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1.
Pharm Biol ; 60(1): 1762-1770, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36086802

RESUMO

CONTEXT: (-)-Epicatechin (EPI) is a crucial substance involved in the protective effects of flavanol-rich foods. Previous studies have indicated EPI has a cardioprotective effect, but the molecular mechanisms in inhibition of cardiac fibrosis are unclear. OBJECTIVE: We evaluated the effect of EPI in preventing cardiac fibrosis and the underlying molecular mechanism related to the SIRT1-SUMO1/AKT/GSK3ß pathway. MATERIALS AND METHODS: Cardiac fibrosis mice model was established with transaortic constriction (TAC). Male C57BL/6 mice were randomly separated into 4 groups. Mice received 1 mg/kg/day of EPI or vehicle orally for 4 weeks. The acutely isolated cardiac fibroblasts were induced to myofibroblasts with 1 µM angiotensin II (Ang II). The cardiac function was measured with the ultrasonic instrument. Histological analysis of mice's hearts was determined with H&E or Masson method. The protein level of fibrosis markers, SUMOylation of SIRT1, and AKT/GSK3ß pathway were quantified by immunofluorescence and western blot. RESULTS: EPI treatment (1 mg/kg/day) could reverse the TAC-induced decline in LVEF (TAC, 61.28% ± 1.33% vs. TAC + EPI, 74.00% ± 1.64%), LVFS (TAC, 28.16% ± 0.89% vs. TAC + EPI, 37.18% ± 1.29%). Meantime, we found that 10 µM EPI blocks Ang II-induced transformation of cardiac fibroblasts into myofibroblasts. The underlying mechanism of EPI-inhibited myofibroblasts transformation involves activation of SUMOylation of SIRT1 through SP1. Furthermore, SUMOylation of SIRT1 inhibited Ang II-induced fibrogenic effect via the AKT/GSK3ß pathway. CONCLUSION: EPI plays a protective effect on cardiac fibrosis by regulating the SUMO1-dependent modulation of SIRT1, which provides a theoretical basis for use in clinical therapies.


Assuntos
Catequina , Miofibroblastos , Angiotensina II/toxicidade , Animais , Catequina/farmacologia , Fibroblastos/patologia , Fibrose , Glicogênio Sintase Quinase 3 beta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuína 1/metabolismo , Ubiquitina
2.
Curr Opin Endocrinol Diabetes Obes ; 29(5): 441-448, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35950703

RESUMO

PURPOSE OF REVIEW: We attempt to provide an historical perspective on progress made in understanding the pathogenesis of thyroid-associated ophthalmopathy (TAO), focusing on the roles of orbital fibroblasts (OF) in the diseased orbit (termed GD-OF) and how these cells differ from those residing in the healthy orbit. GD-OF comprise both residential OF and those apparently derived from CD34 + fibrocytes. RECENT FINDINGS: CD34 + fibrocytes of the monocyte lineage putatively traffic to the TAO orbit from bone marrow. We believe that these fibroblastic cell populations dictate the activity and severity of TAO. Their impact on disease may be moderated by Slit2, a neuron axon guidance repellent synthesized by and released from residential CD34 - OF. Approximately 50% of patients with GD develop clinically meaningful TAO. Relatively few require systemic medical and surgical therapies, while milder disease can be managed with conservative, local care. Determining the intrinsic properties of GD-OF and their expression of Slit2 may explain why some patients with GD develop severe, vision-threatening TAO while others virtually escape any of its manifestations. Such insights should allow for improved and better-tolerated therapies. SUMMARY: Identifying unique characteristics of fibrocytes and GD-OF subsets reveals their apparent roles in tissue activation, inflammation, and remodeling associated with TAO. Better understanding of these cells, their origins, behavior, and factors modulating their activities remains necessary for the development of more targeted, effective, and safe treatments.


Assuntos
Oftalmopatia de Graves , Antígenos CD34/metabolismo , Medula Óssea/metabolismo , Medula Óssea/patologia , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Órbita/metabolismo , Órbita/patologia
3.
Nat Immunol ; 23(9): 1330-1341, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35999392

RESUMO

Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications.


Assuntos
Artrite Reumatoide , Fibroblastos , Proteína Proto-Oncogênica c-ets-1 , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Metaloproteinases da Matriz/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , Ligante RANK/genética , Fatores de Transcrição/metabolismo
4.
Front Immunol ; 13: 942417, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990693

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune disease during which fibroblast-like synoviocytes (FLS) contribute to both joint inflammation and destruction. FLS represent the core component of the synovial membrane. Following inflammation of this membrane, an effusion of cell-rich synovial fluid (SF) fills the joint cavity. Unlikely, SF has been shown to contain fibroblasts with some shared phenotypic traits with the synovial membrane FLS. These cells are called SF-FLS and their origin is still unclear. They are either brought into the synovium via migration through blood vessels, or they could originate within the synovium and exist in projections of the synovial membrane. SF-FLS function and phenotype are poorly documented compared to recently well-characterized synovial membrane FLS subsets. Furthermore, no study has yet reported a SF-FLS single-cell profiling analysis. This review will discuss the origin and cellular characteristics of SF-FLS in patients with RA. In addition, recent advances on the involvement of SF-FLS in the pathogenesis of RA will be summarized. Current knowledge on possible relationships between SF-FLS and other types of fibroblasts, including synovial membrane FLS, circulating fibrocytes, and pre- inflammatory mesenchymal (PRIME) cells will also be addressed. Finally, recent therapeutic strategies employed to specifically target SF-FLS in RA will be discussed.


Assuntos
Artrite Reumatoide , Sinoviócitos , Fibroblastos/patologia , Humanos , Inflamação/patologia , Líquido Sinovial , Sinoviócitos/patologia
5.
Crit Rev Oncog ; 27(1): 1-24, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35993976

RESUMO

Despite advances in treatment, prostate cancer remains a significant cause of morbidity and mortality worldwide. While the vast majority of prostate cancer research has centered on malignant epithelial cells, the tumor mi croenvironment (TME) has recently become increasingly recognized as an important regulator of tumor progression and response to treatment. Among the diverse cell types within the TME, stromal fibroblasts, in particular cancer-associated fibroblasts (CAFs), play an important role in prostate cancer progression. This is highlighted by the prognostic value of CAF markers in prostate cancer, which can predict disease recurrence, metastasis, and patient survival. There are also an increasing number of studies that demonstrate the critical role of CAFs in mediating response to specific therapies and CAF signaling pathways as potential therapeutic targets. However, further investigation into the mechanisms that underpin the interactions between cancer cells and CAFs are required to develop novel therapeutic approaches and identify predictive and prognostic biomarkers in CAFs. In this review, we discuss the current knowledge of CAF-dependent regulatory pathways in prostate tumorigenesis and their prognostic and therapeutic potential. Furthermore, we explore the emerging models and technologies that are likely to progress this field of research in terms of discovery and translation to the clinic.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias da Próstata , Biomarcadores/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Microambiente Tumoral/genética
7.
Cells ; 11(15)2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35954214

RESUMO

Central nervous system (CNS) trauma activates a persistent repair response that leads to fibrotic scar formation within the lesion. This scarring is similar to other organ fibrosis in many ways; however, the unique features of the CNS differentiate it from other organs. In this review, we discuss fibrotic scar formation in CNS trauma, including the cellular origins of fibroblasts, the mechanism of fibrotic scar formation following an injury, as well as the implication of the fibrotic scar in CNS tissue remodeling and regeneration. While discussing the shared features of CNS fibrotic scar and fibrosis outside the CNS, we highlight their differences and discuss therapeutic targets that may enhance regeneration in the CNS.


Assuntos
Traumatismos da Medula Espinal , Traumatismos do Sistema Nervoso , Sistema Nervoso Central/patologia , Cicatriz/patologia , Fibroblastos/patologia , Fibrose , Humanos , Traumatismos da Medula Espinal/patologia
8.
Immunity ; 55(8): 1336-1339, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35947977

RESUMO

Fibroblasts strongly impact tumor progression, but whether they prime the pre-metastatic niche is poorly understood. In this issue of Immunity, Gong and Li et al. identify lung-specific immunosuppressive fibroblasts, which are hijacked by breast cancer cells to facilitate metastasis.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Linhagem Celular Tumoral , Feminino , Fertilizantes , Fibroblastos/patologia , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Melanoma , Metástase Neoplásica/patologia , Neoplasias Cutâneas , Solo , Microambiente Tumoral
9.
Adv Cancer Res ; 156: 201-226, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35961700

RESUMO

Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cell type in the tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA), where they are actively involved in cancer progression through a complex network of interactions with other stromal cells. The majority of the studies investigating CAFs in iCCA have focused their attention on CAF tumor-promoting roles, remarking their potential as therapeutic targets. However, indiscriminate targeting of CAFs in other desmoplastic tumors has ended in failure with no effects or even accelerated cancer progression and reduced survival, indicating the urgent need to better understand the nuances and functions of CAFs to avoid deleterious effects. Indeed, recent single cell RNA sequencing studies have shown that heterogeneous CAF subpopulations coexist in the same tumor, some promoting- and other restricting- tumor growth. Moreover, recent studies have shown that in iCCA, diverse CAF subtypes interact differently with the cells of the TME, suggesting that CAFs may dynamically change their phenotypes during tumor progression, a field that remains uninvestigated. The characterization of heterogenous CAF subpopulations and their functionality, will provide a feasible and safer approach to facilitate the development of new therapeutic approaches aimed at targeting CAFs and their interactions with other stromal cells in the TME rather than solely tumor cells in iCCA. Here, we discuss the origin of CAFs, as well as their heterogeneity, plasticity, mechanisms and targeting strategies to provide a brief snapshot of the current knowledge in iCCA.


Assuntos
Neoplasias dos Ductos Biliares , Fibroblastos Associados a Câncer , Colangiocarcinoma , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Microambiente Tumoral
10.
Cell Stem Cell ; 29(8): 1161-1180, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35931028

RESUMO

Fibroblasts are highly dynamic cells that play a central role in tissue repair and fibrosis. However, the mechanisms by which they contribute to both physiologic and pathologic states of extracellular matrix deposition and remodeling are just starting to be understood. In this review article, we discuss the current state of knowledge in fibroblast biology and heterogeneity, with a primary focus on the role of fibroblasts in skin wound repair. We also consider emerging techniques in the field, which enable an increasingly nuanced and contextualized understanding of these complex systems, and evaluate limitations of existing methodologies and knowledge. Collectively, this review spotlights a diverse body of research examining an often-overlooked cell type-the fibroblast-and its critical functions in wound repair and beyond.


Assuntos
Fibroblastos , Cicatrização , Matriz Extracelular/patologia , Fibroblastos/patologia , Fibrose , Humanos , Pele/patologia , Cicatrização/fisiologia
11.
BMC Oral Health ; 22(1): 366, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028869

RESUMO

BACKGROUND: Peri-implantitis of tooth seriously affects the life quality of patients. This study aimed to investigate the role of HSP90AA1 in the inflammatory of human gingival fibroblasts (HGFs) induced by porphyromonas gingivalis lipopolysaccharide (Pg-LPS), and to provide a potential therapeutic target for clinical treatment of peri-implantitis. METHODS: Pg-LPS (0.1, 1, 10 µg/mL) was used to construct the inflammatory model of HGFs to evaluate the effect of Pg-LPS on HGFs. Then HSP90AA1-siRNA was transfected to construct HSP90AA1 low expression HGFs cell line, and 3-MA was also added. After that, cell viability, apoptosis, the contents of inflammatory cytokines were detected by CCK-8, flow cytometry and ELISA assay, respectively. Intracellular ROS, the expressions of HSP90α, HSP90ß were detected by immunofluorescence. The levels of HSP90AA1, p-NF-κB p65/NF-κB p65, LC3 II/I, ATG5, Beclin-1 and TLR protein were detected by western blot. RESULTS: Pg-LPS treatment didn't affect the viability of HGFs cells, but induced the cell apoptosis and ROS generation, increased the contents of IL-1ß, IL-6, TNF-α, and the protein expressions of HSP90AA1, p-NF-κBp65/NF-κBp65, LC3II/I, ATG5, and Beclin-1 in HGFs. While HSP90AA1-siRNA transfected into Pg-LPS induced HGFs significantly reduced the HSP90AA1, HSP90α, HSP90ß expression, decreased the inflammatory factors, ROS generation, cell apoptosis rate, and autophagy-related proteins and TLR2/4 protein levels. What's more, the addition of autophagy inhibitor 3-MA further promote the effect of HSP90AA1-siRNA on Pg-LPS treated HGFs. CONCLUSIONS: This study showed that HSP90AA1 promoted the inflammatory response of Pg-LPS induced HGFs by regulating autophagy. The addition of 3-MA further confirmed that autophagy may mediate siHSP90AA1 to enhance the inflammatory response.


Assuntos
Fibroblastos , Proteínas de Choque Térmico HSP90 , Peri-Implantite , Porphyromonas gingivalis , Autofagia , Proteína Beclina-1 , Células Cultivadas , Fibroblastos/patologia , Gengiva , Proteínas de Choque Térmico HSP90/genética , Humanos , Inflamação , Lipopolissacarídeos , NF-kappa B , RNA Interferente Pequeno , Espécies Reativas de Oxigênio
12.
Cancer Res ; 82(18): 3291-3306, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-35862581

RESUMO

Tumor-associated macrophages (TAM) play a detrimental role in triple-negative breast cancer (TNBC). In-depth analysis of TAM characteristics and interactions with stromal cells, such as cancer-associated fibroblast (CAF), could provide important biological and therapeutic insights. Here we identify at the single-cell level a monocyte-derived STAB1+TREM2high lipid-associated macrophage (LAM) subpopulation with immune suppressive capacities that is expanded in patients resistant to immune checkpoint blockade (ICB). Genetic depletion of this LAM subset in mice suppressed TNBC tumor growth. Flow cytometry and bulk RNA sequencing data demonstrated that coculture with TNBC-derived CAFs led to reprogramming of blood monocytes towards immune suppressive STAB1+TREM2high LAMs, which inhibit T-cell activation and proliferation. Cell-to-cell interaction modeling and assays in vitro demonstrated the role of the inflammatory CXCL12-CXCR4 axis in CAF-myeloid cell cross-talk and recruitment of monocytes in tumor sites. Altogether, these data suggest an inflammation model whereby monocytes recruited to the tumor via the CAF-driven CXCL12-CXCR4 axis acquire protumorigenic LAM capacities to support an immunosuppressive microenvironment. SIGNIFICANCE: This work identifies a novel lipid-associated macrophage subpopulation with immune suppressive functions, offering new leads for therapeutic interventions in triple-negative breast cancer.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias de Mama Triplo Negativas , Animais , Fibroblastos Associados a Câncer/patologia , Moléculas de Adesão Celular Neuronais , Linhagem Celular Tumoral , Fibroblastos/patologia , Humanos , Inibidores de Checkpoint Imunológico , Lipídeos , Macrófagos , Camundongos , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética
13.
Thorac Cancer ; 13(16): 2377-2384, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35818720

RESUMO

BACKGROUND: Fibroblast-activating protein (FAP) is expressed in cancer-associated fibroblasts (CAFs) in many human carcinomas and in some types of carcinoma cells. Here, we examined the proportion of FAP protein expression in non-small cell lung carcinoma (NSCLC) and investigated the correlation of FAP expression with clinicopathological background. METHODS: In total, 344 NSCLC tissues were examined. Tissue microarrays were constructed, and FAP expression was analyzed using immunohistochemistry. The status of FAP expression in tumor cells and CAFs was correlated with clinicopathological background, molecular features, and patient outcomes. RESULTS: A total of 280 patients (81.4%) had low FAP expression, and 64 patients (18.6%) had high FAP expression in tumor cells. In CAFs, 230 patients (66.9%) had low FAP expression, and 114 patients (33.1%) had high FAP expression. In multivariate analyses, high FAP expression in tumor cells was an independent predictive factor of both overall survival (OS; hazard ratio [HR] = 2.57, 95% confidence interval [CI]: 1.49-4.42, p < 0.001) and recurrence-free survival (RFS; HR = 2.13, 95% CI: 1.38-3.29, p < 0.001). Based on combinations of FAP expression in tumor cells and CAFs, patients with LowT /LowCAFs had better OS and RFS than did those in the other subgroups. By contrast, patients with HighT /HighCAFs had poor OS and RFS compared with those in the other subgroups. CONCLUSIONS: Overall, FAP expression in tumor cells and the combination FAP expression in tumor cells and CAFs were strongly associated with patient survival and may be useful predictive biomarkers for patient outcomes in NSCLC.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Fibroblastos/química , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neoplasias Pulmonares/patologia , Prognóstico
14.
J Clin Invest ; 132(13)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35775488

RESUMO

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with an unmet therapeutic need. Fibrotic remodeling, in which collagen-producing atrial fibroblasts play a crucial role, substantially contributes to arrhythmia promotion and progression. In this issue of the JCI, Lai, Tsai, and co-authors reveal that TGF-ß1 promoted endothelial-mesenchymal transition during AF and put forward the notion that, in the adult heart, atrial fibroblasts can originate from different cellular sources. These important findings extend our understanding of the origin, biology, and function of fibroblasts and offer possibilities for therapeutic targeting of fibrosis in AF.


Assuntos
Fibrilação Atrial , Miocárdio , Fator de Crescimento Transformador beta1 , Fibrilação Atrial/patologia , Transição Epitelial-Mesenquimal , Fibroblastos/patologia , Fibrose/patologia , Átrios do Coração/patologia , Humanos , Miocárdio/patologia , Fator de Crescimento Transformador beta1/metabolismo
15.
J Adv Res ; 39: 103-117, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35777901

RESUMO

INTRODUCTION: Hypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury. OBJECTIVES: In this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs). METHODS: Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of glucose transporter 5 (GLUT5), ketohexokinase (KHK)-A and KHK-C in miR-155-/- and miR-155wt CFs under normoxia or hypoxia. A microarray analysis of circRNAs was performed to identify circHIF1α. Then CoIP, RIP and mass spectrometry analysis were performed and identified SKIV2L2 (MTR4) and transformer 2 alpha (TRA2A), a member of the transformer 2 homolog family. pAd-SKIV2L2 was administrated after coronary artery ligation to investigate whether SKIV2L2 can provide a protective effect on the infarcted heart. RESULTS: When both miR-155-/- and miR-155wt CFs were exposed to hypoxia for 24 h, these two cells exhibited an increased glycolysis and decreased glycogen synthesis, and the expression of KHK-A and KHK-C, the central fructose-metabolizing enzyme, was upregulated. Mechanistically, miR-155 deletion in CFs enhanced SKIV2L2 expression and its interaction with TRA2A, which suppresses the alternative splicing of HIF1α pre-mRNA to form circHIF1α, and then decreased circHIF1α contributed to the activation of fructose metabolism through increasing the production of the KHK-C isoform. Finally, exogenous delivery of SKIV2L2 reduced myocardial damage in the infarcted heart. CONCLUSION: In this study, we demonstrated that miR-155 deletion facilitates the activation of fructose metabolism in hypoxic CFs through regulating alternative splicing of HIF1α pre-mRNA and thus circHIF1ɑ formation.


Assuntos
Síndrome de Fadiga Crônica , Frutose , MicroRNAs , Infarto do Miocárdio , Regulação para Baixo , Síndrome de Fadiga Crônica/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Frutose/metabolismo , Humanos , Hipóxia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Precursores de RNA/metabolismo
16.
Front Immunol ; 13: 922111, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844494

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease that endangers the health of approximately 1% of the global population. Current RA medications on the market mainly include non-steroidal anti-inflammatory drugs, biological agents, and disease-modifying drugs. These drugs aim to inhibit the overactivated immune response or inflammation of RA, but they cannot cure RA. A better understanding of the pathogenesis of RA will provide a new understanding to search for RA targets and for drug development. The infiltration of T cells and hyper-proliferation of fibroblast-like synoviocytes (FLS) in the synovium of patients with RA are significantly upregulated. Furthermore, the abnormal activation of these two types of cells has been confirmed to promote development of the course of A by many studies. This article systematically summarizes the interactions between T cells and FLS in RA synovial tissues, including one-way/mutual regulation and direct/indirect regulation between the two. It further aims to investigate the pathogenesis of RA from the perspective of mutual regulation between T cells and FLS and to provide new insights into RA research.


Assuntos
Artrite Reumatoide , Sinoviócitos , Proliferação de Células , Comunicação , Fibroblastos/patologia , Humanos , Membrana Sinovial , Linfócitos T/patologia
17.
Cells ; 11(15)2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35892569

RESUMO

Fibroblasts are stromal cells found in virtually every tissue and organ of the body. For many years, these cells were often considered to be secondary in functional importance to parenchymal cells. Over the past 2 decades, focused research into the roles of fibroblasts has revealed important roles for these cells in the homeostasis of healthy tissue, and has demonstrated that activation of fibroblasts to myofibroblasts is a key step in disease initiation and progression in many tissues, with fibrosis now recognized as not only an outcome of disease, but also a central contributor to tissue dysfunction, particularly in the heart and lungs. With a growing understanding of both fibroblast and myofibroblast heterogeneity, and the deciphering of the humoral and mechanical cues that impact the phenotype of these cells, fibroblast biology is rapidly becoming a major focus in biomedical research. In this review, we provide an overview of fibroblast and myofibroblast biology, particularly in the heart, and including a discussion of pathophysiological processes such as fibrosis and scarring. We then discuss the central role of Canadian researchers in moving this field forwards, particularly in cardiac fibrosis, and highlight some of the major contributions of these individuals to our understanding of fibroblast and myofibroblast biology in health and disease.


Assuntos
Fibroblastos , Miocárdio , Biologia , Canadá , Diferenciação Celular , Fibroblastos/patologia , Fibrose , Humanos , Miocárdio/patologia
18.
Int J Mol Sci ; 23(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35897650

RESUMO

Fibrotic tissues share many common features with neoplasms where there is an increased stiffness of the extracellular matrix (ECM). In this review, we present recent discoveries related to the role of the mechanosensitive ion channel Piezo1 in several diseases, especially in regulating tumor progression, and how this can be compared with cardiac mechanobiology. Based on recent findings, Piezo1 could be upregulated in cardiac fibroblasts as a consequence of the mechanical stress and pro-inflammatory stimuli that occurs after myocardial injury, and its increased activity could be responsible for a positive feedback loop that leads to fibrosis progression. The increased Piezo1-mediated calcium flow may play an important role in cytoskeleton reorganization since it induces actin stress fibers formation, a well-known characteristic of fibroblast transdifferentiation into the activated myofibroblast. Moreover, Piezo1 activity stimulates ECM and cytokines production, which in turn promotes the phenoconversion of adjacent fibroblasts into new myofibroblasts, enhancing the invasive character. Thus, by assuming the Piezo1 involvement in the activation of intrinsic fibroblasts, recruitment of new myofibroblasts, and uncontrolled excessive ECM production, a new approach to blocking the fibrotic progression can be predicted. Therefore, targeted therapies against Piezo1 could also be beneficial for cardiac fibrosis.


Assuntos
Miocárdio , Miofibroblastos , Fibroblastos/patologia , Fibrose , Coração/fisiologia , Humanos , Canais Iônicos , Miocárdio/patologia , Miofibroblastos/patologia
19.
Nat Commun ; 13(1): 4308, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879297

RESUMO

Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase Pin1, whose overexpression in CAFs has not been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective Pin1 inhibition in CAFs on pancreatic cancer, here we formulate a DNA-barcoded micellular system (DMS) encapsulating the Pin1 inhibitor AG17724. DMS functionalized with CAF-targeting anti-FAP-α antibodies (antiCAFs-DMS) can selectively inhibit Pin1 in CAFs, leading to efficacious but transient tumor growth inhibition. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to obtain a bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT inhibits tumor growth in subcutaneous and orthotopic pancreatic cancer models.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Pancreáticas , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Fibroblastos/patologia , Humanos , Peptidilprolil Isomerase de Interação com NIMA/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Microambiente Tumoral
20.
Pathology ; 54(5): 517-525, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35778287

RESUMO

The pathogenesis of idiopathic pulmonary fibrosis (IPF) and its histological counterpart, usual interstitial pneumonia (UIP) remains debated. IPF/UIP is a disease characterised by respiratory restriction, and while there have been recent advances in treatment, mortality remains high. Genetic and environmental factors predispose to its development and aberrant alveolar repair is thought to be central. Following alveolar injury, the type II pneumocyte (AEC2) replaces the damaged thin type I pneumocytes. Despite the interstitial fibroblast being considered instrumental in formation of the fibrosis, there has been little consideration for a role for AEC2 in the repair of the septal interstitium. Elastin is a complex protein that conveys flexibility and recoil to the lung. The fibroblast is presumed to produce elastin but there is evidence that the AEC2 may have a role in production or deposition. While the lung is an elastic organ, the role of elastin in repair of lung injury and its possible role in UIP has not been explored in depth. In this paper, pathogenetic mechanisms of UIP involving AEC2 and elastin are reviewed and the possible role of AEC2 in elastin generation is proposed.


Assuntos
Fibrose Pulmonar Idiopática , Células Epiteliais Alveolares/patologia , Elastina , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia
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