Intravenously Transplanted Human Multilineage-Differentiating Stress-Enduring Cells Afford Brain Repair in a Mouse Lacunar Stroke Model

Abe, Takatsugu; Aburakawa, Daiki; Niizuma, Kuniyasu; Iwabuchi, Naoya; Kajitani, Takumi; Wakao, Shohei; Kushida, Yoshihiro; Dezawa, Mari; Borlongan, Cesar V.; Tominaga, Teiji

doi:10.1161/strokeaha.119.026589

Cited by 38 publications

(39 citation statements)

References 36 publications

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“…1 a,b). It was also reported that IV-injected Muse cells clearly showed a therapeutic effect in functional recovery of the acute stroke mice model, in a dose-dependent manner 24 . IV-administration has greater advantages over IT-administration because of easy accessibility, less-invasiveness and less-burden for patients.…”

Section: Discussionmentioning

confidence: 92%

“…For ex-vivo dynamics of IV-injection, vehicle (HBSS), Nano-lantern-labeled-MSCs and -Muse cells (1.0 × 10 5 cells/250 μl) were intravenously injected when mice were 14 weeks old. After 7 days, animals were sacrificed under deep anesthesia and analyzed as described previously 24 .…”

Section: Methodsmentioning

confidence: 99%

“…The time point at which mice were unable to roll over within 15 s of being pushed onto their side was recorded as the time of death for sacrifice, at the end-stage (22 weeks-old mice). Each animal was deeply anesthetized by intraperitoneal injection of pentobarbital (20 mg/kg), and then subjected to sampling as described before 24 . Primary antibodies used were: goat anti-GFP antibody (1:500, Abcam, Cambridge, UK); rabbit anti-GFP antibody (1:500, MBL, Woburn, USA); rabbit anti-Iba1 antibody (1:500, Wako, Osaka, Japan); mouse anti-betaIII tubulin (Tuj1) antibody (1:100, Santa Cruz Biotechnology); rabbit anti-glial fibrillary acidic protein (GFAP) antibody (1:500, Dako, Glostrup, Denmark); mouse anti-NeuN antibody (1:100, Millipore, MA, USA); goat anti-vesicular acetylcholine transporter (VAChT) antibody (1:200, Thermo Scientific).…”

Section: Histological Analysismentioning

confidence: 99%

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Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis

Yamashita

Kushida

Wakao

et al. 2020

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 104 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Histological Analysismentioning

confidence: 99%

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Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis

Yamashita

Kushida

Wakao

et al. 2020

Sci Rep

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“…When injected near the postinfarct area in a mouse lacunar stroke model, ∼34% of topically injected human PB-SSEA-3(+) cells expressed the neuronal marker NeuN at 7 d after administration. Similarly, in a mouse lacunar stroke model, locally and intravenously injected human BM- and dermal-Muse cells integrate into the postinfarct tissue and spontaneously differentiate into cells positive for several neuronal markers, including NeuN, at 7 d after administration 12 , 13 , 23 . In the damaged muscle tissue, locally injected human PB-SSEA-3(+) cells expressed satellite cell marker Pax7 and muscle cell marker desmin at 7 d, similar to the spontaneous differentiation of intravenously injected human BM-Muse cells in the mouse muscle degeneration model 3 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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

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“…As in the case with preclinical studies using HIE models, IV administration in rodent lacunar stroke models have shown donor cell migration, differentiation, and engraftment to the peri-infarct area as well as long-term functional recovery. [ 31 ] Clinical trials using IV donor-derived Muse cells (called CL2020 in the clinic) are ongoing for the treatment of myocardial infarction, stroke, and epidermolysis bullosa. Because human Muse cells express human leukocyte antigen (HLA)-G, an inhibitory receptor relevant to immunomodulation in the placenta, allogenic Muse cells may survive in the host tissue long-term without immunosuppression.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Cell-based treatment for perinatal hypoxic-ischemic encephalopathy

2021

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Hypoxic-ischemic encephalopathy (HIE) is a major cause of acute neonatal brain injury and can lead to disabling long-term neurological complications. Treatment for HIE is limited to supportive care and hypothermia within 6 h injury which is reserved for full-term infants. Preclinical studies suggest the potential for cell-based therapies as effective treatments for HIE. Some clinical trials using umbilical cord blood cells, placenta-derived stem cells, mesenchymal stem cells (MSCs), and others have yielded promising results though more studies are needed to optimize protocols and multi-center trials are needed to prove safety and efficacy. To date, the therapeutic effects of most cell-based therapies are hypothesized to stem from the bystander effect of donor cells. Transplantation of stem cells attenuate the aberrant inflammation cascade following HIE and provide a more ideal environment for endogenous neurogenesis and repair. Recently, a subset of MSCs, the multilineage-differentiating stress-enduring (Muse) cells have shown to treat HIE and other models of neurologic diseases by replacing dead or ischemic cells and have reached clinical trials. In this review, we examine the different cell sources used in clinical trials and evaluate the underlying mechanism behind their therapeutic effects. Three databases–PubMed, Web of Science, and ClinicalTrials.gov–were used to review preclinical and clinical experimental treatments for HIE.

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Intravenously Transplanted Human Multilineage-Differentiating Stress-Enduring Cells Afford Brain Repair in a Mouse Lacunar Stroke Model

Cited by 38 publications

References 36 publications

Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis

Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis

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

Cell-based treatment for perinatal hypoxic-ischemic encephalopathy

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