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1.
Biochim Biophys Acta Mol Basis Dis ; 1867(2): 166014, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232817

RESUMO

The coronavirus disease 2019 (COVID-19) has been threatening the globe since the end of November 2019. The disease revealed cracks in the health care system as health care providers across the world were left without guidelines on definitive usage of pharmaceutical agents or vaccines. The World Health Organization (WHO) declared COVID-19 as a pandemic on the 11th of March 2020. Individuals with underlying systemic disorders have reported complications, such as cytokine storms, when infected with the virus. As the number of positive cases and the death toll across the globe continue to rise, various researchers have turned to cell based therapy using stem cells to combat COVID-19. The field of stem cells and regenerative medicine has provided a paradigm shift in treating a disease with minimally invasive techniques that provides maximal clinical and functional outcome for patients. With the available evidence of immunomodulatory and immune-privilege actions, mesenchymal stem cells (MSCs) can repair, regenerate and remodulate the native homeostasis of pulmonary parenchyma with improved pulmonary compliance. This article revolves around the usage of novel MSCs therapy for combating COVID-19.


Assuntos
/epidemiologia , Síndrome da Liberação de Citocina/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Pandemias , /imunologia , /imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/patologia
2.
Lab Med ; 52(1): 24-35, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32729620

RESUMO

The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.


Assuntos
/patologia , Síndrome da Liberação de Citocina/prevenção & controle , Transplante de Células-Tronco Mesenquimais/métodos , /patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , /mortalidade , Estado Terminal , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Progressão da Doença , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
3.
Life Sci ; 263: 118588, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33049279

RESUMO

The severe acute respiratory syndrome-novel coronavirus mediated COVID-19 has been recently declared a pandemic by the World Health Organization. The primary target of the SARS-CoV-2 virus is the human lungs governed by the ACE-2 receptor of epithelial type II cells/endothelial cells, which promote modulation of the immune response of host cells through generating cytokine storm, inflammation, severe pneumonia symptoms, and secondary complications such as acute respiratory distress syndrome. Although numerous antiviral and anti-parasitic drugs are under clinical trials to combat this pandemic, to date, neither a specific treatment nor any successful vaccine has been established, urging researchers to identify any potential candidate for combating the disease. Mesenchymal stem cells own self-renewal, differentiation, homing, immunomodulation and remains unaffected by the coronavirus on the virtue of the absence of ACE-2 receptors, indicating that MSC's could be used an ameliorative approach for COVID-19. MSCs have shown to combat the disease via various pathways such as repairing the lung epithelial and endothelial cells, reducing hyperimmune response, maintaining the renin-angiotensin system. Although MSCs-based treatment approaches for COVID-19 is still under consideration with limited data, many human clinical trials of MSC's has been initiated to explore their potential for COVID 19 treatment. The current review summarizes and emphasizes on how MSC's modulate the immune response, can repair the lungs from the impact of the virus, and various aspects of MSC's as a remedial source for COVID-19, to provide better insight for biomedical researchers and for those who are fascinated by stem cells as a therapeutic approach.


Assuntos
/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Animais , Células Endoteliais/imunologia , Células Epiteliais/imunologia , Humanos , Imunomodulação/fisiologia , Pulmão/imunologia , Pulmão/virologia , Células-Tronco Mesenquimais/imunologia , Regeneração/fisiologia , /isolamento & purificação
4.
PLoS One ; 15(10): e0240319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33021986

RESUMO

Human mesenchymal stem/stromal cells (hMSCs) are a promising therapy for acute respiratory distress syndrome (ARDS) and other inflammatory conditions. While considerable research has focused on paracrine effects and mitochondrial transfer that improve lung fluid balance, hMSCs are well known to have immunomodulatory properties as well. Some of these immunomodulatory properties have been related to previously reported paracrine effectors such as indoleamine-2,3-dioxygenase (IDO), but these effects cannot fully account for cell-contact dependent immunomodulation. Here, we report that CD40 is upregulated on hMSCs under the same conditions previously reported to induce IDO. Further, CD40 transcription is also upregulated on hMSCs by ARDS pulmonary edema fluid but not by hydrostatic pulmonary edema fluid. Transcription of CD40, as well as paracrine effectors TSG6 and PTGS2 remained significantly upregulated for at least 12 hours after withdrawal of cytokine stimulation. Finally, induction of this immune phenotype altered the transdifferentiation of hMSCs, one of their hallmark properties. CD40 may play an important role in the immunomodulatory effects of hMSCs in ARDS and inflammation.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Antígenos CD40/genética , Citocinas/farmacologia , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/citologia , /terapia , Moléculas de Adesão Celular/genética , Transdiferenciação Celular , Células Cultivadas , Ciclo-Oxigenase 2/genética , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Transcrição Genética , Regulação para Cima
5.
Life Sci ; 262: 118493, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32979360

RESUMO

The outbreak of COVID-19 in December 2019, has become an urgent and serious public health emergency. At present, there is no effective treatment or vaccine for COVID-19. Therefore, there is a crucial unmet need to develop a safe and effective treatment for COVID-19 patients. Mesenchymal stem cells (MSCs) are widely used in basic science and in a variety of clinical trials. MSCs are able to engraft to the damaged tissues after transplantation and promote tissue regeneration, besides MSCs able to secrete immunomodulatory factors that suppress the cytokine storms. Moreover, the contribution of MSCs to prevent cell death and inhibit tissue fibrosis is well established. In the current review article, the potential mechanisms by which MSCs contribute to the treatment of COVID-19 patients are highlighted. Also, current trials that evaluated the potential of MSC-based treatments for COVID-19 are briefly reviewed.


Assuntos
/imunologia , Imunomodulação/fisiologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , /imunologia , Humanos
6.
Hum Cell ; 33(4): 907-918, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32780299

RESUMO

Acute respiratory distress syndrome (ARDS) is the main cause for the COVID-19 infection-related morbidity and mortality. Recent clinical evidences suggest increased level of cytokines and chemokines targeting lung tissue as a prominent etiological factor. The immunomodulatory effect of mesenchymal stem cells (MSCs) as the alternative therapy for the treatment of inflammatory and autoimmune diseases is well known. Several studies have also revealed that similar therapeutic impacts of parent MSCs are also exhibited by MSCs-derived extracellular vesicles (EVs) including exosomes. In this review, we explored the therapeutic potential of both MSCs and exosomes in mitigating the COVID-19 induced cytokine storm as well as promoting the regeneration of alveolar tissue, attributed to the intrinsic cytokines and growth factor present in the secretome. The preliminary studies have demonstrated the safety and efficacy of MSCs and exosomes in mitigating symptoms associated with COVID-19. Thus, they can be used on compassionate basis, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of COVID-19. However, more preclinical and clinical studies are warranted to understand their mechanism of action and further establish their safety and efficacy.


Assuntos
Infecções por Coronavirus/terapia , Exossomos , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/terapia , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Células-Tronco Mesenquimais/imunologia , Pandemias , Pneumonia Viral/etiologia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , /mortalidade , /terapia
7.
Nat Immunol ; 21(9): 974-982, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32747813

RESUMO

Mesenchymal cells are mesoderm-derived stromal cells that are best known for providing structural support to organs, synthesizing and remodeling the extracellular matrix (ECM) and regulating development, homeostasis and repair of tissues. Recent detailed mechanistic insights into the biology of fibroblastic mesenchymal cells have revealed they are also significantly involved in immune regulation, stem cell maintenance and blood vessel function. It is now becoming evident that these functions, when defective, drive the development of complex diseases, such as various immunopathologies, chronic inflammatory disease, tissue fibrosis and cancer. Here, we provide a concise overview of the contextual contribution of fibroblastic mesenchymal cells in physiology and disease and bring into focus emerging evidence for both their heterogeneity at the single-cell level and their tissue-specific, spatiotemporal functional diversity.


Assuntos
Matriz Extracelular/metabolismo , Fibroblastos/imunologia , Inflamação/imunologia , Células-Tronco Mesenquimais/imunologia , Neoplasias/imunologia , Animais , Fibrose , Homeostase , Humanos , Imunidade , Imunomodulação , Neoplasias/patologia , Especificidade de Órgãos
8.
Life Sci ; 259: 118218, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32784057

RESUMO

AIMS: The balance between various CD4+ T cell subsets through highly regulated differentiation of naïve T cells is critical to ensure proper immune response, disruption of which may cause autoimmunity and cancers. miR-10a has been reported to regulate the fate of naïve T cells. Mesenchymal stem cells (MSC) derived exosomes are known effective immunomodulators and ideal vehicles for delivery of microRNAs. This study was aimed to examine the impacts of miR-10a on CD4+ cell fate upon exosomal delivery in combination with immunomodulatory effects of MSCs. MAIN METHODS: Exosomes isolated form adipose tissue derived mesenchymal stem cells (AD-MSC-Exo) were transfected with miR-10a and added to naïve T cells purified from mouse spleen. AD-MSC-Exos were characterized and the efficacy of miR-10a delivery was evaluated. The expression levels of T-bet, GATA3, RORγt, and Foxp3 and the secreted levels of IFN-γ, IL-4, IL-17, and TGF-ß respectively specific to Th1, Th2, Th17 and Treg, were assessed by qPCR and ELISA. KEY FINDINGS: Being transferred by AD-MSC-Exo, miR-10a was effectively induced in CD4+ T cells. Upon treatment with miR-10a loaded exosomes, the expression levels of RORγt and Foxp3 were enhanced and that of T-bet was reduced. Similarly, the secreted levels of IL-17, and TGF-ß were increased and that of IFN-γ was decreased. SIGNIFICANCE: Our data indicate that miR-10a loaded exosomes, promote Th17 and Tregs response while reduce that of Th1. Promotion of both Th17 and Tregs in concert, mediated by the combined effect of miR-10a and MSC-Exo, indicate new therapeutic potentials, particularly in line with novel anti-tumor immunotherapeutic strategies.


Assuntos
Exossomos/imunologia , Células-Tronco Mesenquimais/imunologia , MicroRNAs/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adiposidade/fisiologia , Adulto , Animais , Diferenciação Celular/fisiologia , Técnicas de Cocultura , Exossomos/genética , Feminino , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/citologia , Células Th17/classificação
9.
Cell Transplant ; 29: 963689720940719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841042

RESUMO

Coronavirus disease 2019 or COVID-19 is highly infectious, which can lead to acute and chronic debilitating symptoms, as well as mortality. The advent of safe and effective vaccines or antiviral drugs remains distant in the future. Practical public health measures, such as social distancing, hand washing, and wearing a face mask, are the current recommended guidelines by the Centers for Disease Control and Prevention for limiting the spread of the virus. Weakened immune system and aberrant inflammation represent a major pathological symptom of COVID-19 patients. Based on the unique immunomodulatory properties of both convalescent plasma and stem cells, we discuss here their potential use for treating COVID-19.


Assuntos
Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/terapia , Anticorpos Neutralizantes/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Humanos , Imunização Passiva/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Prática de Saúde Pública , Carga Viral
10.
Cell Transplant ; 29: 963689720952089, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32830527

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, originating from Wuhan, China, is known to cause severe acute respiratory symptoms. The occurrence of a cytokine storm in the lungs is a critical step in the disease pathogenesis, as it causes pathological lesions, pulmonary edema, and acute respiratory distress syndrome, potentially resulting in death. Currently, there is no effective treatment that targets the cytokine storm and helps regenerate the damaged tissue. Mesenchymal stem cells (MSCs) are known to act as anti-inflammatory/immunomodulatory candidates and activate endogenous regeneration. As a result, MSC therapy is a potential treatment approach for COVID-19. Intravenous injection of clinical-grade MSCs into COVID-19 patients can induce an immunomodulatory response along with improved lung function. Dental pulp stem cells (DPSCs) are considered a potential source of MSCs for immunomodulation, tissue regeneration, and clinical application. Although some current clinical trials have treated COVID-19 patients with DPSCs, this therapy has not been approved. Here, we review the potential use of DPSCs and their significance in the development of a therapy for COVID-19.


Assuntos
Infecções por Coronavirus/terapia , Polpa Dentária/citologia , Imunomodulação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Pneumonia Viral/terapia , Betacoronavirus/imunologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Polpa Dentária/imunologia , Humanos , Imunoterapia/métodos , Inflamação/imunologia , Inflamação/terapia , Pulmão/imunologia , Pulmão/fisiologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/terapia , Células-Tronco Mesenquimais/citologia , Pandemias , Pneumonia Viral/imunologia , Regeneração
11.
Sci Rep ; 10(1): 10740, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612100

RESUMO

Extracellular vesicles derived from mesenchymal stem cells (MSCs) represent a novel approach for regenerative and immunosuppressive therapy. Recently, cytochalasin B-induced microvesicles (CIMVs) were shown to be effective drug delivery mediators. However, little is known about their immunological properties. We propose that the immunophenotype and molecular composition of these vesicles could contribute to the therapeutic efficacy of CIMVs. To address this issue, CIMVs were generated from murine MSC (CIMVs-MSCs) and their cytokine content and surface marker expression determined. For the first time, we show that CIMVs-MSCs retain parental MSCs phenotype (Sca-1+, CD49e+, CD44+, CD45-). Also, CIMVs-MSCs contained a cytokine repertoire reflective of the parental MSCs, including IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12(p40), IL-13, IL-17, CCL2, CCL3, CCL4, CCL5, CCL11, G-CSF, GM-CSF and TNF-α. Next, we evaluated the immune-modulating properties of CIMVs-MSCs in vivo using standard preclinical tests. MSCs and CIMVs-MSCs reduced serum levels of anti-sheep red blood cell antibody and have limited effects on neutrophil and peritoneal macrophage activity. We compared the immunomodulatory effect of MSCs, CIMVs and EVs. We observed no immunosuppression in mice pretreated with natural EVs, whereas MSCs and CIMVs-MSCs suppressed antibody production in vivo. Additionally, we have investigated the biodistribution of CIMVs-MSCs in vivo and demonstrated that CIMVs-MSCs localized in liver, lung, brain, heart, spleen and kidneys 48 h after intravenous injection and can be detected 14 days after subcutaneous and intramuscular injection. Collectively our data demonstrates immunomodulatory efficacy of CIMVs and supports their further preclinical testing as an effective therapeutic delivery modality.


Assuntos
Micropartículas Derivadas de Células/imunologia , Citocalasina B/farmacologia , Citocinas/imunologia , Vesículas Extracelulares/imunologia , Imunossupressores/farmacologia , Macrófagos Peritoneais/imunologia , Células-Tronco Mesenquimais/imunologia , Animais , Micropartículas Derivadas de Células/efeitos dos fármacos , Células Cultivadas , Vesículas Extracelulares/efeitos dos fármacos , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos
12.
Front Immunol ; 11: 1563, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719683

RESUMO

COVID-19 is a disease characterized by a strong inflammatory response in severe cases, which fails to respond to corticosteroid therapy. In the context of the current COVID-19 outbreak and the critical information gaps regarding the disease, several different therapeutic strategies are under investigation, including the use of stem cells. In the present manuscript, we provide an analysis of the rationale underlying the application of stem cells to manage COVID-19, and also a comprehensive compendium of the 69 clinical trials underway worldwide aiming to investigate the application of stem cells to treat COVID-19. Even though data are still scarce, it is already possible to observe the protagonism of China in testing mesenchymal stem cells (MSCs) for COVID-19. Furthermore, it is possible to determine that current efforts focus on the use of multiple infusions of high numbers of stem cells and derived products, as well as to acknowledge the positive results obtained by independent groups who publicized the therapeutic benefits provided by such therapies in 51 COVID-19 patients. In such a rapid-paced field, up-to-date systematic studies and meta-analysis will aid the scientific community to separate hype from hope and offer an unbiased position to the society and governments.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus , Surtos de Doenças , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Pandemias , Pneumonia Viral , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia
13.
Sci Rep ; 10(1): 10142, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576889

RESUMO

Bone marrow mesenchymal stromal cells (MSCs) have been studied for decades as potent immunomodulators. Clinically, they have shown some promise but with limited success. Here, we report the ability of a scalable hollow fiber bioreactor to effectively maintain ideal MSC function as a single population while also being able to impart an immunoregulatory effect when cultured in tandem with an inflamed lymphocyte population. MSCs were seeded on the extraluminal side of hollow fibers within a bioreactor where they indirectly interact with immune cells flowing within the lumen of the fibers. MSCs showed a stable and predictable metabolite and secreted factor profile during several days of perfusion culture. Exposure of bioreactor-seeded MSCs to inflammatory stimuli reproducibly switched MSC secreted factor profiles and altered microvesicle composition. Furthermore, circulating, activated human peripheral blood mononuclear cells (PBMCs) were suppressed by MSC bioreactor culture confirmed by a durable change in their immunophenotype and function. This platform was useful to study a model of immobilized MSCs and circulating immune cells and showed that monocytes play an important role in MSC driven immunomodulation. This coculture technology can have broad implications for use in studying MSC-immune interactions under flow conditions as well as in the generation of ex vivo derived immune cellular therapeutics.


Assuntos
Reatores Biológicos , Técnicas de Cultura de Células/métodos , Técnicas de Reprogramação Celular/métodos , Imunomodulação/imunologia , Linfócitos/imunologia , Células-Tronco Mesenquimais/imunologia , Células da Medula Óssea , Células Cultivadas , Reprogramação Celular , Humanos , Leucócitos Mononucleares/imunologia
14.
Tissue Cell ; 64: 101330, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32473704

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent, genomic stable, self-renewable, and culturally expandable adult stem cells. MSCs facilitate tissue development, maintenance and repair, and produce secretory factors that support engraftment and trophic functions, marking them an attractive option in cell therapy, regenerative medicine and tissue engineering. METHOD: In this review, we summarize the recent researches regarding the isolation and characterization of MSCs, therapeutic applications and advanced engineering techniques. We also discuss the advantages and limitations that remain to be overcome for MSCs based therapy. RESULTS: It has been demonstrated that MSCs are able to modulate endogenous tissue and immune cells. Preclinical studies and early phase clinical trials have shown their great potential for tissue engineering of bone, cartilage, marrow stroma, muscle, fat, and other connective tissues. CONCLUSIONS: MSC-based therapy show considerable promise to rebuild damaged or diseased tissues, which could be a promising therapeutic method for regeneration medicine.


Assuntos
Células-Tronco Mesenquimais , Medicina Regenerativa/métodos , Células-Tronco Adultas , Osso e Ossos/patologia , Anormalidades Cardiovasculares/terapia , Diferenciação Celular , Humanos , Inflamação/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Engenharia Tecidual
15.
Cell Res ; 30(9): 794-809, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32546764

RESUMO

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from that of umbilical cord mesenchymal stem cells (UCMSCs), such as higher expression levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and the FDA-approved drug pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury and acute respiratory distress syndrome, our findings suggest that IMRCs are ready for clinical trials on lung disorders.


Assuntos
Células-Tronco Embrionárias Humanas/imunologia , Lesão Pulmonar/terapia , Pulmão/patologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Animais , Células Cultivadas , Feminino , Fibrose , Haplorrinos , Células-Tronco Embrionárias Humanas/citologia , Humanos , Imunidade , Imunomodulação , Pulmão/imunologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL
16.
Eur J Immunol ; 50(10): 1571-1579, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32441311

RESUMO

Tissue-resident memory (Trm) cells are specialized components of both CD4+ and CD8+ T cell subsets that persist in peripheral nonlymphoid tissues following infections and provide fast response in case of a secondary invasion by the same pathogen. Trm cells express the surface markers CD69, CD103, and the immune checkpoint molecule PD-1. Trm cells develop not only in the context of infections but also in tumors, where they can provide a line of defense as suggested by the positive correlation between the frequency of tumor-infiltrating Trm cells and patients' survival. Trm cells persistence in peripheral tissues depends on their adaptation to the local microenvironment and the presence of survival factors, mainly IL-7, IL-15, and Notch ligands. However, the cell sources of these factors are largely unknown, especially in the context of tumors. Here, we show that head-neck squamous cell carcinoma (HNSCC) is enriched in CD4+ and CD8+ T cells with a Trm phenotype. Moreover, we show that mesenchymal stromal cells that accumulate in HNSCC are a source of survival factors and allow proper expression of Trm-typical markers in a VCAM1-dependent manner.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Linfócitos do Interstício Tumoral/imunologia , Células-Tronco Mesenquimais/imunologia , Comunicação Celular , Movimento Celular , Células Cultivadas , Humanos , Memória Imunológica , Interleucina-15/metabolismo , Interleucina-7/metabolismo , Fenótipo , Receptores Notch/metabolismo , Microambiente Tumoral , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
Acta Biochim Biophys Sin (Shanghai) ; 52(6): 654-664, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32372074

RESUMO

In the current study, we aimed to investigate the effects of miR-155 on CD4+ T cell-mediated immune response in the pathogenesis of atherosclerosis. CD34+ hematopoietic stem cells, CD4+ T lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs) were harvested from the same donor. Knockdown of miR-155 in the CD4+ T cells was achieved by lentiviral transfection, whereas control RNA-transfected or untransfected lymphocytes were used as controls. The transfected CD4+ T cells were activated by incubating with oxidized low-density lipoprotein-treated dendritic cells. The proliferative capacities, phenotype distribution, and cytokine secretion profiles of the activated CD4+ T cells from different groups were evaluated. The activated lymphocytes were used to treat ECs co-cultivated with VSMCs. The ability of the CD4+ T cells to induce the apoptosis of the ECs and to promote the proliferation of the VSMCs was investigated. Inhibition of miR-155 was found to significantly reduce the proliferation rate of the transfected CD4+ T cells. CD4+ T lymphocytes transfected with the miR-155 inhibitor showed increased populations of T helper type 2 and regulatory T cells, as well as more production of anti-inflammatory cytokines. MiR-155 knockdown was also shown to significantly hamper the ability to CD4+ T cells to induce EC apoptosis and to promote the growth of VSMCs. Our data suggested that inhibition of miR-155 in CD4+ T cells could slow down the formation of atherosclerotic plaques. These results lay the groundwork for future research on the therapeutic potential of miR-155 against atherosclerosis-associated cardiovascular diseases.


Assuntos
Apoptose/imunologia , Aterosclerose/imunologia , Células Endoteliais/imunologia , MicroRNAs/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Apoptose/genética , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/patologia , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , MicroRNAs/genética , Linfócitos T Reguladores/patologia , Células Th2/patologia
18.
Stem Cell Res Ther ; 11(1): 207, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32460839

RESUMO

The novel coronavirus disease 2019 (COVID-19) has grown to be a global public health emergency since patients were first detected in Wuhan, China. Thus far, no specific drugs or vaccines are available to cure the patients with COVID-19 infection. The immune system and inflammation are proposed to play a central role in COVID-19 pathogenesis. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. Intravenous infusion of MSCs has shown promising results in COVID-19 treatment. Here, we report a case of a severe COVID-19 patient treated with human umbilical cord Wharton's jelly-derived MSCs (hWJCs) from a healthy donor in Liaocheng People's Hospital, China, from February 24, 2020. The pulmonary function and symptoms of the patient with COVID-19 pneumonia was significantly improved in 2 days after hWJC transplantation, and recovered and discharged in 7 days after treatment. After treatment, the percentage and counts of lymphocyte subsets (CD3+, CD4+, and CD8+ T cell) were increased, and the level of IL-6, TNF-α, and C-reactive protein is significantly decreased after hWJC treatment. Thus, the intravenous transplantation of hWJCs was safe and effective for the treatment of patients with COVID-19 pneumonia, especially for the patients in a critically severe condition. This report highlights the potential of hWJC infusions as an effective treatment for COVID-19 pneumonia.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Pneumonia Viral/terapia , Betacoronavirus/genética , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Humanos , Imunomodulação , Infusões Intravenosas , Interleucina-6/sangue , Interleucina-6/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/virologia , Masculino , Células-Tronco Mesenquimais/imunologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Cordão Umbilical/citologia , Cordão Umbilical/imunologia , Geleia de Wharton/citologia , Geleia de Wharton/imunologia
19.
Hum Cell ; 33(3): 444-458, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32378164

RESUMO

Mesenchymal stem cells (MSCs) possess the capabilities of self-renewal and multipotent differentiation. Firstly isolated from bone marrow, MSCs are subsequently identified from various post-natal tissue types. Based the differentiation into tissue-specific cells, MSCs were capable of replacing damaged and diseased tissues. In addition, MSCs have been demonstrated to possess important immunomodulatory properties. Increasing data showed that MSCs exhibited tropism for sites of the tumor microenvironment and interacted with tumor cells closely through paracrine signaling. Therefore, better understanding of crosstalk between MSCs and tumor cells will be able to develop potential strategies in the treatment of tumors in the future. Herein, we summarize the research progress of the influence of MSCs on tumor cells and the prospect of their application in tumor therapy in this review.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Neoplasias/terapia , Microambiente Tumoral/fisiologia , Células da Medula Óssea , Comunicação Celular , Diferenciação Celular , Imunomodulação , Células-Tronco Mesenquimais/imunologia
20.
Hum Cell ; 33(3): 470-475, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32447573

RESUMO

Osteoarthritis is a chronic degenerative joint disease with an incidence of 81% among people aged over 65 years in China. Osteoarthritis significantly decreases the quality of life of patients, causing physical and psychological damage and posing a serious economic burden. Clinical treatments for osteoarthritis include drug and surgical treatments. Drug treatment can successfully alleviate pain but not satisfactorily reverse joint damage, while surgical intervention is typically used to treat end-stage disease. Stem cells are multi-potential progenitor cells with self-renewal and multi-lineage differentiation abilities, and can differentiate into many kinds of cells, including chondrocytes. Umbilical cord stem cells, also known as Wharton's jelly mesenchymal stem cells (WJ-MSCs), have become the first choice for cartilage regeneration engineering owing to their availability and convenience of collection. This article reviews the biological characterization of WJ-MSCs in recent years, their advantages compared with other stem cells, and their application in the treatment of osteoarthritis in animal experiments and clinical trials.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Osteoartrite/terapia , Animais , Diferenciação Celular , Células Cultivadas , Sangue Fetal/citologia , Humanos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/fisiologia
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