(+) lipid droplets,<ref name=WakaoPNAS /> [[desmin]] <ref name=Kuroda />) |
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# Endodermal- ([[GATA-6]], [[α-fetoprotein]], [[cytokeratin]]-7,<ref name=Kuroda /> [[albumin]] <ref name=WakaoPNAS />) lineages both spontaneously and under cytokine induction.<ref name=Kuroda /> |
# Endodermal- ([[GATA-6]], [[α-fetoprotein]], [[cytokeratin]]-7,<ref name=Kuroda /> [[albumin]] <ref name=WakaoPNAS />) lineages both spontaneously and under cytokine induction.<ref name=Kuroda /> |
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===In vivo=== |
===In vivo=== |
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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.<ref name=Kuroda /> This was shown in human Muse cells infused into animal models with [[fulminant hepatitis]],<ref name=Kuroda /> partial hepatectomy,<ref name=":8" /> [[muscle degeneration]],<ref name=Kuroda /> skin injury,<ref name=":10" /><ref name=Kuroda /><ref name=":11">{{ |
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.<ref name=Kuroda /> This was shown in human Muse cells infused into animal models with [[fulminant hepatitis]],<ref name=Kuroda /> partial hepatectomy,<ref name=":8" /> [[muscle degeneration]],<ref name=Kuroda /> skin injury,<ref name=":10" /><ref name=Kuroda /><ref name=":11">{{cite journal |doi=10.5966/sctm.2015-0037 }}</ref> stroke<ref name=":9" /> and [[spinal cord injury]].<ref name=WakaoCells>{{cite journal |doi=10.3390/cells1041045 }}</ref> |
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== Non-tumorigenicity == |
== Non-tumorigenicity == |
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===Expression of genes related to pluripotency and cell cycle=== |
===Expression of genes related to pluripotency and cell cycle=== |
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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.<ref name=WakaoPNAS /> 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.<ref name=KitadaJ>{{cite journal |
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.<ref name=WakaoPNAS /> 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.<ref name=KitadaJ>{{cite journal |doi=10.1007/s00018-012-0994-5 }}</ref> |
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===Transplantation into mouse testes=== |
===Transplantation into mouse testes=== |
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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 [[teratoma]]s, even after six months.<ref name=Kuroda /> Thus, Muse cells are pluripotent but are non-tumorigenic. Similarly, epiblast stem cells cultured under certain conditions also do not form teratomas in testes, even though they show pluripotency in vitro.<ref>{{cite journal |
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 [[teratoma]]s, even after six months.<ref name=Kuroda /> Thus, Muse cells are pluripotent but are non-tumorigenic.{{fact}} Similarly, epiblast stem cells cultured under certain conditions also do not form teratomas in testes,{{fact}} even though they show pluripotency in vitro.<ref>{{cite journal |doi=10.1016/j.cell.2008.08.035 }}</ref> Thus, pluripotent stem cells do not always show teratoma formation when transplanted in vivo.{{fact}} |
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== Tissue repair == |
== Tissue repair == |
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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 wit [[fulminant hepatitis]],<ref name="Kuroda" /> partial hepatectomy,<ref name=":8" /> [[muscle degeneration]],<ref name="Kuroda" /> skin injury,<ref name=":10" /><ref name="Kuroda" /><ref name=":11" /> stroke<ref name=":9" /> and [[spinal cord injury]].<ref name="WakaoCells" /> Infused Muse cells integrated into each damaged tissue and differentiated into human albumin- and human anti-trypsin-expressing hepatocytes in the liver,<ref name=Kuroda /> human dystrophin-expressing cells in the muscle,<ref name=Kuroda /> [[neurofilament]] and [[MAP-2]]-expressing neuronal cells in the spinal cord <ref name=WakaoCells /> and stroke,<ref name=":9" /> and cytokerain14-expressing epidermal cells in the skin,<ref name=":10" /><ref name=Kuroda /><ref name=":11" /> respectively. |
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 wit [[fulminant hepatitis]],<ref name="Kuroda" /> partial hepatectomy,<ref name=":8" /> [[muscle degeneration]],<ref name="Kuroda" /> skin injury,<ref name=":10" /><ref name="Kuroda" /><ref name=":11" /> stroke<ref name=":9" /> and [[spinal cord injury]].<ref name="WakaoCells" /> Infused Muse cells integrated into each damaged tissue and differentiated into human albumin- and human anti-trypsin-expressing hepatocytes in the liver,<ref name=Kuroda /> human dystrophin-expressing cells in the muscle,<ref name=Kuroda /> [[neurofilament]] and [[MAP-2]]-expressing neuronal cells in the spinal cord <ref name=WakaoCells /> and stroke,<ref name=":9" /> and cytokerain14-expressing epidermal cells in the skin,<ref name=":10" /><ref name=Kuroda /><ref name=":11" /> respectively. |
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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.<ref name=KurodaNature>{{cite journal |
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.<ref name=KurodaNature>{{cite journal |doi=10.1038/nprot.2013.076 }}</ref>{{medrs|date=November 2013}} Precise conditions such as the number and source of Muse cells for each organ regeneration requires further investigation. |
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Currently, Life Science Institute, Inc. and its parent company, Mitsubishi Chemical Holdings Corporation Group, have established a cell-processing procedure that is compliant with the Japansese 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. |
Currently, Life Science Institute, Inc. and its parent company, Mitsubishi Chemical Holdings Corporation Group, have established a cell-processing procedure that is compliant with the Japansese 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.<ref name=":13">{{cite web |url=http://www.nature.com/nature/outlook/regenerative-medicine/pdf/Clio.pdf |title=Development of Muse cell therapy for KAITEKI society }}{{psc}}</ref> |
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== Basic characteristics == |
== Basic characteristics == |
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===Location in vivo=== |
===Location in vivo=== |
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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,<ref name=Kuroda /> dermis <ref name=WakaoPNAS /> and adipose tissue.<ref name=Heneidi>{{cite journal |
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,<ref name=Kuroda /> dermis <ref name=WakaoPNAS /> and adipose tissue.<ref name=Heneidi>{{cite journal |doi=10.1371/journal.pone.0064752 }}</ref> 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.<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /> |
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===Duality=== |
===Duality=== |
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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. |
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.{{fact}} |
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===Formation of clusters similar to embryoid body of ES cells in suspension=== |
===Formation of clusters similar to embryoid body of ES cells in suspension=== |
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* Adipose-derived stem cells (Lonza Co.) has around 1 to 7% SSEA-3 positive Muse cells. |
* Adipose-derived stem cells (Lonza Co.) has around 1 to 7% SSEA-3 positive Muse cells. |
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* 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. |
* 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. |
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* 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 [[karyotype]]s. Also, they were consistently positive for pluripotency markers and alkaline phosphatase staining. Goat Muse cells showed [[triploblast]]ic differentiation capability both in vivo and in vitro and remained undifferentiated over eight passages in suspension culture. |
* 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 [[karyotype]]s. Also, they were consistently positive for pluripotency markers and alkaline phosphatase staining. Goat Muse cells showed [[triploblast]]ic differentiation capability both in vivo and in vitro and remained undifferentiated over eight passages in suspension culture.<ref>{{Cite journal |doi=10.1089/cell.2012.0073 }}</ref> |
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== Collection methods == |
== Collection methods == |
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== Muse cells as a primary source of iPS cells == |
== Muse cells as a primary source of iPS cells == |
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In 2009, a study showed that only SSEA-3+ cells generate induced pluripotent stem (iPS) cells in human fibroblasts.<ref> |
In 2009, a study showed that only SSEA-3+ cells generate induced pluripotent stem (iPS) cells in human fibroblasts.<ref>{{cite journal |doi=10.1371/journal.pone.0007118 }}</ref> 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.<ref name=Wakaocyto /><ref name=WakaoPNAS /> |
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== Derived melanocytes == |
== Derived melanocytes == |
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== Regenerative medicine == |
== Regenerative medicine == |
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* 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%).<ref name=WakaoCells /> 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.<ref>{{cite journal |
* 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%).<ref name=WakaoCells /> 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.<ref>{{cite journal |doi=10.1016/s0167-8140(02)00059-2 }}</ref> |
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* 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.<ref>{{cite journal |
* 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.<ref>{{cite journal |doi=10.1007/s00005-011-0139-9 }}</ref> Therefore, if Muse cells were purified or enriched, the effectiveness of currently performed MSC transplantation is expected to see vast improvements.<ref name=":3" /> |
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* 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]]. |
* 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]]. |
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* Currently, Life Science Institute, Inc. and its parent company, Mitsubishi Chemical Holdings Corporation Group, have established a cell-processing procedure that is compliant with the Japansese 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. |
* Currently, Life Science Institute, Inc. and its parent company, Mitsubishi Chemical Holdings Corporation Group, have established a cell-processing procedure that is compliant with the Japansese 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.<ref name=":13" /> |
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==See also== |
==See also== |
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==Further reading== |
==Further reading== |
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* {{cite journal |doi=10.1111/pin.12129 }} |
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* {{cite journal|authors=Wakao, S., Akashi, H., Kushida, Y. and Dezawa, M |year=2014|doi=10.1111/pin.12129|title=Muse cells, newly found non-tumorigenic pluripotent stem cells, reside in human mesenchymal tissues|journal=Pathology International|volume=64|pages=1–9|url=http://onlinelibrary.wiley.com/doi/10.1111/pin.12129/full}} |
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* {{cite journal |doi=10.1002/stem.2206 }} |
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* {{cite journal|authors=Uchida, H., Morita, T., Niizuma, K., Kushida, Y., Kuroda, Y., Wakao, S., Sakata, H., Matsuzaka, Y., Mushiake, H., Tominaga, T., Borlongan, C. V. and Dezawa, M. |year=2015|doi=10.1002/stem.2206|title=Transplantation of Unique Subpopulation of Fibroblasts, Muse Cells, Ameliorates Experimental Stroke Possibly Via Robust Neuronal Differentiation|journal=STEM CELLS|volume=34|pages=160-73|url=http://onlinelibrary.wiley.com/doi/10.1002/stem.2206/abstract|pmid=26388204}} |
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== References == |
== References == |
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Revision as of 16:17, 30 December 2016
A Muse cell (multi-lineage differentiating stress enduring cell) is a endogenous non-tumorigenic pluripotent stem cell discovered by Mari Dezawa and her research group[1] They reside in the connective tissue of nearly every organ, bone marrow and peripheral blood.[1][2][3][4] They are collectable from commercially obtainable mesenchymal cells such as human fibroblasts, bone marrow-mesenchymal stem cells and adipose-derived stem cells.[5][6][7] 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.
Characteristics
- Stress-tolerant.[8]
- Can be isolated as cells positive for SSEA-3, a well known human embryonic stem cell marker.[1][2][3][4]
- 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][6][9]
- Accumulate into damaged tissue by intravenous or local injections.[10][11][12]
- Replenish new functional cells through spontaneous differentiation into tissue-compatible cells.[1][10][11][12]
- 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.[9]
- 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+,[citation needed] a well-known marker for undifferentiated human ES cells.[13] They are also positive for general mesenchymal stem cell markers such as CD105, CD90 and CD29.[14] 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][15]
Differentiation capacity
In vitro
Muse cells can differentiate into:
- Ectodermal- (cells positive for nestin, NeuroD, Musashi, neurofilament, MAP-2,[16] melanocyte markers (tyrosinase, MITF, gf100, TRP-1, DCT) [17]),
- Mesodermal- (brachyury, Nkx2-5, smooth muscle actin,[14] osteocalcin, oil red-(+) lipid droplets,[16] desmin [14])
- Endodermal- (GATA-6, α-fetoprotein, cytokeratin-7,[14] albumin [16]) lineages both spontaneously and under cytokine induction.[14]
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.[17] 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.[14] This was shown in human Muse cells infused into animal models with fulminant hepatitis,[14] partial hepatectomy,[10] muscle degeneration,[14] skin injury,[12][14][18] stroke[11] and spinal cord injury.[19]
Non-tumorigenicity
Low telomerase activity
Muse cells are characterized by low telomerase activity, a strong indicator of tumorigenicity. Hela cells and human fibroblast-derived iPS cells showed high telomerase activity while Muse were at nearly the same level as that in somatic cells such as fibroblasts. This indicates the non-tumorigenic nature of Muse cells.[1][6][9]
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.[16] 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.[20]
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.[14] Thus, Muse cells are pluripotent but are non-tumorigenic.[citation needed] Similarly, epiblast stem cells cultured under certain conditions also do not form teratomas in testes,[citation needed] even though they show pluripotency in vitro.[21] Thus, pluripotent stem cells do not always show teratoma formation when transplanted in vivo.[citation needed]
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 wit fulminant hepatitis,[14] partial hepatectomy,[10] muscle degeneration,[14] skin injury,[12][14][18] stroke[11] and spinal cord injury.[19] Infused Muse cells integrated into each damaged tissue and differentiated into human albumin- and human anti-trypsin-expressing hepatocytes in the liver,[14] human dystrophin-expressing cells in the muscle,[14] neurofilament and MAP-2-expressing neuronal cells in the spinal cord [19] and stroke,[11] and cytokerain14-expressing epidermal cells in the skin,[12][14][18] 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.[22][unreliable medical source?] 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 Corporation Group, have established a cell-processing procedure that is compliant with the Japansese 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.[23]
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,[14] dermis [16] and adipose tissue.[24] 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][2][3][4]
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.[citation needed]
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.[1][6][7]
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).[19]
Self-renewal
Muse cells are able to self-renew, maintaining their proliferative activity, pluripotency marker expression and a normal karyotype.[19]
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[7] 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.[2]
- 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.[6][7]
- 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.[25]
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:
- Preparation of mesenchymal cells from either dermal fibroblasts or fresh bone marrow-derived mononuclear cells.
- Isolation of Muse cells by FACS as cells positive for SSEA-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.[14]
- 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.[24]
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:
- 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.
- Basic expression level of pluripotency genes in non-Muse cells is very low or undetectable level compared to Muse cells.[16]
- 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.[26] 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.[15][16]
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.[17]
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%).[19] 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.[27]
- 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.[28] Therefore, if Muse cells were purified or enriched, the effectiveness of currently performed MSC transplantation is expected to see vast improvements.[3]
- 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.
- Currently, Life Science Institute, Inc. and its parent company, Mitsubishi Chemical Holdings Corporation Group, have established a cell-processing procedure that is compliant with the Japansese 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.[23]
See also
Further reading
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