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1.
Cell Commun Signal ; 22(1): 170, 2024 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459564

RESUMO

Heterogeneous cancer-associated fibroblasts (CAFs) play important roles in cancer progression. However, the specific biological functions and regulatory mechanisms involved in endometrial cancer have yet to be elucidated. We aimed to explore the potential mechanisms of heterogeneous CAFs in promoting endometrial cancer progression. The presence of melanoma cell adhesion molecule (MCAM; CD146) positive CAFs was confirmed by tissue multi-immunofluorescence (mIF), and fluorescence activated cell sorting (FACS). The biological functions were determined by wound healing assays, tuber formation assays and cord formation assays. The effects of CD146+CAFs on endometrial cancer cells were studied in vitro and in vivo. The expression level of interleukin 10 (IL-10) was measured by quantitative real time polymerase chain reaction (qRT-PCR), western boltting and enzyme linked immunosorbent assays (ELISAs). In addition, the transcription factor STAT3 was identified by bioinformatics methods and chromatin immunoprecipitation (ChIP). A subtype of CAFs marked with CD146 was found in endometrial cancer and correlated with poor prognosis. CD146+CAFs promoted angiogenesis and vasculogenic mimicry (VM) in vitro. A xenograft tumour model also showed that CD146+CAFs can facilitate tumour progression. The expression of IL-10 was elevated in CD146+CAFs. IL-10 promoted epithelial-endothelial transformation (EET) and further VM formation in endometrial cancer cells via the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signalling pathway. This process could be blocked by the JAK1/STAT3 inhibitor niclosamide. Mechanically, STAT3 can bind to the promoter of cadherin5 (CDH5) to promote its transcription which may be stimulated by IL-10. We concluded that CD146+CAFs could promote angiogenesis and VM formation via the IL-10/JAK1/STAT3 signalling pathway. These findings may lead to the identification of potential targets for antiangiogenic therapeutic strategies for endometrial cancers.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias do Endométrio , Feminino , Humanos , Fibroblastos Associados a Câncer/metabolismo , Antígeno CD146/metabolismo , Linhagem Celular Tumoral , Neoplasias do Endométrio/metabolismo , Interleucina-10 , Janus Quinase 1 , Fator de Transcrição STAT3/metabolismo
2.
J Mol Med (Berl) ; 102(1): 11-21, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37993561

RESUMO

Vascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials.


Assuntos
Moléculas de Adesão Celular , Nefropatias , Humanos , Antígeno CD146/metabolismo , Rim/metabolismo , Nefropatias/etiologia , Fatores de Risco
3.
Mol Biol Cell ; 35(3): ar31, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38117590

RESUMO

The WRAMP structure is a protein network associated with tail-end actomyosin contractility, membrane retraction, and directional persistence during cell migration. A marker of WRAMP structures is melanoma cell adhesion molecule (MCAM) which dynamically polarizes to the cell rear. However, factors that mediate MCAM polarization are still unknown. In this study, BioID using MCAM as bait identifies the ERM family proteins, moesin, ezrin, and radixin, as WRAMP structure components. We also present a novel image analysis pipeline, Protein Polarity by Percentile ("3P"), which classifies protein polarization using machine learning and facilitates quantitative analysis. Using 3P, we find that depletion of moesin, and to a lesser extent ezrin, decreases the proportion of cells with polarized MCAM. Furthermore, although copolarized MCAM and ERM proteins show high spatial overlap, 3P identifies subpopulations with ERM proteins closer to the cell periphery. Live-cell imaging confirms that MCAM and ERM protein polarization is tightly coordinated, but ERM proteins enrich at the cell edge first. Finally, deletion of a juxtamembrane segment in MCAM previously shown to promote ERM protein interactions impedes MCAM polarization. Our findings highlight the requirement for ERM proteins in recruitment of MCAM to WRAMP structures and an advanced computational tool to characterize protein polarization.


Assuntos
Antígeno CD146 , Melanoma , Humanos , Citoesqueleto de Actina/metabolismo , Antígeno CD146/metabolismo , Membrana Celular/metabolismo , Movimento Celular , Melanoma/metabolismo
4.
Biochem Biophys Res Commun ; 693: 149370, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38100998

RESUMO

CD146/MCAM has garnered significant attention for its potential contribution to cardiovascular disease; however, the transcriptional regulation and functions remain unclear. To explore these processes regarding cardiomyopathy, we employed doxorubicin, a widely used stressor for cardiomyocytes. Our in vitro study on H9c2 cardiomyoblasts highlights that, besides impairing the fatty acid uptake in the cells, doxorubicin suppressed the expression of fatty acid binding protein 4 (Fabp4) along with the histone deacetylase 9 (Hdac9), bromodomain and extra-terminal domain proteins (BETs: Brd2 and Brd4), while augmented the production of CD146/MCAM. Silencing and chemical inhibition of Hdac9 further augmented CD146/MCAM and deteriorated fatty acid uptake. In contrast, chemical inhibition of BETs as well as silencing of MCAM/CD146 ameliorated fatty acid uptake. Moreover, protein kinase C (PKC) inhibition abrogated CD146/MCAM, particularly in the nucleus. Taken together, our results suggest that epigenetic dysregulation of Hdac9, Brd2, and Brd4 alters CD146/MCAM expression, deteriorating fatty acid uptake by downregulating Fabp4. This process depends on the PKC-mediated nuclear translocation of CD146. Thus, this study highlights a pivotal role of CD146/MCAM in doxorubicin-induced cardiomyopathy.


Assuntos
Cardiomiopatias , Fatores de Transcrição , Humanos , Antígeno CD146/genética , Antígeno CD146/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Epigênese Genética
5.
Int Immunopharmacol ; 127: 111410, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38109838

RESUMO

Chronic obstructive pulmonary disease (COPD) is a leading cause of global death. As a molecule beyond adhesion, CD146 is involved in COPD pathogenesis. However, the mechanisms of CD146 in COPD remain largely elusive. We hypothesized that CD146 regulates the production of matrix metalloproteinase-9 (MMP-9) in macrophages and thereby contributes to COPD. Here, we constructed a murine model of COPD using lipopolysaccharide (LPS) and porcine pancreatic elastase (PPE). In COPD-like mice, LPS and PPE decreased the pulmonary expression of CD146. MMP-9 expression and bioactivity were increased in CD146 knockout COPD-like mice. In vitro, LPS decreased CD146 expression in macrophages. With or without LPS challenge, CD146-defective macrophages produced more MMP-9. Transcriptome analysis based on next-generation sequencing (NGS) revealed that S100A9 regulated MMP-9 production in CD146-defective macrophages. Targeting S100A9 with paquinimod decreased lung inflammation and alleviated alveolar destruction in COPD-like mice. Collectively, our study suggests that CD146 negatively regulates MMP-9 production in macrophages via the S100A9 pathway in COPD.


Assuntos
Metaloproteinase 9 da Matriz , Doença Pulmonar Obstrutiva Crônica , Animais , Camundongos , Calgranulina B/genética , Calgranulina B/metabolismo , Antígeno CD146/genética , Antígeno CD146/metabolismo , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Suínos
6.
Int J Oral Maxillofac Implants ; 38(6): 1200-1210, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38085752

RESUMO

PURPOSE: To analyze the process of early oral osseointegration of titanium (Ti) implants in diabetic 129/Sv mice through microCT and histologic and immunohistochemical analysis. MATERIALS AND METHODS: A group of 30 male 129/Sv mice was equally subdivided into two groups: (1) nondiabetic (ND), in which mice did not undergo systemic alterations and received a standard diet, and (2) diabetic (D), in which mice were provided a high-fat diet from the age of 6 weeks until the conclusion of the study and received two intraperitoneal (IP) injections of streptozotocin (STZ) at a concentration of 100 mg/Kg each. Each mouse underwent extraction of a maxillary first molar, and customized Ti screws (0.50 mm diameter, 1.5 mm length) were placed in the residual alveolar sockets of the palatal roots. At 7 and 21 days after implant placement, the animals were euthanized for maxilla and pancreas collection. Maxillae containing Ti implants were analyzed with microCT, histology, and immunohistochemistry for cells that were positive for F4/80, CD146, runt-related transcription factor 2 (Runx2), and proliferating cell nuclear antigen (PCNA). Pancreata were histologically analyzed. Quantitative data were statistically analyzed with a significance level at 5% (P < .05). RESULTS: ND mice presented successful healing and osseointegration, with a significantly higher fraction of bone volume compared to D mice, both at the alveolar sockets (53.39 ± 5.93 and 46.08 ± 3.18, respectively) and at the implant sites (68.88 ± 7.07 and 44.40 ± 6.98, respectively) 21 days after implant placement. Histologic evaluation revealed that the ND mice showed a significant decrease in inflammatory infiltrate and a significant increase in newly formed bone matrix at 21 days, whereas peri-implant sites in the D mice were predominantly encapsulated by fibrous tissue and chronic inflammatory infiltrate. Immunohistochemical characterization revealed higher Runx2 osteoblast differentiation and higher cell proliferation activity in the ND mice at 7 days, while higher amounts of macrophages were present in D mice at 7 and 21 days. Interestingly, no differences were found in CD146-positive cells when comparing ND and D mice. CONCLUSIONS: This study evaluated the effects of immediate dental implant placement in 129/Sv diabetic mice by using specific healing markers to identify changes in cellular events involved in early oral osseointegration. This approach may serve as tool to evaluate new materials and surface coatings to improve osseointegration in diabetic patients.


Assuntos
Implantes Dentários , Diabetes Mellitus Experimental , Humanos , Masculino , Camundongos , Animais , Lactente , Osseointegração , Subunidade alfa 1 de Fator de Ligação ao Core , Antígeno CD146 , Titânio/química
7.
J Orthop Surg Res ; 18(1): 969, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38102700

RESUMO

BACKGROUND: The use of adipose stem cell (ADSCs) subpopulations in cartilage repair remains poorly characterized. In this study, we constructed an albumin magnetic sphere with specific targeting of CD146 (CD146-AMs) for sorting a subpopulation of CD146-positive ADSCs (CD146 + ADSCs) and explored the role of CD146 + ADSCs on joint pain and cartilage repair in rats with knee osteoarthritis (KOA). METHODS: CD146-AMs were prepared and analyzed in materialistic characterization tests. Subpopulations of CD146 + ADSCs were sorted using CD146-AMs. Surface labeling, viability, and proliferation of a subpopulation of CD146 + ADSCs were evaluated in vitro. Molecular characterization of mRNA and protein expression profiles was analyzed by microarray. A rat KOA pain model was established by the iodoacetic acid method, and KOA pain and the promotion of cartilage repair were assessed after treatment with bilateral joint cavity injections of CD146 + ADSCs. RESULTS: The CD146-AMs prepared in this study had an average particle size of 242.63 ± 6.74 nm, an average potential of 33.82 ± 3.53 mv, and high CD146 targeting and low cytotoxicity. The positive rate of enriched CD146 + ADSCs was 98.21% and showed a high level of stem cell marker expression and good cell viability. Gene and protein expression profiles showed that CD146 + ADSCs have different cellular functions, especially in regulating inflammation. In the KOA model, low, medium and high concentrations of CD146 + ADSCs were able to improve KOA pain and promote cartilage repair in a concentration-dependent trend. CONCLUSIONS: The CD146-AMs prepared in this study were able to safely and efficiently sort out the CD146 + ADSCs subpopulation. The subpopulation of CD146 + ADSCs has a unique molecular profile that ameliorates KOA pain and repairs cartilage damage in rats, providing a new idea for KOA treatment.


Assuntos
Cartilagem Articular , Osteoartrite do Joelho , Ratos , Animais , Osteoartrite do Joelho/terapia , Osteoartrite do Joelho/metabolismo , Antígeno CD146/metabolismo , Cartilagem Articular/cirurgia , Células-Tronco , Dor/metabolismo , Fenômenos Magnéticos
8.
Klin Onkol ; 37(6): 447-452, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38158233

RESUMO

BACKGROUND: Recent developments regarding the contribution of microRNAs (miRNAs) to tumor angiogenesis and the oncogenic effects of miRNAs point to their potential role in breast cancer angiogenesis. Tumor-derived exosomes are considered a rich source of miRNAs that can regulate the function of other cells in the tumor microenvironment, including vascular endothelial cells. This study analyzes the effect of tamoxifen chemotherapy on the expression of a key miRNA, miR-573, involved in the angiogenesis of the tumor exosomes and introduces a regulatory link between this miRNA and the CD146 gene associated with the vascular endothelial growth factor (VEGF) messaging pathway. MATERIALS AND METHODS: MCF-7 breast cancer cells were purchased and cultured in a complete culture medium. These cells were treated with tamoxifen and then their exosomes were extracted from the culture medium. The RNAs of the exosomes were isolated and the expression of miR-573, VEGF, and CD146 genes in the exosomes was investigated using the real-time polymerase chain reaction (PCR) method. RESULTS: The results of this study showed that tamoxifen treatment increased the expression of miR-573 in exosomes derived from MCF-7 cancer cells. The expression of CD146 and VEGF genes in drug-treated cell exosomes had a downward pattern. CONCLUSION: The results of this experiment demonstrated that the treatment of breast cancer cells with tamoxifen reduces the expression of VEGF and CD146 by increasing miR-573. Thus, angiogenesis is reduced and, therefore, its anti-tumor effects are applied.


Assuntos
Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Antígeno CD146/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Microambiente Tumoral
9.
Stem Cell Res Ther ; 14(1): 334, 2023 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-37981679

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are adult stem cells with self-renewal and multi-directional differentiation potential and possess the functions of immunomodulation, regulation of cell growth, and repair of damage. Over recent years, MSCs have been found to regulate the secretion of inflammatory factors and to exert regulatory effects on various lymphocytes in inflammatory states, and on the subsequent repair of tissue damage caused by inflammation. In the present study, we analyzed the effects of tissue inflammation on the characteristics of MSCs. METHODS: Human fat derived from the infrapatellar fat pad (IPFP) of knees with differing degrees of inflammation was extracted from specimens derived from total knee arthroplasties. HE and immunohistochemical staining was performed to directly observe the evidence and degree of inflammation in human infrapatellar fat pad tissue in order to classify MSCs cells, by their origin, into highly inflamed and lowly inflamed groups, and to study the effect of tissue inflammation on cell acquisition rates via cellular counting data. Flow cytometry assays were performed to investigate the effect of tissue inflammation on MSC surface marker expression. Trilineage differentiation, including osteogenesis, adipogenesis, and chondrogenesis, was performed to assess the effect of tissue inflammation on the ability of MSCs to undergo directed differentiation. The effect of tissue inflammation on the ability of MSCs to proliferate was investigated via clone formation studies. RNA-sequencing was performed to evaluate the transcriptomes of MSCs derived from different areas of inflammation. The effect of tissue inflammation on tissue repair capacity and safety of MSCs was investigated via a murine model of acute liver injury. RESULTS: The results of cell count data indicate that a high degree of tissue inflammation significantly decreases the acquisition rate of MSCs, and the proportion of CD34+ and CD146+ cells. The results of our trilineage differentiation assay show that a higher degree of inflammation decreases osteogenic differentiation and enhances adipogenic and chondrogenic differentiation of MSCs. However, these differences were not statistically significant. Clone formation assays indicate that the degree of tissue inflammation at the MSC source does not significantly affect the proliferative capacity of MSCs. The transcriptomes of MSCs remain relatively stable in fat pad tissues derived from both highly and lowly inflamed samples. The results of acute liver injury investigations in mice indicate that MSCs of high and low inflammatory tissue origin have no significant difference in their tissue repair capability. CONCLUSIONS: High tissue inflammation at the source of MSCs reduces the acquisition rate of MSCs and the percentage of CD34+ and CD146+ cells acquisition. However, source tissue inflammation may not significantly affect trilineage differentiation potential and proliferative capacity of MSCs. Also, MSCs obtained from differing source degrees of inflammation retain stable and similar transcriptomic profile and are both safe and efficacious for tissue repair/regeneration without detectable differences.


Assuntos
Células-Tronco Mesenquimais , Osteogênese , Adulto , Humanos , Animais , Camundongos , Osteogênese/fisiologia , Antígeno CD146/metabolismo , Modelos Animais de Doenças , Células-Tronco Mesenquimais/metabolismo , Diferenciação Celular , Tecido Adiposo , Inflamação/metabolismo , Fígado , Condrogênese , Células Cultivadas
10.
Ginekol Pol ; 94(12): 950-958, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37934895

RESUMO

OBJECTIVES: The study investigated the stem cell expression profiles and differentiation capacities of mesenchymal stem cells (MSCs) from different tissues, specifically human eutopic endometrium MSCs (eut-MSCs), ectopic endometrium MSCs (ect-MSCs), and umbilical cord MSCs (UC-MSCs). Our aim was to identify any similarities in subpopulations among these MSCs and lay a foundation for MSCs repair. MATERIAL AND METHODS: MSCs were isolated from endometrial tissue (n = 5), endometriosis tissue (n = 6), and umbilical cords (n = 7). Flow cytometry was used to examine cell phenotype, and three lineage tests were conducted to evaluate the differentiation capacity of the MSCs. RESULTS: Eut-MSCs expressed CD44 (98.00 ± 0.96%), CD73 (99.54 ± 0.02%), CD140b (99.16 ± 0.50%), CD146 (93.87 ± 2.27%), SUSD2 (50.76 ± 8.15%), and CD271 (2.1 ± 1.22%). Ect-MSCs expressed CD44 (98.23 ± 1.60%), CD73 (99.63 ± 0.04%), CD140b (98.13 ± 0.53%), CD146 (93.88 ± 3.19%), SUSD2 (49.33 ± 6.36%), and CD271 (2.85 ± 1.17%). UC-MSCs expressed CD44 (99.11 ± ± 0.42%), CD73 (99.65 ± 0.12%), CD140b (99.84 ± 0.42%), CD146 (88.09 ± 4.20%), SUSD2 (72.87 ± 7.13%), and CD271 (6.19 ± 2.08%). The expression of SUSD2 and CD271 in UC-MSCs was slightly but not significantly higher than that in ect-MSCs and eut-MSCs. However, CD44, CD73, CD140b, and CD146 showed similar expression levels in UC-MSCs, ect-MSCs, and eut-MSCs. All three types of MSCs demonstrated the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes. CONCLUSIONS: Our findings indicate that ect-MSCs, eut-MSCs, and UC-MSCs have similar stem cell phenotypes and the ability to differentiate into three lineages.


Assuntos
Células-Tronco Mesenquimais , Feminino , Humanos , Antígeno CD146/metabolismo , Endométrio , Cordão Umbilical , Adapaleno/metabolismo , Células Cultivadas
11.
Cancer Commun (Lond) ; 43(11): 1244-1266, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37856423

RESUMO

BACKGROUND: As a rapid-progressing tumor, breast malignant phyllodes tumors (PTs) are challenged by the lack of effective therapeutic strategies and suitable prognostic markers. This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression, and to identify a novel prognosis marker and treatment target of breast malignant PTs. METHODS: The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing (scRNA-seq), immunostaining, real-time PCR and other methodologies. Functional experiments including proliferation assay, colony formation assay, transwell assay, and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs. The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft (PDX) model. Transcriptome sequencing, proteomic analysis, co-immunoprecipitation, and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism. RESULTS: In this study, the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in the α-SMA+ fibroblast subset. Furthermore, a progressive elevation in the level of CD146 was observed with the malignant progression of PTs. More importantly, CD146 was found to serve as an independent predictor for recurrence in PT patients. Furthermore, CD146 was found to augment the viability and invasion of PTs. Mechanistically, CD146 acted as a protective "shield" to prevent the degradation of Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2), thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and enhancing malignant behaviors of PT cells. In the malignant PT organoid and PDX model, a significant suppression of malignant PT growth was observed after the application of AA98. CONCLUSIONS: These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs. The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.


Assuntos
Neoplasias da Mama , Tumor Filoide , Animais , Feminino , Humanos , Neoplasias da Mama/patologia , Antígeno CD146/genética , Modelos Animais de Doenças , Proteínas de Membrana , Fosfatidilinositol 3-Quinases , Tumor Filoide/genética , Tumor Filoide/metabolismo , Tumor Filoide/patologia , Proteômica , Proteínas Proto-Oncogênicas c-akt
12.
ACS Nano ; 17(18): 18008-18024, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37695238

RESUMO

Spinal cord injury (SCI) disrupts the blood-spinal cord barrier (BSCB), potentially exacerbating nerve damage and emphasizing the criticality of preserving the BSCB integrity during SCI treatment. This study explores an alternative therapeutic approach for SCI by identifying a subpopulation of exosomes with stable BSCB function and achieving a specific targeted delivery. Specific subpopulations of CD146+CD271+ umbilical cord mesenchymal stem cells (UCMSCs) were isolated, from which engineered exosomes (RGD-CD146+CD271+ UCMSC-Exos) with targeted neovascularization function were obtained through gene transfection. In vivo and in vitro experiments were performed to explore the targeting and therapeutic effects of RGD-CD146+CD271+ UCMSC-Exos and the potential mechanisms underlying BSCB stabilization and neural function recovery. The results demonstrated that RGD-CD146+CD271+ UCMSC-Exos exhibited physical and chemical properties similar to those of regular exosomes. Notably, following intranasal administration, RGD-CD146+CD271+ UCMSC-Exos exhibited enhanced aggregation at the SCI center and demonstrated the specific targeting of neovascular endothelial cells. In the SCI model, intranasal administration of RGD-CD146+CD271+ UCMSC-Exos reduced Evans blue dye leakage, increased tight junction protein expression, and improved neurological function recovery. In vitro testing revealed that RGD-CD146+CD271+ UCMSC-Exos treatment significantly reduced the permeability of bEnd.3 cells subjected to oxygen-glucose deprivation, thereby restoring the integrity of tight junctions. Moreover, further exploration of the molecular mechanism underlying BSCB stabilization by CD146+CD271+ UCMSC-Exos identified the crucial role of the miR-501-5p/MLCK axis in this process. In conclusion, targeted delivery of RGD-CD146+CD271+ UCMSC-Exos presents a promising and effective treatment option for SCI.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Traumatismos da Medula Espinal , Camundongos , Humanos , Animais , Antígeno CD146 , Células Endoteliais , Adapaleno , Traumatismos da Medula Espinal/terapia , Fatores Imunológicos , Oligopeptídeos/farmacologia
13.
Eur J Emerg Med ; 30(5): 347-355, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37598373

RESUMO

BACKGROUND AND IMPORTANCE: Diagnosing acute heart failure (AHF) is difficult in elderly patients presenting with acute dyspnea to the emergency department. OBJECTIVES: To assess the diagnostic accuracy of NT-proBNP, high-sensitivity cardiac troponin-I (Hs-cTnI), soluble ST2 (ST2), galectin-3 and CD146 alone and in combination for diagnosing AHF in elderly patients presenting with acute dyspnea to the emergency department. DESIGN, SETTINGS AND PARTICIPANTS: This was a prospective, multicenter study performed between September 2016 and January 2020, including elderly patients presenting with acute dyspnea to the emergency department of 6 French hospitals. INTERVENTION: Measurement of NT-proBNP, hs-cTnI, ST2, galectin-3 and CD146. OUTCOME MEASURE AND ANALYSIS: The reference standard, AHF, was adjudicated by two independent physicians based on ED and hospitalization clinical, biological (excluding biomarkers), radiological and echocardiography data (performed by a cardiologist in the cardiology department specifically for this study). Three exploratory methods (two using a cross-sectional approach with logistic regression and counting all biomarker combinations, and one using a sequential approach with gray zone optimizations) were applied to create comprehensive combinations of the 5 biomarkers for measuring diagnostic accuracy. MAIN RESULTS: Two hundred thirty-eight patients (median age of 85 years, IQR = 8) were analyzed, and 110 (46%) were diagnosed with AHF. The accuracies of NT-proBNP, CD146, hs-cTnI, galectin-3, and ST2 were 0.72 [95% confidence interval (CI) 0.66-0.77], 0.63 (95% CI 0.57-0.69), 0.59 (95% CI 0.53-0.65), 0.55 (95% CI 0.49-0.61) and 0.51 (95% CI 0.45-0.57), respectively. Regardless of the approach used or how the 5 biomarkers were combined, the best accuracy for diagnosing AHF (0.73, 95% CI 0.67-0.78) did not differ from that of NT-proBNP alone. CONCLUSION: In this study, NT-proBNP alone exhibited the best diagnostic accuracy for diagnosing AHF in elderly patients presenting with acute dyspnea to the emergency departments. None of the other biomarkers alone or combined improved the accuracy compared to NT-proBNP, which is the only biomarker to use in this setting.


Assuntos
Galectina 3 , Insuficiência Cardíaca , Idoso , Humanos , Criança , Antígeno CD146 , Proteína 1 Semelhante a Receptor de Interleucina-1 , Estudos Prospectivos , Hospitalização , Dispneia/diagnóstico , Dispneia/etiologia , Serviço Hospitalar de Emergência , Insuficiência Cardíaca/diagnóstico
14.
Med Microbiol Immunol ; 212(5): 391-405, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37650914

RESUMO

Cryptococcus neoformans (C. neoformans) is an important opportunistic fungal pathogen for pulmonary cryptococcosis. Previously, we demonstrated that CD146 mediated the adhesion of C. neoformans to the airway epithelium. CD146 is more than an adhesion molecule. In the present study, we aimed to explore the roles of CD146 in the inflammatory response in pulmonary cryptococcosis. CD146 was decreased in lung tissues from patients with pulmonary cryptococcosis. Similarly, C. neoformans reduced pulmonary CD146 expression in mice following intratracheal inoculation. To explore the pathological roles of CD146 reduction in pulmonary cryptococcosis, CD146 knockout (KO) mice were inoculated with C. neoformans via intratracheal instillation. CD146 deficiency aggravated C. neoformans infection, as evidenced by a shortened survival time and increased fungal burdens in the lung. Inflammatory type 2 cytokines (IL-4, IL-5, and TNF-α) and alternatively activated macrophages were increased in the pulmonary tissues of CD146 KO-infected mice. CD146 is expressed in immune cells (macrophages, etc.) and nonimmune cells, i.e., epithelial cells and endothelial cells. Bone marrow chimeric mice were established and infected with C. neoformans. CD146 deficiency in immune cells but not in nonimmune cells increased fungal burdens in the lung. Mechanistically, upon C. neoformans challenge, CD146 KO macrophages produced more neutrophil chemokine KC and inflammatory cytokine TNF-α. Meanwhile, CD146 KO macrophages decreased the fungicidity and production of reactive oxygen species. Collectively, C. neoformans infection decreased CD146 in pulmonary tissues, leading to inflammatory type 2 responses, while CD146 deficiency worsened pulmonary cryptococcosis.


Assuntos
Criptococose , Cryptococcus neoformans , Animais , Camundongos , Antígeno CD146 , Citocinas , Células Endoteliais , Camundongos Knockout , Fator de Necrose Tumoral alfa
15.
Int J Mol Sci ; 24(15)2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37569284

RESUMO

Adipose stem and progenitor cells (ASPCs) have been isolated from humans and animals for use in regenerative medicine and therapy. However, knowledge of ASPCs in other species is limited. Particularly, ASPCs in livestock are expected to enhance the fat content and meat composition. In this study, we isolated bovine ASPCs using cell surface markers. Specifically, we focused on ASPC markers in humans and experimental animals, namely CD26, CD146, and CD54. Stromal vascular fraction cells from bovine fat were separated using flow cytometry before primary culture. We evaluated the self-renewal and adipogenic potential of each fraction. We identified four cell populations: CD26-CD146+CD54+, CD26-CD146+CD54-, CD26-CD146-, and CD26+CD146-. Among them, the CD26-CD146+ fraction, particularly CD54+, demonstrated the properties of preadipocytes (PreAs), characterized by slow proliferation and a high adipogenic capacity. In conclusion, we could collect and characterize possible PreAs as CD26-CD146+CD54+ or CD26-CD146+CD54-, which are expected for in vitro bovine adipogenic assays in the future.


Assuntos
Dipeptidil Peptidase 4 , Células-Tronco , Humanos , Bovinos , Animais , Dipeptidil Peptidase 4/metabolismo , Diferenciação Celular , Antígeno CD146/metabolismo , Células-Tronco/metabolismo , Citometria de Fluxo , Obesidade/metabolismo , Tecido Adiposo/metabolismo
16.
J Oral Pathol Med ; 52(7): 660-665, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37336496

RESUMO

BACKGROUND: Vascular anomalies and tumors are common in the head, neck, and craniofacial areas and are associated with abnormalities in the angiomatous architecture. However, the etiology and molecular basis for the pathogenesis of most vascular lesions are still unknown. Pericytes are mural cells that surround endothelial cells. Besides angiogenesis and other physiological functions, pericytes play an important role in vascularized tissue repair and as resident mesenchymal stem/progenitor cells. Perivascular cells demonstrate a distinct immunohistochemical profile, including expression of alpha-smooth muscle actin (α-SMA), CD146, CD105, and PDGFRß, without endothelial differentiation (absence of CD31 and CD34 immunoreactivity). These pericyte markers have been shown to be expressed in soft tissue hemangiomas. However, they have not been fully examined in intraosseous hemangiomas. METHODS: In this study, we compared mesenchymal stem cell (MSC) expression of CD146 and α-SMA markers in pericytes from hemangiomas from different tissues and malignant vascular tumors. RESULTS: The results demonstrated an increased expression of pericyte markers in perivascular cells of benign hemangiomas, especially intraosseous hemangiomas and a significantly reduced expression of pericyte markers in malignant angiosarcomas. CONCLUSION: The evidence provides insight into the function of pericytes in vascular tumors and suggests their role in vascular tumor disease types.


Assuntos
Hemangioma , Neoplasias Vasculares , Humanos , Pericitos/metabolismo , Pericitos/patologia , Neoplasias Vasculares/metabolismo , Neoplasias Vasculares/patologia , Antígeno CD146/metabolismo , Células Endoteliais/metabolismo , Hemangioma/metabolismo , Hemangioma/patologia
17.
Cell Mol Immunol ; 20(8): 908-923, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37308559

RESUMO

As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.


Assuntos
Inflamassomos , Neoplasias , Animais , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antígeno CD146/metabolismo , Macrófagos , Microambiente Tumoral
18.
Theranostics ; 13(7): 2319-2336, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37153740

RESUMO

Netrin-1 binds to the high-affinity receptor CD146 to activate downstream signaling and angiogenesis. Here, we examine the role and underlying mechanisms of G protein subunit alpha i1 (Gαi1) and Gαi3 in Netrin-1-induced signaling and pro-angiogenic activity. In mouse embryonic fibroblasts (MEFs) and endothelial cells, Netrin-1-induced Akt-mTOR (mammalian target of rapamycin) and Erk activation was largely inhibited by silencing or knockout of Gαi1/3, whereas signaling was augmented following Gαi1/3 overexpression. Netrin-1 induced Gαi1/3 association with CD146, required for CD146 internalization, Gab1 (Grb2 associated binding protein 1) recruitment and downstream Akt-mTOR and Erk activation. Netrin-1-induced signaling was inhibited by CD146 silencing, Gab1 knockout, or Gαi1/3 dominant negative mutants. Netrin-1-induced human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation were inhibited by Gαi1/3 short hairpin RNA (shRNA), but were potentiated by ectopic Gαi1/3 overexpression. In vivo, intravitreous injection of Netrin-1 shRNA adeno-associated virus (AAV) significantly inhibited Akt-mTOR and Erk activation in murine retinal tissues and reduced retinal angiogenesis. Endothelial knockdown of Gαi1/3 significantly inhibited Netrin1-induced signaling and retinal angiogenesis in mice. Netrin-1 mRNA and protein expression were significantly elevated in retinal tissues of diabetic retinopathy (DR) mice. Importantly, silence of Netrin-1, by intravitreous Netrin-1 shRNA AAV injection, inhibited Akt-Erk activation, pathological retinal angiogenesis and retinal ganglion cells degeneration in DR mice. Lastly, Netrin-1 and CD146 expression is significantly increased in the proliferative retinal tissues of human proliferative diabetic retinopathy patients. Together, Netrin-1 induces CD146-Gαi1/3-Gab1 complex formation to mediate downstream Akt-mTOR and Erk activation, important for angiogenesis in vitro and in vivo.


Assuntos
Retinopatia Diabética , Proteínas Proto-Oncogênicas c-akt , Humanos , Animais , Camundongos , Antígeno CD146/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Netrina-1 , Fibroblastos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , RNA Interferente Pequeno , Proteínas de Transporte , Mamíferos/metabolismo
19.
Aging Cell ; 22(8): e13873, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37254638

RESUMO

Aging is one of the major etiological factors driving intervertebral disc (IVD) degeneration, the main cause of low back pain. The nucleus pulposus (NP) includes a heterogeneous cell population, which is still poorly characterized. Here, we aimed to uncover main alterations in NP cells with aging. For that, bovine coccygeal discs from young (12 months) and old (10-16 years old) animals were dissected and primary NP cells were isolated. Gene expression and proteomics of fresh NP cells were performed. NP cells were labelled with propidium iodide and analysed by flow cytometry for the expression of CD29, CD44, CD45, CD146, GD2, Tie2, CD34 and Stro-1. Morphological cell features were also dissected by imaging flow cytometry. Elder NP cells (up-regulated bIL-6 and bMMP1 gene expression) presented lower percentages of CD29+, CD44+, CD45+ and Tie2+ cells compared with young NP cells (upregulated bIL-8, bCOL2A1 and bACAN gene expression), while GD2, CD146, Stro-1 and CD34 expression were maintained with age. NP cellulome showed an upregulation of proteins related to endoplasmic reticulum (ER) and melanosome independently of age, whereas proteins upregulated in elder NP cells were also associated with glycosylation and disulfide bonds. Flow cytometry analysis of NP cells disclosed the existence of 4 subpopulations with distinct auto-fluorescence and size with different dynamics along aging. Regarding cell morphology, aging increases NP cell area, diameter and vesicles. These results contribute to a better understanding of NP cells aging and highlighting potential anti-aging targets that can help to mitigate age-related disc disease.


Assuntos
Degeneração do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Animais , Bovinos , Núcleo Pulposo/metabolismo , Antígeno CD146/metabolismo , Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Envelhecimento/metabolismo
20.
J Transl Med ; 21(1): 242, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-37013608

RESUMO

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted. METHODS: We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture. RESULTS: We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4-44.3%) and 33.6% (IQR 22.9-43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions. CONCLUSION: These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.


Assuntos
Síndrome de Fadiga Crônica , Canais de Cátion TRPM , Humanos , Células Matadoras Naturais , Antígeno CD146
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