Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 115
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Ther ; 28(1): 100-118, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31607541

RESUMO

Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.

2.
Stroke ; 51(2): 601-611, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31826733

RESUMO

Background and Purpose- Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell-based product CL2020 remain unanswered. Methods- Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5×104 cells/body; medium dose=1×104 cells/body; low dose=5×103 cells/body) at subacute phase (≈9 days after onset) and chronic phase (≈30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed. Results- Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase-treated and chronic-phase-treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase-treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity. Conclusions- Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke.

3.
Brain Nerve ; 71(8): 895-900, 2019 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-31346146

RESUMO

Muse cells are non-tumorigenic reparative endogenous stem cells identified by SSEA-3+. They are pluripotent and are stably mobilized from the bone marrow to the peripheral blood and distribute to organ connective tissue, where they contribute to daily minute repair of damaged/lost cells by spontaneous differentiation into tissue-constituent cells. Muse cells specifically home to damaged site to repair the tissue by simultaneous differentiation into multiple tissue-constituent cells. When the number of endogenous Muse cells is not sufficient, administration of exogenous Muse cells delivers robust functional recovery. Muse cells do not need to be "induced" or genetically manipulated. Intravenous drip is the main method of administration, making surgical operation unnecessary. Because Muse cells have an immunomodulatory system similar to the placenta, donor-derived Muse cells can be directly administered to patients without HLA-matching or immunosuppression therapy. Allogeneic Muse cells remain in the host tissue as differentiated cells for more than half a year. Clinical trials for the treatment of myocardial infarction, stroke and epidermolysis bullosa with intravenous injection of donor-derived Muse cells are currently conducted by the Life Science Institute Inc. Muse cells may safely provide clinically relevant effects compatible with the 'body's natural repair systems' by a simple cost-effective strategy.


Assuntos
Infusões Intravenosas , Células-Tronco Pluripotentes/citologia , Medicina Regenerativa , Transplante de Células-Tronco , Diferenciação Celular , Humanos
4.
Hypertension ; 73(6): 1283-1290, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31006333

RESUMO

Peripheral 18-oxocortisol (18oxoF) level could contribute to the detection of aldosterone-producing adenoma (APA) in patients with primary aldosteronism. However, peripheral 18oxoF varies among such patients, which is a big drawback concerning its clinical application. We studied 48 cases of APA, 35 harboring KCNJ5 mutation, to clarify the significance of clinical and pathological parameters about peripheral 18oxoF. Peripheral 18oxoF concentration ranged widely from 0.50 to 183.13 ng/dL and correlated positively with intratumoral areas stained positively for steroidogenic enzymes ( P<0.0001). The peripheral 18oxoF level also correlated significantly with that of circulating aldosterone ( P<0.0001) but not with that of cortisol, a precursor of 18oxoF. However, a significant correlation was detected between peripheral 18oxoF and intratumoral glucocorticoids ( P<0.05). In addition, peripheral 18oxoF correlated positively with the number of hybrid cells double positive for 11ß-hydroxylase and aldosterone synthase ( P<0.0001). Comparing between the cases with and those without KCNJ5 mutation, the KCNJ5-mutated group demonstrated a significantly higher concentration of peripheral 18oxoF (28.4±5.6 versus 3.0±0.9 ng/dL, P<0.0001) and a larger intratumoral environment including the hybrid cells ( P<0.001), possibly representing a deviation from normal aldosterone biosynthesis. After multivariate analysis, KCNJ5 mutation status turned out to be the most associated factor involved in 18oxoF synthesis in APA ( P<0.0001). Results of our present study first revealed that enhanced 18oxoF synthesis in APA could come from a functional deviation of aldosterone biosynthesis from the normal zona glomerulosa and the utility of peripheral 18oxoF measurement could be influenced by the prevalence of KCNJ5 mutation in an APA.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , DNA de Neoplasias/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Hidrocortisona/análogos & derivados , Mutação/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Análise Mutacional de DNA , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Hidrocortisona/biossíntese , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
Cell Transplant ; 28(7): 907-923, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30997834

RESUMO

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

6.
Glia ; 67(5): 950-966, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30637802

RESUMO

Direct conversion is considered a promising approach to obtain tissue-specific cells for cell therapies; however, this strategy depends on exogenous gene expression that may cause undesired adverse effects such as tumorigenesis. By optimizing the Schwann cell induction system, which was originally developed for trans-differentiation of bone marrow mesenchymal stem cells into Schwann cells, we established a system to directly convert adult human skin fibroblasts into cells comparable to authentic human Schwann cells without gene introduction. Serial treatments with beta-mercaptoethanol, retinoic acid, and finally a cocktail of basic fibroblast growth factor, forskolin, platelet-derived growth factor-AA, and heregulin-ß1 (EGF domain) converted fibroblasts into cells expressing authentic Schwann cell markers at an efficiency of approximately 75%. Genome-wide gene expression analysis suggested the conversion of fibroblasts into the Schwann cell-lineage. Transplantation of induced Schwann cells into severed peripheral nerve of rats facilitated axonal regeneration and robust functional recovery in sciatic function index comparable to those of authentic human Schwann cells. The contributions of induced Schwann cells to myelination of regenerated axons and re-formation of neuromuscular junctions were also demonstrated. Our data clearly demonstrated that cells comparable to functional Schwann cells feasible for the treatment of neural disease can be induced from adult human skin fibroblasts without gene introduction. This direct conversion system will be beneficial for clinical applications to peripheral and central nervous system injuries and demyelinating diseases.


Assuntos
Diferenciação Celular/fisiologia , Fibroblastos/fisiologia , Traumatismos dos Nervos Periféricos/cirurgia , Recuperação de Função Fisiológica/fisiologia , Células de Schwann/fisiologia , Células de Schwann/transplante , Animais , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Humanos , Locomoção/fisiologia , Masculino , Microscopia Eletrônica , Proteína P0 da Mielina/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição SOXE/metabolismo , Células de Schwann/ultraestrutura , Soro/fisiologia , Pele/citologia , Fatores de Tempo , Tretinoína/farmacologia
7.
Adv Exp Med Biol ; 1103: 1-11, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30484221

RESUMO

Multilineage-differentiating stress-enduring (Muse) cells, identified as cells positive for the pluripotent marker stage-specific embryonic antigen (SSEA-3+), were discovered as stress-tolerant pluripotent stem cells from among mesenchymal stem cells (MSCs) and fibroblasts, as well as from the adult human bone marrow mononucleated fraction. MSCs are a crude population of cells that differentiate into multiple cell types covering all three germ layers in low proportion and were thus deduced to contain a genuine pluripotent stem cell subpopulation. Muse cells constitute several percent of MSCs and 1 of ~3000 bone marrow mononucleated cells. They exhibit pluripotent gene expression as well as trilineage differentiation and self-renewal capabilities at the single-cell level, while, in contrast, MSC cells other than Muse cells do not exhibit these characteristics. These characteristics indicate that Muse cells correspond to the subpopulation of MSC cells responsible for the pluripotent aspect of MSCs. In addition to their pluripotency, Muse cells play an important role in vivo as endogenous stem cells that contribute to tissue homeostasis through daily reparative maintenance and to tissue reconstruction through their unique reparative functions following serious tissue damage. This chapter describes how my research team discovered Muse cells.


Assuntos
Linhagem da Célula , Células-Tronco Mesenquimais/citologia , Células-Tronco Pluripotentes/citologia , Estresse Fisiológico , Diferenciação Celular , Fibroblastos/citologia , Humanos
8.
Adv Exp Med Biol ; 1103: 13-41, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30484222

RESUMO

Multilineage-differentiating stress-enduring (Muse) cells exhibit the core characteristics of pluripotent stem cells, namely, the expression of pluripotency markers and the capacity for trilineage differentiation both in vitro and in vivo and self-renewability. In addition, Muse cells have unique characteristics not observed in other pluripotent stem cells such as embryonic stem cells, control of pluripotency by environmental switch of adherent suspension, symmetric and asymmetric cell division, expression of factors relevant to stress tolerance, and distinctive tissue distribution. Pluripotent stem cells were recently classified into two discrete states, naïve and primed. These two states have multiple functional differences, including their proliferation rate, molecular properties, and growth factor dependency. The properties exhibited by Muse cells are similar to those of primed pluripotent stem cells while with some uniqueness. In this chapter, we provide a comprehensive description of the basic characteristics of Muse cells.


Assuntos
Linhagem da Célula , Células-Tronco Pluripotentes/citologia , Estresse Fisiológico , Diferenciação Celular , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia
9.
Adv Exp Med Biol ; 1103: 43-68, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30484223

RESUMO

The dynamics and actions of Muse cells at a time of physical crisis are unique and highly remarkable compared with other stem cell types. When the living body is in a steady state, low levels of Muse cells are mobilized to the peripheral blood, possibly from the bone marrow, and supplied to the connective tissue of nearly every organ. Under conditions of serious tissue damage, such as acute myocardial infarction and stroke, Muse cells are highly mobilized to the peripheral blood, drastically increasing their numbers in the peripheral blood within 24 h after the onset of tissue injury. The alerting signal, sphingosine-1-phosphate, attracts Muse cells to the damaged site mainly via the sphingosine-1-phosphate receptor 2, enabling them to preferentially home to site of injury. After homing, Muse cells spontaneously differentiate into tissue-compatible cells and replenish new functional cells for tissue repair. Because Muse cells have pleiotropic effects, including paracrine, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects, these cells synergistically deliver long-lasting functional and structural recovery. This chapter describes how Muse cells exert their reparative effects in vivo.


Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes/citologia , Regeneração , Ferimentos e Lesões/fisiopatologia , Movimento Celular , Humanos , Lisofosfolipídeos , Receptores de Lisoesfingolipídeo , Esfingosina/análogos & derivados
10.
Adv Exp Med Biol ; 1103: 69-101, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30484224

RESUMO

This chapter provides the detailed method for isolation of Muse cells and evaluation of their pluripotency. The basic population of Muse cells is cultured mesenchymal stem cells such as bone marrow-mesenchymal stem cells, fibroblasts, and adipose-derived stem cells. The detailed method for handling mesenchymal stem cells is also provided in this protocol.


Assuntos
Separação Celular/métodos , Células-Tronco Pluripotentes/citologia , Adipócitos/citologia , Células da Medula Óssea/citologia , Células Cultivadas , Fibroblastos/citologia , Humanos , Células-Tronco Mesenquimais/citologia
11.
Adv Exp Med Biol ; 1103: 305-307, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30484237

RESUMO

Among many kinds of somatic stem cells, hematopoietic stem cells are the cells that have been successfully applied to treating leukemia patients as forms of bone marrow and cord blood transplantation. Mesenchymal stem cells, collectable from several sources including the bone marrow and adipose tissue, are also widely applied to clinical trials for their easy accessibility and low risks of tumorigenesis, while their outcomes were shown to be not clinically relevant in several target diseases. The most important issue for the stem cells is whether the cells are safe and effective for curing diseases. In this chapter, the outline of the clinical trial in Muse cells is discussed.


Assuntos
Células-Tronco Pluripotentes/citologia , Transplante de Células-Tronco , Tecido Adiposo/citologia , Células da Medula Óssea/citologia , Ensaios Clínicos como Assunto , Humanos , Células-Tronco Mesenquimais/citologia
12.
Regen Ther ; 8: 15-19, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30271861

RESUMO

The 16th Congress of the Japanese Society for Regenerative Medicine was held from March 7-9, 2017, at Sendai International Center (Sendai city). The theme of this congress was "the renaissance of regenerative medicine" and it was an opportunity for information exchange between industry-leading researchers, doctors/dentists, and industry professionals. The objectives of the congress were to provide a place to promote and develop research in regenerative medicine. Numerous topics were covered in the 1 presidential lecture, 1 congress chair's lecture, 3 special lectures, the special symposia (2 sessions, 10 topics), symposia (41 sessions, 227 topics), evening symposia (3 sessions, 12 topics), joint symposium with another society (1 session, 4 topics), and presentations covering regular presentations including distinct presentations (oral presentations, 2 sessions, 8 topics), oral presentations (65 sessions, 383 topics), and poster presentations (44 sessions, 339 topics). There were co-organized seminars including 31 sessions for co-organized luncheon seminars, 2 sessions for co-organized evening seminars, and an up-to-date technology introduction corner, which hosted 153 organizations. Additionally, 4 special seminars and 3 hands-on training programs were hosted as part of the hands-on learning program for high school students during the congress. There were 3527 participants, and the event was a great success.

13.
Dev Growth Differ ; 60(6): 326-340, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29984494

RESUMO

Proliferation of ependymal cells of the adult spinal cord (SCEp cells) in the intact condition has been considered as a quite rare event. To visualize proliferating/proliferated SCEp cells, we used the intensive 5-bromo-2'-deoxyuridine (BrdU) administration method to find that about two cells in the ependymal layer incorporated BrdU in a 10-µm-thick section. Because these two cells were not considered to undergo further proliferation, we analyzed the positioning and motility of two neighboring BrdU-incorporated proliferated cells and elucidated the tendency of the movement of SCEp cells to the outer side inside the ependymal layer. Even if it was rare, one of the proliferated cells in the ependymal layer differentiated into astrocytes. Gene introduction of Notch intracellular domain (NICD), a constitutively active form of Notch1, into SCEp cells demonstrated both increase in proliferation and induction of differentiation into astrocytes. Overexpression of Sox2 promoted proliferation in SCEp cells. The reaction of gene introduction of NICD and Sox2 indicates the similarity of intracellular signaling between SCEp cells and neural stem cells. Also, considering the fact that SCEp cells express these two factors in the intact condition, Notch and Sox2 are important for the cell fate control of SCEp cells in the intact condition.


Assuntos
Astrócitos/metabolismo , Diferenciação Celular , Proliferação de Células , Epêndima/metabolismo , Células-Tronco Neurais/metabolismo , Transdução de Sinais/fisiologia , Animais , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/fisiologia , Astrócitos/citologia , Epêndima/citologia , Regulação da Expressão Gênica , Masculino , Células-Tronco Neurais/citologia , Ratos , Ratos Wistar , Fatores de Transcrição SOXB1
14.
Cell Transplant ; 27(6): 979-993, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29707971

RESUMO

Posttransplantation lung ischemia-reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin-eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin-6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury.


Assuntos
Lesão Pulmonar Aguda/terapia , Pulmão/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Traumatismo por Reperfusão/terapia , Lesão Pulmonar Aguda/patologia , Animais , Diferenciação Celular , Linhagem Celular , Sobrevivência Celular , Modelos Animais de Doenças , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
15.
Cell Transplant ; 27(2): 285-298, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29637816

RESUMO

Multilineage-differentiating stress-enduring (Muse) cells are endogenous nontumorigenic stem cells collectable as stage-specific embryonic antigen 3 (SSEA-3) + from various organs including the bone marrow and are pluripotent-like. The potential of human bone marrow-derived Muse cells to commit to cardiac lineage cells was evaluated. We found that (1) initial treatment of Muse cells with 5'-azacytidine in suspension culture successfully accelerated demethylation of cardiac marker Nkx2.5 promoter; (2) then transferring the cells onto adherent culture and treatment with early cardiac differentiation factors including wingless-int (Wnt)-3a, bone morphogenetic proteins (BMP)-2/4, and transforming growth factor (TGF) ß1; and (3) further treatment with late cardiac differentiation cytokines including cardiotrophin-1 converted Muse cells into cardiomyocyte-like cells that expressed α-actinin and troponin-I with a striation-like pattern. MLC2a expression in the final step suggested differentiation of the cells into an atrial subtype. MLC2v, a marker for a mature ventricular subtype, was expressed when cells were treated with Dickkopf-related protein 1 (DKK-1) and Noggin, inhibitors of Wnt3a and BMP-4, respectively, between steps (2) and (3). None of the steps included exogenous gene transfection, making induced cells feasible for future clinical application.


Assuntos
Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes/metabolismo , Antígenos Glicosídicos Associados a Tumores/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Proteína Homeobox Nkx-2.5/metabolismo , Humanos , Miócitos Cardíacos/citologia , Células-Tronco Pluripotentes/citologia , Antígenos Embrionários Estágio-Específicos/metabolismo , Fatores de Crescimento Transformadores/metabolismo
17.
J Thorac Cardiovasc Surg ; 155(6): 2301-2313.e4, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29559260

RESUMO

OBJECTIVES: Aortic aneurysms result from the degradation of multiple components represented by endothelial cells, vascular smooth muscle cells, and elastic fibers. Cells that can replenish these components are desirable for cell-based therapy. Intravenously injected multilineage-differentiating stress-enduring (Muse) cells, endogenous nontumorigenic pluripotent-like stem cells, reportedly integrate into the damaged site and repair the tissue through spontaneous differentiation into tissue-compatible cells. We evaluated the therapeutic efficacy of Muse cells in a murine aortic aneurysm model. METHODS: Human bone marrow Muse cells, isolated as stage-specific embryonic antigen-3+ from bone marrow mesenchymal stem cells, or non-Muse cells (stage-specific embryonic antigen-3- cells in mesenchymal stem cells), bone marrow mesenchymal stem cells, or vehicle was intravenously injected at day 0, day 7, and 2 weeks (20,000 cells/injection) after inducing aortic aneurysms by periaortic incubation of CaCl2 and elastase in severe combined immunodeficient mice. RESULTS: At 8 weeks, infusion of human Muse cells attenuated aneurysm dilation, and the aneurysmal size in the Muse group corresponded to approximately 62.5%, 55.6%, and 45.6% in the non-Muse, mesenchymal stem cell, and vehicle groups, respectively. Multiphoton laser confocal microscopy revealed that infused Muse cells migrated into aneurysmal tissue from the adventitial side and penetrated toward the luminal side. Histologic analysis demonstrated robust preservation of elastic fibers and spontaneous differentiation into endothelial cells and vascular smooth muscle cells. CONCLUSIONS: After intravenous injection, Muse cells homed and expanded to the aneurysm from the adventitial side. Subsequently, Muse cells differentiated spontaneously into vascular smooth muscle cells and endothelial cells, and elastic fibers were preserved. These Muse cell features together led to substantial attenuation of aneurysmal dilation.


Assuntos
Aneurisma Aórtico/cirurgia , Transplante de Medula Óssea , Diferenciação Celular/fisiologia , Células Endoteliais , Animais , Aorta/citologia , Aorta/fisiologia , Células da Medula Óssea/citologia , Movimento Celular , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/transplante , Humanos , Injeções Intravenosas , Camundongos
18.
Circ Res ; 122(8): 1069-1083, 2018 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-29475983

RESUMO

RATIONALE: Multilineage-differentiating stress enduring (Muse) cells, pluripotent marker stage-specific embryonic antigen-3+ cells, are nontumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow. Their therapeutic efficiency has not been validated in acute myocardial infarction. OBJECTIVE: The main objective of this study is to clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells in a rabbit acute myocardial infarction model and their mechanisms of tissue repair. METHODS AND RESULTS: In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with ≈14.5% of injected GFP (green fluorescent protein)-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1PR2 [sphingosine monophosphate receptor 2]-specific antagonist JTE-013 coinjection) and genetically (S1PR2-siRNA [small interfering ribonucleic acid]-introduced Muse cells) to be mediated through the S1P (sphingosine monophosphate)-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin-43, and vascular markers. GCaMP3 (GFP-based Ca calmodulin probe)-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. 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. These effects were partially attenuated by the administration of GATA4-gene-silenced Muse 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. CONCLUSIONS: Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction.


Assuntos
Lisofosfolipídeos/fisiologia , Infarto do Miocárdio/cirurgia , Células-Tronco Pluripotentes/transplante , Receptores de Lisoesfingolipídeo/fisiologia , Esfingosina/análogos & derivados , Aloenxertos , Animais , Autoenxertos , Diferenciação Celular , Movimento Celular/fisiologia , Fator de Transcrição GATA4/antagonistas & inibidores , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/fisiologia , Sobrevivência de Enxerto , Proteínas de Fluorescência Verde/análise , Xenoenxertos , Humanos , Luciferases/análise , Proteínas Luminescentes/análise , Masculino , Infarto do Miocárdio/patologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Coelhos , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/genética , Proteínas Recombinantes de Fusão/análise , Especificidade da Espécie , Esfingosina/fisiologia
19.
Adv Exp Med Biol ; 1103: C1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31236853

RESUMO

The below listed corrections have been carried out in the following pages of the current version.

20.
Circ J ; 82(2): 561-571, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28931784

RESUMO

BACKGROUND: Multilineage differentiating stress-enduring (Muse) cells are SSEA3+and CD105+double-positive pluripotent-like stem cells. We aimed to examine the mobilization of Muse cells into peripheral blood after acute myocardial infarction (AMI) and their effects on left ventricular (LV) function and remodeling.Methods and Results:In 79 patients with AMI, 44 patients with coronary artery disease (CAD), and 64 normal subjects (Control), we measured the number of Muse cells in the peripheral blood by fluorescence-activated cell sorting. Muse cells were measured on days 0, 1, 7, 14, and 21 after AMI. Plasma sphingosine-1-phosphate (S1P) levels were measured. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. Muse cell number on day 1 was significantly higher in the AMI (276±137 cells/100 µL) than in the CAD (167±89 cells/100 µL) and Control (164±125 cells/100 µL) groups. Muse cell number peaked on day 1, and had gradually decreased on day 21. Muse cell number positively correlated with plasma S1P levels. Patients with a higher increase in the number of Muse cells in the peripheral blood but not those with a lower increase in number of Muse cells in the acute phase showed improved LV function and remodeling in the chronic phase. CONCLUSIONS: Endogenous Muse cells were mobilized into the peripheral blood after AMI. The number of Muse cells could be a predictor of prognosis in patients with AMI.


Assuntos
Mobilização de Células-Tronco Hematopoéticas , Infarto do Miocárdio/patologia , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Estudos de Casos e Controles , Contagem de Células , Doença Crônica , Humanos , Lisofosfolipídeos/sangue , Masculino , Pessoa de Meia-Idade , Células-Tronco de Sangue Periférico , Valor Preditivo dos Testes , Prognóstico , Esfingosina/análogos & derivados , Esfingosina/sangue , Células-Tronco , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA