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1.
Signal Transduct Target Ther ; 6(1): 328, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471088

RESUMO

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Microambiente Celular/imunologia , Pulmão/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/patologia , Interferon-alfa/imunologia , Interleucina-6/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360901

RESUMO

The oxidative properties of nanomaterials arouse legitimate concerns about oxidative damage in biological systems. On the other hand, the undisputable benefits of nanomaterials promote them for biomedical applications; thus, the strategies to reduce oxidative potential are urgently needed. We aimed at analysis of nitrogen-containing carbon quantum dots (N-CQDs) in terms of their biocompatibility and internalization by different cells. Surprisingly, N-CQD uptake does not contribute to the increased oxidative stress inside cells and lacks cytotoxic influence even at high concentrations, primarily through protein corona formation. We proved experimentally that the protein coating effectively limits the oxidative capacity of N-CQDs. Thus, N-CQDs served as an immobilization support for three different enzymes with the potential to be used as therapeutics. Various kinetic parameters of immobilized enzymes were analyzed. Regardless of the enzyme structure and type of reaction catalyzed, adsorption on the nanocarrier resulted in increased catalytic efficiency. The enzymatic-protein-to-nanomaterial ratio is the pivotal factor determining the course of kinetic parameter changes that can be tailored for enzyme application. We conclude that the above properties of N-CQDs make them an ideal support for enzymatic drugs required for multiple biomedical applications, including personalized medical therapies.


Assuntos
Biocatálise , Carbono/química , Carbono/farmacologia , Nitrogênio/química , Nitrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Coroa de Proteína/metabolismo , Pontos Quânticos/química , Pontos Quânticos/metabolismo , Células A549 , Animais , Apirase/química , Apirase/farmacologia , Catalase/química , Catalase/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Enzimas Imobilizadas/química , Enzimas Imobilizadas/farmacologia , Células HeLa , Humanos , Ratos , Espécies Reativas de Oxigênio/metabolismo , beta-Galactosidase/química , beta-Galactosidase/farmacologia
3.
Nat Immunol ; 22(9): 1140-1151, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426691

RESUMO

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismo
4.
Biomolecules ; 11(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200257

RESUMO

Water content is an important factor in lipase-catalyzed reactions in organic media but is frequently ignored in the study of lipases by molecular dynamics (MD) simulation. In this study, Candida antarctica lipase B, Candida rugosa lipase and Rhizopus chinensis lipase were used as research models to explore the mechanisms of lipase in micro-aqueous organic solvent (MAOS) media. MD simulations indicated that lipases in MAOS systems showed unique conformations distinguished from those seen in non-aqueous organic solvent systems. The position of water molecules aggregated on the protein surface in MAOS media is the major determinant of the unique conformations of lipases and particularly impacts the distribution of hydrophilic and hydrophobic amino acids on the lipase surface. Additionally, two maxima were observed in the water-lipase radial distribution function in MAOS systems, implying the formation of two water shells around lipase in these systems. The energy landscapes of lipases along solvent accessible areas of catalytic residues and the minimum energy path indicated the dynamic open states of lipases in MAOS systems differ from those in other solvent environments. This study confirmed the necessity of considering the influence of the microenvironment on MD simulations of lipase-catalyzed reactions in organic media.


Assuntos
Microambiente Celular/fisiologia , Biologia Computacional/métodos , Lipase/química , Simulação de Dinâmica Molecular , Água/química , Basidiomycota/química , Basidiomycota/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Lipase/análise , Lipase/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Saccharomycetales/química , Saccharomycetales/metabolismo , Água/metabolismo
5.
J Leukoc Biol ; 110(3): 433-447, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34254348

RESUMO

As one of the first arriving immune cells after dental implantation, Mϕs own the abilities to polarize into to a spectrum of diverse phenotypes, from "classically activated" M1 Mϕs to "alternatively activated" M2 Mϕs. Herein, it was hypothesized that Mϕ phenotypes dynamically adapt after dental implantation, and the changes ensue a cascade of coordinated interplay with the bone-forming osteoblast and the bone-resorbing osteoclast. Results showed that the remodelling process after dental implantation was similar with the standard response to tissue injury (exampled by tooth extraction models), only with the delay of bone regeneration phases. Additionally, Mϕ activation in both groups underwent a transition from M1 Mϕs dominated to M2-type dominated stage, but the persistence of M1 Mϕs occurred in rat model of dental implantation. Further research in vitro showed that M1 Mϕs are involved in osteoclast activities via secreting the highest levels of TNF-α and IL-1ß, as well as being the potential precursor of osteoclasts. Besides, they also recruited BMSCs by secreting the highest levels of chemoattractants, CCL2 and VEGF. M2 Mϕs accelerated osteogenesis in the subsequent stage via their capability to secrete osteogenesis-related proteins, BMP-2 and TGF-ß1. However, the osteogenic differentiation of BMSCs was inhibited when cultured in a high concentration of conditioned media from each Mϕ phenotype, meaning that the immune strategies should be controlled within the proper ranges. These results suggest that coordinated efforts by both M1 and M2 Mϕs for bone remodelling, which may highlight an optimization strategy for tissue engineering implants.


Assuntos
Processo Alveolar/patologia , Remodelação Óssea , Polaridade Celular , Microambiente Celular , Implantação Dentária , Macrófagos/patologia , Animais , Regeneração Óssea , Diferenciação Celular , Proliferação de Células , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Modelos Animais , Osteoclastos/metabolismo , Osteogênese , Fenótipo , Células RAW 264.7 , Ratos Sprague-Dawley , Titânio , Extração Dentária
6.
FEBS Lett ; 595(16): 2147-2159, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245002

RESUMO

Stem cell-based therapy has been highlighted as a potential avenue to promote tissue regeneration, where stimulation of stem cells to differentiate into the targeted cell type is essential. One of the factors that induce stem cells to differentiate is their surrounding microenvironment. In this study, the correlation between mild reductant and early osteogenic commitment was evaluated. A cell surface-reducing microenvironment significantly silenced the transforming growth factor (TGF)-ß signaling pathway of mesenchymal stem cells (MSCs), followed by increased focal adhesion and inhibition of cell membrane protein dimerization. Furthermore, in vivo transplantation of MSCs exposed to the reducing microenvironment resulted in an early osteogenic commitment and neobone formation. Thus, these results highlight the potential of cell surface-reducing microenvironment to influence early osteogenic commitment.


Assuntos
Microambiente Celular , Osteogênese , Adesão Celular , Diferenciação Celular , Humanos , Células-Tronco Mesenquimais/citologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
7.
ACS Appl Mater Interfaces ; 13(27): 32316-32331, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34210131

RESUMO

Pathogenic bacterial infection has become a serious medical threat to global public health. Once the skin has serious defects, bacterial invasion and the following chain reactions will be a thorny clinical conundrum, which takes a long time to heal. Although various strategies have been used to eradicate bacteria, the treatment which can simultaneously disinfect and regulate the infection-related host responses is rarely reported. Herein, inspired by the host microenvironment, a photoenhanced dual-functional nanomedicine is constructed (Hemin@Phmg-TA-MSN) for localized bacterial ablation and host microenvironment modulation. The "NIR-triggered local microthermal therapy" and positively charged surface endow the nanomedicine with excellent bacterial capture and killing activities. Meanwhile, the nanomedicine exhibits broad-spectrum reactive oxygen species (ROS) scavenging activity via the synergistic effect of hemin and tannic acid with photoenhanced electron and hydrogen transfers. Furthermore, the in vivo experiments demonstrate that the dual-functional nanomedicine not only presents robust bacterial eradication capability, but also triggers the oxidative stress and inflammatory microenvironment regulation. The work not only shows a facile and effective way for infected wound management but also provides a new horizon for designing novel and efficient anti-infection therapy shifting focus from bacteria treatment to host microenvironment modulation.


Assuntos
Microambiente Celular/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Raios Infravermelhos , Nanomedicina/métodos , Cicatrização/efeitos da radiação , Animais , Feminino , Camundongos
8.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204881

RESUMO

Mesenchymal stem cells (MSCs) are broadly applied in regenerative therapy to replace cells that are lost or impaired during disease. The low survival rate of MSCs after transplantation is one of the major limitations heavily influencing the success of the therapy. Unfavorable microenvironments with inflammation and oxidative stress in the damaged regions contribute to MSCs loss. Most of the strategies developed to overcome this obstacle are aimed to prevent stress-induced apoptosis, with little attention paid to senescence-another common stress reaction of MSCs. Here, we proposed the strategy to prevent oxidative stress-induced senescence of human endometrial stem cells (hMESCs) based on deferoxamine (DFO) application. DFO prevented DNA damage and stress-induced senescence of hMESCs, as evidenced by reduced levels of reactive oxygen species, lipofuscin, cyclin D1, decreased SA-ß-Gal activity, and improved mitochondrial function. Additionally, DFO caused accumulation of HIF-1α, which may contribute to the survival of H2O2-treated cells. Importantly, cells that escaped senescence due to DFO preconditioning preserved all the properties of the initial hMESCs. Therefore, once protecting cells from oxidative damage, DFO did not alter further hMESCs functioning. The data obtained may become the important prerequisite for development of a new strategy in regenerative therapy based on MSCs preconditioning using DFO.


Assuntos
Desferroxamina/farmacologia , Endométrio/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Microambiente Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Ciclina D1/genética , Endométrio/citologia , Endométrio/crescimento & desenvolvimento , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Inflamação/induzido quimicamente , Inflamação/patologia , Lipofuscina/genética , Células-Tronco Mesenquimais/efeitos dos fármacos , Espécies Reativas de Oxigênio , Medicina Regenerativa , Transdução de Sinais/efeitos dos fármacos
9.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205072

RESUMO

Two-photon microscopy enables monitoring cellular dynamics and communication in complex systems, within a genuine environment, such as living tissues and, even, living organisms. Particularly, its application to understand cellular interactions in the immune system has brought unique insights into pathophysiologic processes in vivo. Simultaneous multiplexed imaging is required to understand the dynamic orchestration of the multiple cellular and non-cellular tissue compartments defining immune responses. Here, we present an improvement of our previously developed method, which allowed us to achieve multiplexed dynamic intravital two-photon imaging, by using a synergistic strategy. This strategy combines a spectrally broad range of fluorophore emissions, a wave-mixing concept for simultaneous excitation of all targeted fluorophores, and an unmixing algorithm based on the calculation of spectral similarities with previously measured fluorophore fingerprints. The improvement of the similarity spectral unmixing algorithm here described is based on dimensionality reduction of the mixing matrix. We demonstrate its superior performance in the correct pixel-based assignment of probes to tissue compartments labeled by single fluorophores with similar spectral fingerprints, as compared to the full-dimensional similarity spectral unmixing approach.


Assuntos
Comunicação Celular/genética , Microambiente Celular/genética , Microscopia de Fluorescência/métodos , Imagem Molecular/métodos , Algoritmos , Linhagem Celular , Corantes Fluorescentes/química , Fótons
10.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207340

RESUMO

Mass spectrometry (MS) used in proteomic approaches is able to detect hundreds of proteins in a single assay. Although undeniable high analytical power of MS, data acquired sometimes lead to confusing results, especially during a search of very selective, unique interactions in complex biological matrices. Here, we would like to show an example of such confusing data, providing an extensive discussion on the observed phenomenon. Our investigations focus on the interaction between the Zika virus NS3 protease, which is essential for virus replication. This enzyme is known for helping to remodel the microenvironment of the infected cells. Several reports show that this protease can process cellular substrates and thereby modify cellular pathways that are important for the virus. Herein, we explored some of the targets of NS3, clearly shown by proteomic techniques, as processed during infection. Unfortunately, we could not confirm the biological relevance of protein targets for viral infections detected by MS. Thus, although mass spectrometry is highly sensitive and useful in many instances, also being able to show directions where cell/virus interaction occurs, we believe that deep recognition of their biological role is essential to receive complete insight into the investigated process.


Assuntos
Espectrometria de Massas/métodos , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/metabolismo , Infecção por Zika virus/virologia , Zika virus/metabolismo , Células A549 , Animais , Linhagem Celular , Linhagem Celular Tumoral , Microambiente Celular/fisiologia , Chlorocebus aethiops , Células HEK293 , Humanos , Proteômica/métodos , Transdução de Sinais/fisiologia , Células Vero
11.
Aging (Albany NY) ; 13(13): 16938-16956, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34292877

RESUMO

Macrophage accumulation and nitrosative stress are known mechanisms underlying age-related cardiovascular pathology and functional decline. The cardiac muscle microenvironment is known to change with age, yet the direct effects of these changes have yet to be studied in-depth. The present study sought to better elucidate the role that biochemical and biomechanical alterations in cardiac tissue have in the altered phenotype and functionality of cardiac resident macrophages observed with increasing age. To accomplish this, naïve bone marrow derived macrophages from young mice were seeded onto either functionalized poly-dimethyl-siloxane hydrogels ranging in stiffness from 2kPA to 64kPA or onto tissue culture plastic, both of which were coated with either young or aged solubilized mouse cardiac extracellular matrix (cECM). Both biomechanical and biochemical alterations were found to have a significant effect on macrophage polarization and function. Increased substrate stiffness was found to promote macrophage morphologies associated with pro-inflammatory macrophage activation, increased expression of pro-inflammatory inducible nitric oxide synthase protein with increased nitric oxide secretion, and attenuated arginase activity and protein expression. Additionally, exposure to aged cECM promoted attenuated responsivity to both canonical pro-inflammatory and anti-inflammatory cytokine signaling cues when compared to young cECM treated cells. These results suggest that both biomechanical and biochemical changes in the cardiovascular system play a role in promoting the age-related shift towards pro-inflammatory macrophage populations associated with cardiovascular disease development.


Assuntos
Microambiente Celular/fisiologia , Coração/fisiologia , Macrófagos/fisiologia , Macrófagos/ultraestrutura , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Arginase/metabolismo , Fenômenos Biomecânicos , Células da Medula Óssea , Citocinas/metabolismo , DNA/biossíntese , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Fenótipo , Transdução de Sinais , Técnicas de Cultura de Tecidos
12.
Science ; 373(6554): 516-522, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326233

RESUMO

Technological advancements in blood glucose monitoring and therapeutic insulin administration have improved the quality of life for people with type 1 diabetes. However, these efforts fall short of replicating the exquisite metabolic control provided by native islets. We examine the integrated advancements in islet cell replacement and immunomodulatory therapies that are coalescing to enable the restoration of endogenous glucose regulation. We highlight advances in stem cell biology and graft site design, which offer innovative sources of cellular material and improved engraftment. We also cover cutting-edge approaches for preventing allograft rejection and recurrent autoimmunity. These insights reflect a growing understanding of type 1 diabetes etiology, ß cell biology, and biomaterial design, together highlighting therapeutic opportunities to durably replace the ß cells destroyed in type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Imunomodulação , Células Secretoras de Insulina/transplante , Transplante das Ilhotas Pancreáticas , Animais , Autoimunidade , Glicemia/metabolismo , Diferenciação Celular , Engenharia Celular , Microambiente Celular , Diabetes Mellitus Tipo 1/metabolismo , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Tolerância Imunológica , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/fisiologia , Células-Tronco Pluripotentes/transplante , Transplante de Células-Tronco
13.
Cancer Sci ; 112(10): 3995-4004, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34310776

RESUMO

Multiple myeloma (MM) is a refractory plasma cell tumor. In myeloma cells, the transcription factor IRF4, the master regulator of plasma cells, is aberrantly upregulated and plays an essential role in oncogenesis. IRF4 forms a positive feedback loop with MYC, leading to additional tumorigenic properties. In recent years, molecular targeted therapies have contributed to a significant improvement in the prognosis of MM. Nevertheless, almost all patients experience disease progression, which is thought to be a result of treatment resistance induced by various elements of the bone marrow microenvironment. Among these, the hypoxic response, one of the key processes for cellular homeostasis, induces hypoxia-adapted traits such as undifferentiation, altered metabolism, and dissemination, leading to drug resistance. These inductions are caused by ectopic gene expression changes mediated by the activation of hypoxia-inducible factors (HIFs). By contrast, the expression levels of IRF4 and MYC are markedly reduced by hypoxic stress. Notably, an anti-apoptotic capability is usually acquired under both normoxic and hypoxic conditions, but the mechanism is distinct. This fact strongly suggests that myeloma cells may survive by switching their dependent regulatory factors from IRF4 and MYC (normoxic bone marrow region) to HIF (hypoxic bone marrow microenvironment). Therefore, to achieve deep remission, combination therapeutic agents, which are complementarily effective against both IRF4-MYC-dominant and HIF-dominated fractions, may become an important therapeutic strategy for MM.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fatores Reguladores de Interferon/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Hipóxia Tumoral/fisiologia , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células da Medula Óssea/fisiologia , Desdiferenciação Celular , Hipóxia Celular/fisiologia , Movimento Celular/fisiologia , Microambiente Celular/fisiologia , MicroRNA Circulante/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/fisiologia , Retroalimentação Fisiológica , Glicólise/fisiologia , Hexoquinase/metabolismo , Homeostase , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fatores Imunológicos/uso terapêutico , Fatores Reguladores de Interferon/genética , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/genética , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/fisiologia , Oxigênio , Pressão Parcial , Inibidores de Proteassoma/uso terapêutico , Proteínas Proto-Oncogênicas c-myc/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Regulação para Cima
14.
Front Immunol ; 12: 624746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149687

RESUMO

Mesenchymal stem cells (MSCs) are multipotent adult stromal cells widely studied for their regenerative and immunomodulatory properties. They are capable of modulating macrophage plasticity depending on various microenvironmental signals. Current studies have shown that metabolic changes can also affect macrophage fate and function. Indeed, changes in the environment prompt phenotype change. Therefore, in this review, we will discuss how MSCs orchestrate macrophage's metabolic plasticity and the impact on their function. An improved understanding of the crosstalk between macrophages and MSCs will improve our knowledge of MSC's therapeutic potential in the context of inflammatory diseases, cancer, and tissue repair processes in which macrophages are pivotal.


Assuntos
Comunicação Celular , Plasticidade Celular , Reprogramação Celular , Metabolismo Energético , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Microambiente Celular , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Células-Tronco Mesenquimais/imunologia , Fenótipo , Transdução de Sinais
15.
Cardiovasc Res ; 117(10): 2161-2174, 2021 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-34114614

RESUMO

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.


Assuntos
Pesquisa Biomédica , Cardiologia , Proliferação de Células , Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Regeneração , Animais , COVID-19/patologia , COVID-19/virologia , Comunicação Celular , Microambiente Celular , Exossomos/metabolismo , Exossomos/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/virologia , Fenótipo , RNA não Traduzido/metabolismo , SARS-CoV-2/patogenicidade
16.
Front Immunol ; 12: 625922, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34168640

RESUMO

Low density neutrophils (LDNs) are described in a number of inflammatory conditions, cancers and infections and associated with immunopathology, and a mechanistic role in disease. The role of LDNs at homeostasis in healthy individuals has not been investigated. We have developed an isolation protocol that generates high purity LDNs from healthy donors. Healthy LDNs were identical to healthy normal density neutrophils (NDNs), aside from reduced neutrophil extracellular trap formation. CD66b, CD16, CD15, CD10, CD54, CD62L, CXCR2, CD47 and CD11b were expressed at equivalent levels in healthy LDNs and NDNs and underwent apoptosis and ROS production interchangeably. Healthy LDNs had no differential effect on CD4+ or CD8+ T cell proliferation or IFNγ production compared with NDNs. LDNs were generated from healthy NDNs in vitro by activation with TNF, LPS or fMLF, suggesting a mechanism of LDN generation in disease however, we show neutrophilia in people with Cystic Fibrosis (CF) was not due to increased LDNs. LDNs are present in the neutrophil pool at homeostasis and have limited functional differences to NDNs. We conclude that increased LDN numbers in disease reflect the specific pathology or inflammatory environment and that neutrophil density alone is inadequate to classify discrete functional populations of neutrophils.


Assuntos
Separação Celular , Citometria de Fluxo , Neutrófilos/imunologia , Antígenos CD/metabolismo , Apoptose , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Microambiente Celular , Centrifugação com Gradiente de Concentração , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Armadilhas Extracelulares/metabolismo , Voluntários Saudáveis , Homeostase , Humanos , Interferon gama/metabolismo , Contagem de Leucócitos , Transtornos Leucocíticos/imunologia , Transtornos Leucocíticos/metabolismo , Ativação Linfocitária , Ativação de Neutrófilo , Neutrófilos/metabolismo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-8B/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
17.
Cell Death Dis ; 12(7): 628, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145224

RESUMO

With an increasing aging society, China is the world's fastest growing markets for oral implants. Compared with traditional oral implants, immediate implants cause marginal bone resorption and increase the failure rate of osseointegration, but the mechanism is still unknown. Therefore, it is important to further study mechanisms of tension stimulus on osteoblasts and osteoclasts at the early stage of osseointegration to promote rapid osseointegration around oral implants. The results showed that exosomes containing circ_0008542 from MC3T3-E1 cells with prolonged tensile stimulation promoted osteoclast differentiation and bone resorption. Circ_0008542 upregulated Tnfrsf11a (RANK) gene expression by acting as a miR-185-5p sponge. Meanwhile, the circ_0008542 1916-1992 bp segment exhibited increased m6A methylation levels. Inhibiting the RNA methyltransferase METTL3 or overexpressing the RNA demethylase ALKBH5 reversed osteoclast differentiation and bone resorption induced by circ_0008542. Injection of circ_0008542 + ALKBH5 into the tail vein of mice reversed the same effects in vivo. Site-directed mutagenesis study demonstrated that 1956 bp on circ_0008542 is the m6A functional site with the abovementioned biological functions. In conclusion, the RNA methylase METTL3 acts on the m6A functional site of 1956 bp in circ_0008542, promoting competitive binding of miRNA-185-5p by circ_0008542, and leading to an increase in the target gene RANK and the initiation of osteoclast bone absorption. In contrast, the RNA demethylase ALKBH5 inhibits the binding of circ_0008542 with miRNA-185-5p to correct the bone resorption process. The potential value of this study provides methods to enhance the resistance of immediate implants through use of exosomes releasing ALKBH5.


Assuntos
Reabsorção Óssea/metabolismo , Comunicação Celular , Diferenciação Celular , Exossomos/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese , RNA Circular/metabolismo , Células 3T3 , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Microambiente Celular , Exossomos/transplante , Feminino , Mecanotransdução Celular , Metilação , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Osseointegração , Osteoblastos/transplante , Osteoclastos/patologia , Células RAW 264.7 , RNA Circular/genética , Ratos , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Estresse Mecânico
18.
J Leukoc Biol ; 110(2): 257-270, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34075637

RESUMO

Immune cells such as T cells, macrophages, dendritic cells, and other immunoregulatory cells undergo metabolic reprogramming in cancer and inflammation-derived microenvironment to meet specific physiologic and functional demands. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are characterized by immunosuppressive activity, which plays a key role in host immune homeostasis. In this review, we have discussed the core metabolic pathways, including glycolysis, lipid and fatty acid biosynthesis, and amino acid metabolism in the MDSCs under various pathologic situations. Metabolic reprogramming is a determinant of the phenotype and functions of MDSCs, and is therefore a novel therapeutic possibility in various diseases.


Assuntos
Metabolismo Energético , Imunomodulação , Redes e Vias Metabólicas , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Adenosina/metabolismo , Aminoácidos/metabolismo , Biomarcadores , Microambiente Celular/imunologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Espaço Extracelular/metabolismo , Glucose/metabolismo , Homeostase , Humanos , Metabolismo dos Lipídeos , Terapia de Alvo Molecular , Células Supressoras Mieloides/efeitos dos fármacos
19.
Nat Commun ; 12(1): 3514, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112772

RESUMO

3D culture of cells in designer biomaterial matrices provides a biomimetic cellular microenvironment and can yield critical insights into cellular behaviours not available from conventional 2D cultures. Hydrogels with dynamic properties, achieved by incorporating either degradable structural components or reversible dynamic crosslinks, enable efficient cell adaptation of the matrix and support associated cellular functions. Herein we demonstrate that given similar equilibrium binding constants, hydrogels containing dynamic crosslinks with a large dissociation rate constant enable cell force-induced network reorganization, which results in rapid stellate spreading, assembly, mechanosensing, and differentiation of encapsulated stem cells when compared to similar hydrogels containing dynamic crosslinks with a low dissociation rate constant. Furthermore, the static and precise conjugation of cell adhesive ligands to the hydrogel subnetwork connected by such fast-dissociating crosslinks is also required for ultra-rapid stellate spreading (within 18 h post-encapsulation) and enhanced mechanosensing of stem cells in 3D. This work reveals the correlation between microscopic cell behaviours and the molecular level binding kinetics in hydrogel networks. Our findings provide valuable guidance to the design and evaluation of supramolecular biomaterials with cell-adaptable properties for studying cells in 3D cultures.


Assuntos
Biomimética/métodos , Adesão Celular , Técnicas de Cultura de Células/métodos , Microambiente Celular , Hidrogéis/química , Células-Tronco Mesenquimais/metabolismo , Organoides/metabolismo , Osteogênese , Adamantano/química , Materiais Biocompatíveis/química , Ácido Cólico , Simulação por Computador , Reagentes para Ligações Cruzadas/química , Ciclodextrinas/química , Matriz Extracelular , Humanos , Cinética , Ligantes , Mecanotransdução Celular , Células-Tronco Mesenquimais/citologia , Simulação de Dinâmica Molecular , Organoides/citologia , Termodinâmica
20.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071037

RESUMO

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.


Assuntos
Plasma Rico em Plaquetas , Animais , Células Cultivadas , Microambiente Celular , Condrócitos/efeitos dos fármacos , Condrogênese , Citocinas/administração & dosagem , Citocinas/uso terapêutico , Grânulos Citoplasmáticos/química , Cobaias , Humanos , Ácido Hialurônico/farmacologia , Ácido Hialurônico/uso terapêutico , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Injeções Intra-Articulares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Neurotransmissores/administração & dosagem , Neurotransmissores/uso terapêutico , Osteoartrite do Joelho , Plasma Rico em Plaquetas/química , Resultado do Tratamento
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