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Hu Y, Ou HJ, Wang HL, Zhou WJ. The role of LECT2 in kidney fibrosis progression and endoplasmic reticulum stress. Life Sci 2025; 375:123714. [PMID: 40398731 DOI: 10.1016/j.lfs.2025.123714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 05/08/2025] [Accepted: 05/12/2025] [Indexed: 05/23/2025]
Abstract
AIMS Our previous studies showed that Leukocyte Cell-Derived Chemotaxin 2 (LECT2), as a ligand for Tie1, modulates vascular endothelial cell function, promoting hepatic fibrosis. These findings prompted an investigation into whether LECT2 effects kidney fibrosis. This study aimed to elucidate the role of LECT2 in kidney fibrosis and its regulation of C/EBP homologous protein (CHOP) expression. MATERIALS AND METHODS We utilized Lect2-KO mice, Lect2-2 A-Cre-Rosa26-LSL-tdTomato reporter mice, and EA.hy926 cells overexpressing LECT2 to establish models of kidney fibrosis and endoplasmic reticulum stress (ERS). The expression characteristics of LECT2 in fibrotic kidneys, its effects on CHOP expression, and the mechanisms by which LECT2 modulates kidney fibrosis were systematically investigated. KEY FINDINGS Lect2 expression was upregulated in clinical fibrotic kidney samples and mouse models of fibrotic kidneys. Lect2-KO mice demonstrated reduced fibrosis and less impairment of kidney function in a kidney fibrosis model. In Lect2-KO mice, expression of the ERS marker CHOP was increased, and vascular endothelial cells were activated to express CHOP earlier, reducing kidney function damage. Overexpression of LECT2 decreased apoptosis, promoted cell survival, and upregulated the expression of profibrotic factors through activation of the EGFR/AKT/PI3K pathway. Lect2 deficiency in fibrotic kidneys led to attenuated myofibroblast activation and reduced collagen deposition. SIGNIFICANCE The absence of LECT2 alleviates kidney fibrosis by inhibiting the EGFR/PI3K/AKT pathway, activating ERS, promoting partial endothelial cell apoptosis, and reducing the secretion of profibrotic factors. LECT2 emerges as a promising therapeutic target for kidney fibrosis, and its inhibition offers a potential strategy for CKD treatment.
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Affiliation(s)
- Yang Hu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hai-Jun Ou
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hong-Lei Wang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wei-Jie Zhou
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Division of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510515, China.
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Jiao Q, Xu X, Xu L, Wang Y, Pang S, Hao J, Liu X, Zhao Y, Qi W, Qin L, Huang T, Li J, Wang T. Knockdown of eIF3a alleviates pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition via TGFβ1/SMAD pathway. J Transl Med 2025; 23:524. [PMID: 40346622 PMCID: PMC12065328 DOI: 10.1186/s12967-025-06505-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 04/13/2025] [Indexed: 05/11/2025] Open
Abstract
OBJECTIVE Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vascular remodeling and involves Endothelial-to-Mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs). EndMT is a complex cell differentiation process, mainly showing the detachment of endothelial cell migration and reducing endothelial cell characteristics to varying degrees, acquiring mesenchymal cell characteristics. In addition, numerous studies have reported that eIF3a over expression plays an important role in the occurrence and development of fibrotic diseases, cancer, and degenerative lesions, however, the mechanisms of eIF3a affecting the dysfunction of pulmonary arterial endothelial cells remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of eIF3a-knockdown inhibiting EndMT by regulating TGFβ1/SMAD signal pathway in PAH. METHODS In this study, we screened the potential target genes associated with idiopathic pulmonary arterial hypertension (IPAH) by WGCNA to provide a reference for the diagnosis and treatment of PAH. By constructing WGCNA, which indicated that the blue module (module-trait associations between modules and clinical feature information were calculated to selected the optimum module) is most closely associated with IPAH, we further screened out 10 up-regulated candidate biomarker genes. Male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), AAV1-shRNA-NC group and AAV1-shRNA-eIF3a group. The eIF3a-knockdown rat model was constructed by adeno-associated virus type-1 (AAV1) infection, PAH was evaluated according to hemodynamic alteration, right heart hypertrophy and histopathological changes in the lung tissue. Hematoxylin eosin (H&E) staining was used to assess the morphological changes of pulmonary arteries in rats of each treatment group. Co-localization of eIF3a with alpha-small muscle action (α-SMA) and co-localization of eIF3a with endothelial marker (CD31) were detected by double-label immunofluorescence. Immunohistochemistry (IHC) and Western blot (WB) experiments were performed to assess the expression of eIF3a, EndMT and TGFβ1/SMAD signal related proteins. In vitro, primary rat pulmonary artery endothelial cells (PAECs) were transfected with si-eIF3a to investigate the effects of eIF3a-knockdown on hypoxia-induced EndMT in PAECs and further elucidate its underlying molecular mechanisms. RESULTS By WGCNA analysis, we screened the up-regulated hub genes of TMF1, GOLGB1, ARMC8, PRPF40 A, EIF3 A, ROCK2, EIF5B, CCP110, and KRR1 associated with PAH, and in order to verify the potential role of eIF3a in the development of pulmonary arterial hypertension, MCT-induced PAH rat model was constructed successfully. The expression of eIF3a was increased in MCT-treated lungs. Knockdown of eIF3a significantly inhibited the pulmonary arterial hypertension and vascular remodeling in MCT-induced PAH rat model, ameliorated MCT-induced increases of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Double-labeled immunofluorescence showed eIF3a was mostly co-localized with CD31, this result indicated that the development of MCT-induced PAH was related to the regulation of PAECs function (most likely associated with the change of EndMT in endothelial cells). WB showed that the expressions of EndMT related proteins were significantly increased by regulating TGFβ1/SMAD signaling pathway in MCT-induced PAH rat lung tissues, however, knockdown of eIF3a markedly attenuated these changes. In addition, we observed the same results in rat PAECs with chronic hypoxia exposure. These results indicate that eIF3a-knockdown inhibited EndMT by regulating TGFβ1/SMAD signaling pathway in PAECs, thereby improving the development of MCT-induced PAH. CONCLUSIONS Knockdown of eIF3a inhibited EndMT in PAECs regulating TGFβ1/SMAD signaling pathway, significantly alleviated the changes of RVSP, RVH and vascular remodeling in MCT-induced PAH rats, eIF3a may be a promising and novel therapeutic target for the treatment of PAH.
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Affiliation(s)
- Qiuhong Jiao
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Xiufeng Xu
- Department of Geriatrics, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Longwu Xu
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Yuying Wang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Shulan Pang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Jie Hao
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Xiaohong Liu
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Yudan Zhao
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Wanpeng Qi
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Limin Qin
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Tao Huang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Jingtian Li
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Tao Wang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China.
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Jimenez SA, Mendoza FA, Piera-Velazquez S. A review of recent studies on the pathogenesis of Systemic Sclerosis: focus on fibrosis pathways. Front Immunol 2025; 16:1551911. [PMID: 40308583 PMCID: PMC12040652 DOI: 10.3389/fimmu.2025.1551911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 03/07/2025] [Indexed: 05/02/2025] Open
Abstract
Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology characterized by the development of frequently progressive cutaneous and internal organ fibrosis accompanied by severe vascular alterations. The pathogenesis of SSc is highly complex and, despite extensive investigation, has not been fully elucidated. Numerous studies have suggested that unknown etiologic factors cause multiple alterations in genetically receptive hosts, leading to SSc development and progression. These events may be functionally and pathologically interconnected and include: 1) Structural and functional microvascular and endothelial cell abnormalities; 2) Severe oxidative stress and high reactive oxygen species (3); Frequently progressive cutaneous and visceral fibrosis; 4) Transdifferentiation of various cell types into activated myofibroblasts, the cells ultimately responsible for the fibrotic process; 5) Establishment of a chronic inflammatory process in various affected tissues; 6) Release of cytokines, chemokines, and growth factors from the inflammatory cells; 7) Abnormalities in humoral and cellular immunity with the production of specific autoantibodies; and 8) Epigenetic alterations including changes in multiple non-coding RNAs. These events manifest with different levels of intensity in the affected organs and display remarkable individual variability, resulting in a wide heterogeneity in the extent and severity of clinical manifestations. Here, we will review some of the recent studies related to SSc pathogenesis.
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Affiliation(s)
- Sergio A. Jimenez
- Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Fabian A. Mendoza
- Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, PA, United States
- Division of Rheumatology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United States
| | - Sonsoles Piera-Velazquez
- Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, PA, United States
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Chu T, Tong J, Zhu Z, Zhang G, Weng Y, Sun L, Sun L, Cui J, Liu J, Xiao Y, Zhang L, Song Y. Single-nucleus RNA sequencing decodes abnormal cell-collagen communication in a sheep endometrial fibrosis model. Int J Biol Macromol 2025; 303:140628. [PMID: 39920948 DOI: 10.1016/j.ijbiomac.2025.140628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 02/01/2025] [Accepted: 02/01/2025] [Indexed: 02/10/2025]
Abstract
Endometrial fibrosis in sheep reduces reproductive performance with elusive therapeutic targets. The fibrotic endometrium is a complex ecosystem with heterogeneous cells and their interactions. The molecular characterization of key cells and the mechanisms of these interactions are unclear. To uncover the key molecular features of sheep endometrial fibrosis tissue, we used single-nucleus RNA sequencing to profile the transcriptional characterization of sheep endometrial cells from both normal and fibrotic tissues, aiming to clarify the mechanisms of fibrosis development. Histomorphological analysis revealed significant collagen deposition in fibrotic endometrial tissue. The transcription atlas of sheep endometrial cells was created, identifying eight main endometrial cell types. Key findings include the abnormal expression of collagen-related genes in fibrotic cells and the identification of endothelial cells and fibroblasts as major contributors to fibrogenesis with aberrant receptor-ligand interactions involving collagen-related genes. Fibroblasts had a tendency to differentiate into myofibroblasts in fibroblast-mediated fibrosis progression. In vitro experiments demonstrated the role of fibroblasts in fibroblast activation through the PERK/eIF2α/CHOP stress pathway. Additionally, fibrosis disturbs the immune microenvironment. This study highlights that high collagen gene expression in injured endometrial cells leads to abnormal tissue repair and fibrosis, offering valuable insights for understanding endometrial fibrosis at the single-cell level.
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Affiliation(s)
- Tingting Chu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Jiashun Tong
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Zhongshi Zhu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Guoliang Zhang
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, Shandong 266109, PR China.
| | - Yunan Weng
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, PR China
| | - Lei Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Le Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Jiuzeng Cui
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Jiaxin Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Yuhang Xiao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China
| | - Lei Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
| | - Yuxuan Song
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
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Wu J, Wang J, Pei Z, Zhu Y, Zhang X, Zhou Z, Ye C, Song M, Hu Y, Xue P, Zhao G. Endothelial senescence induced by PAI-1 promotes endometrial fibrosis. Cell Death Discov 2025; 11:89. [PMID: 40050610 PMCID: PMC11885584 DOI: 10.1038/s41420-025-02377-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/07/2025] [Accepted: 02/24/2025] [Indexed: 03/09/2025] Open
Abstract
Intrauterine adhesions (IUAs), also known as Asherman's syndrome (AS), represent a significant cause of uterine infertility for which effective treatment remains elusive. The endometrium's ability to regenerate cyclically depends heavily on the growth and regression of its blood vessels. However, trauma to the endometrial basal layer can disrupt the subepithelial capillary plexus, impeding regeneration. This damage results in the replacement of native cells with fibroblasts and myofibroblasts, ultimately leading to fibrosis. Endothelial cells (ECs) play a pivotal role in the vascular system, extending beyond their traditional barrier function. Through single-cell sequencing and experimental validation, we discovered that ECs undergo senescence in IUA patients, impairing angiogenesis and fostering stromal cell fibrosis. Further analysis revealed significant interactions between ECs and PAI-1+ stromal cells. PAI-1, derived from stromal cells, promotes EC senescence via the urokinase-type plasminogen activator receptor (uPAR). Notably, prior to fibrosis onset, TGF-β upregulates PAI-1 expression in stromal cells in a SMAD dependent manner. In an IUA mouse model, inhibiting PAI-1 mitigated EC senescence and endometrial fibrosis. Our findings underscore the crucial role of EC senescence in IUA pathogenesis, contributing to vascular reduction and fibrosis. Targeting PAI-1 represents a promising therapeutic strategy to suppress EC senescence and alleviate endometrial fibrosis, offering new insights into the treatment of IUAs.
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Affiliation(s)
- Jing Wu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jie Wang
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhongrui Pei
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yaru Zhu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xier Zhang
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zihan Zhou
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Chunying Ye
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Minmin Song
- Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China
| | - Yali Hu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Pingping Xue
- Department of Reproductive Medicine Center, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
| | - Guangfeng Zhao
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Zou Y, Shi H, Li Y, Li T, Liu N, Liu B. Heat shock protein 27 downregulation attenuates isoprenaline-induced myocardial fibrosis and diastolic dysfunction by modulating the endothelial-mesenchymal transition. Biochem Pharmacol 2024; 230:116612. [PMID: 39515591 DOI: 10.1016/j.bcp.2024.116612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 10/11/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Heart failure (HF), an end-stage clinical syndrome secondary to cardiac impairment, significantly affects patients' quality of life and long-term prognosis. Myocardial fibrosis leads to systolic and diastolic dysfunction, and promotes the progression of HF. Several studies involving the modulation of myocardial fibrosis have been conducted in an effort to improve cardiac function. Heat shock protein 27 (HSP27) is a small chaperone protein that is overexpressed in cellular stress states. HSP27 modulates epithelial-mesenchymal transition, playing a crucial role in the pathology of several fibrotic diseases. However, its association with myocardial fibrosis regulation is unknown. This study aimed to investigate the mechanisms by which HSP27 regulates myocardial fibrosis. We created cardiac-specific HSP25 (the murine ortholog of human HSP27) knockout mice and found that HSP25 knockdown inhibited endothelial-mesenchymal transition (EndMT), attenuated myocardial fibrosis, and ameliorated diastolic dysfunction in isoproterenol-induced HF mice via echocardiography, histology, and western bloting. In vitro, HSP27 knockdown attenuated transforming growth factor beta-induced EndMT, whereas HSP27 overexpression promoted EndMT. Furthermore, the SMAD3/SNAIL1 pathway was found to be crucial for HSP27-mediated EndMT regulation. As an essential molecule in EndMT regulation and myocardial fibrosis modulation, HSP27 may hold promise as a therapeutic target for patients with HF.
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Affiliation(s)
- Yifei Zou
- Department of Cardiology, Second Hospital of Jilin University, No. 4026 Yatai Street, Changchun 130041, China
| | - Henghe Shi
- Department of Cardiology, Second Hospital of Jilin University, No. 4026 Yatai Street, Changchun 130041, China
| | - Yinghao Li
- Department of Cardiology, Second Hospital of Jilin University, No. 4026 Yatai Street, Changchun 130041, China
| | - Tianyi Li
- Department of Cardiology, Second Hospital of Jilin University, No. 4026 Yatai Street, Changchun 130041, China
| | - Ning Liu
- Department of Cardiology, Second Hospital of Jilin University, No. 4026 Yatai Street, Changchun 130041, China.
| | - Bin Liu
- Department of Cardiology, Second Hospital of Jilin University, No. 4026 Yatai Street, Changchun 130041, China.
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Chen J, Yang Y, Su S, Zhang S, Huang J, Chen H, Yang X, Sang A. ANGPTL4 promotes choroidal neovascularization and subretinal fibrosis through the endothelial‒mesenchymal transition. Int Ophthalmol 2024; 44:441. [PMID: 39586852 DOI: 10.1007/s10792-024-03348-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 10/25/2024] [Indexed: 11/27/2024]
Abstract
PURPOSE This study aimed to investigate the possible mechanisms by which ANGPTL4 is involved in the pathogenesis of choroidal neovascularization (CNV) and subretinal fibrosis. METHODS Differentially expressed genes in retinal pigmented epithelium (RPE)-choroid-sclera complex tissues from nAMD patients and control individuals were identified via the GEO database, followed by GO and KEGG analyses. A Venn diagram was used to identify EndMT-related DEGs. A logistic regression model was constructed to screen for prognostic genes. Laser-induced CNV mouse models were established and validated with FFA and OCTA. The expression of ANGPTL4 and EndMT-related markers in the RPE-choroid-sclera complex was measured via RT‒qPCR and Western blotting. TGF-β2-induced HUVECs were used as EndMT cell models, and specific siRNAs targeting ANGPTL4 (si-ANGPTL4) were designed and screened. The effects of ANGPTL4 knockdown on the migration and invasion of HUVECs were also examined. Laser-induced CNV mouse models were constructed, and an intravitreal injection of cholesterol-modified si-ANGPTL4 was used to knock down ANGPTL4. FFA, OCTA and immunofluorescence staining were used to observe CNV formation and subretinal fibrosis, and the expression of ANGPTL4 and EndMT-related markers was determined. RESULTS ANGPTL4 expression was significantly increased in mice with CNV and colocalized with IB4. In TGF-β2-induced EndMT, ANGPTL4 was also upregulated, and its knockdown led to the inhibition of EndMT and cell migration and invasion, while its overexpression promoted the EndMT process. ANGPTL4 knockdown reduced the formation of CNV and subretinal fibrosis in mice with CNV by suppressing EndMT. CONCLUSIONS ANGPTL4 may promote CNV and subretinal fibrosis through EndMT, suggesting that ANGPTL4 may be a novel potential target for nAMD therapy.
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Affiliation(s)
- Jia Chen
- Suzhou Medical College of Soochow University, Suzhou, 215123, China
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Ying Yang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong University, Nantong, 226001, China
| | - Shu Su
- Suzhou Medical College of Soochow University, Suzhou, 215123, China
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Shenglai Zhang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong University, Nantong, 226001, China
| | - Ju Huang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Dalian Medical University, Dalian, 116044, China
| | - Hong Chen
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Dalian Medical University, Dalian, 116044, China
| | - Xiaowei Yang
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China.
- Nantong University, Nantong, 226001, China.
| | - Aimin Sang
- Suzhou Medical College of Soochow University, Suzhou, 215123, China.
- Eye Institute, Affiliated Hospital of Nantong University, Nantong, 226001, China.
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Baldassarro VA, Alastra G, Cescatti M, Quadalti C, Lorenzini L, Giardino L, Calzà L. SARS-CoV-2-related peptides induce endothelial-to-mesenchymal transition in endothelial capillary cells derived from different body districts: focus on membrane (M) protein. Cell Tissue Res 2024; 397:241-262. [PMID: 38953987 DOI: 10.1007/s00441-024-03900-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/30/2024] [Indexed: 07/04/2024]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19, may lead to multiple organ dysfunctions and long-term complications. The induction of microvascular dysfunction is regarded as a main player in these pathological processes. To investigate the possible impact of SARS-CoV-2-induced endothelial-to-mesenchymal transition (EndMT) on fibrosis in "long-COVID" syndrome, we used primary cultures of human microvascular cells derived from the lungs, as the main infection target, compared to cells derived from different organs (dermis, heart, kidney, liver, brain) and to the HUVEC cell line. To mimic the virus action, we used mixed SARS-CoV-2 peptide fragments (PepTivator®) of spike (S), nucleocapsid (N), and membrane (M) proteins. TGFβ2 and cytokine mix (IL-1β, IL-6, TNFα) were used as positive controls. The percentage of cells positive to mesenchymal and endothelial markers was quantified by high content screening. We demonstrated that S+N+M mix induces irreversible EndMT in all analyzed endothelial cells via the TGFβ pathway, as demonstrated by ApoA1 treatment. We then tested the contribution of single peptides in lung and brain cells, demonstrating that EndMT is triggered by M peptide. This was confirmed by transfection experiment, inducing the endogenous expression of the glycoprotein M in lung-derived cells. In conclusion, we demonstrated that SARS-CoV-2 peptides induce EndMT in microvascular endothelial cells from multiple body districts. The different peptides play different roles in the induction and maintenance of the virus-mediated effects, which are organ-specific. These results corroborate the hypothesis of the SARS-CoV-2-mediated microvascular damage underlying the multiple organ dysfunctions and the long-COVID syndrome.
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Affiliation(s)
- Vito Antonio Baldassarro
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Bologna, Italy
- Interdepartmental Centre for Industrial Research in Health Sciences and Technology ICIR-HST, University of Bologna, Bologna, Italy
| | - Giuseppe Alastra
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Bologna, Italy
| | | | - Corinne Quadalti
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
| | - Luca Lorenzini
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Bologna, Italy
- Interdepartmental Centre for Industrial Research in Health Sciences and Technology ICIR-HST, University of Bologna, Bologna, Italy
| | - Luciana Giardino
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Bologna, Italy
- Interdepartmental Centre for Industrial Research in Health Sciences and Technology ICIR-HST, University of Bologna, Bologna, Italy
| | - Laura Calzà
- Interdepartmental Centre for Industrial Research in Health Sciences and Technology ICIR-HST, University of Bologna, Bologna, Italy.
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy.
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Qin T, Song X, Shao Q, Zhang J, Sui H. Resveratrol ameliorates pathological fibrosis of the myodural bridge by regulating the SIRT3/TGF-β1/Smad pathway. Heliyon 2024; 10:e34974. [PMID: 39145011 PMCID: PMC11320322 DOI: 10.1016/j.heliyon.2024.e34974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 07/17/2024] [Accepted: 07/19/2024] [Indexed: 08/16/2024] Open
Abstract
Purpose Pathological fibrosis of the myodural bridge (MDB) affects cerebrospinal fluid circulation. However, no optimal drug treatments are available. We aimed to explore the antifibrotic effect of resveratrol on bleomycin-induced pathological fibrosis of the MDB and its underlying mechanisms. Methods Genes common to the potential targets of resveratrol were determined using network pharmacology, genes related to muscle and tendon fibrosis were acquired from the GeneCards database, and genes related to MDB development were determined using Venny. These genes were considered potential resveratrol treatment targets in bleomycin-induced pathological fibrosis of the MDB and were annotated using bioinformatics methods. We validated the intersected genes using quantitative real-time polymerase chain reaction (qRT-PCR) and performed molecular docking analysis to calculate the binding activity between the target gene and resveratrol. Hematoxylin and eosin and Masson staining were used to detect the morphological changes in bleomycin-induced fibrosis of the MDB following resveratrol treatment. We used qRT-PCR and immunohistochemistry to evaluate the expression of the sirtuin 3 (SIRT3)/transforming growth factor-β1 (TGF-β1)/Smad pathway and the profibrotic markers α-smooth muscle actin (α-SMA) and Collagen Ⅰ. Results Through network pharmacology and bioinformatics analyses, we identified four core intersected genes, and SIRT3 expression was validated using qRT-PCR. Molecular docking analysis revealed that resveratrol had good binding affinity for SIRT3. Resveratrol ameliorated morphological abnormalities in bleomycin-induced pathological fibrosis of the MDB by inhibiting fibroblast activation and excessive collagen fiber deposition. Resveratrol exerted its antifibrotic effect by regulating the SIRT3/TGF-β1/Smad pathway. Conclusion Resveratrol has an antifibrotic effect in bleomycin-induced pathological fibrosis of the MDB in vivo and may be considered a novel therapeutic strategy.
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Affiliation(s)
- Tao Qin
- Department of Anatomy, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
- Graduate School, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
| | - Xue Song
- Department of Anatomy, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
- Graduate School, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
| | - Qing Shao
- Department of Anatomy, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
- Graduate School, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
| | - Jianfei Zhang
- Department of Anatomy, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
| | - Hongjin Sui
- Department of Anatomy, Dalian Medical University, 9 West Section, Lushun South Road, Dalian, Liaoning Province, 116044, China
- Dalian Hoffen Preservation Technique Institution, No.36, Guangyuan Street, Lushunkou Economic Development Zone, Dalian, 116052, China
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10
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Wang M, Mo D, Zhang N, Yu H. Ferroptosis in diabetic cardiomyopathy: Advances in cardiac fibroblast-cardiomyocyte interactions. Heliyon 2024; 10:e35219. [PMID: 39165946 PMCID: PMC11334834 DOI: 10.1016/j.heliyon.2024.e35219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/19/2024] [Accepted: 07/24/2024] [Indexed: 08/22/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a common complication of diabetes, and its pathogenesis remains elusive. Ferroptosis, a process dependent on iron-mediated cell death, plays a crucial role in DCM via disrupted iron metabolism, lipid peroxidation, and weakened antioxidant defenses. Hyperglycemia, oxidative stress, and inflammation may exacerbate ferroptosis in diabetes. This review emphasizes the interaction between cardiac fibroblasts and cardiomyocytes in DCM, influencing ferroptosis occurrence. By exploring ferroptosis modulation for potential therapeutic targets, this article offers a fresh perspective on DCM treatment. The study systematically covers the interplay, mechanisms, and targeted drugs linked to ferroptosis in DCM development.
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Affiliation(s)
| | | | - Ning Zhang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Haichu Yu
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
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11
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Contursi A, Tacconelli S, Di Berardino S, De Michele A, Patrignani P. Platelets and extracellular vesicles in disease promotion via cellular cross-talk and eicosanoid biosynthesis. Prostaglandins Other Lipid Mediat 2024; 173:106848. [PMID: 38723943 DOI: 10.1016/j.prostaglandins.2024.106848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/12/2024] [Accepted: 05/03/2024] [Indexed: 06/17/2024]
Abstract
New insights have been gained on the role of platelets beyond thrombosis. Platelets can accumulate in damaged and inflamed tissues, acting as a sentinel to detect and repair tissue damage. However, by releasing several soluble factors, including thromboxane A2 (TXA2) and 12-hydroxyeicosatetraenoic acid, and extracellular vesicles (EVs), platelets can activate vascular cells, stromal, such as fibroblasts, immune cells, and cancer cells, leading to atherosclerosis, vascular restenosis, tissue fibrosis, and tumor metastasis. Platelet-derived extracellular vesicles (PEVs) are released when platelets are activated and can transfer their cargo to other cell types, thus contributing to the development of diseases. Inhibitors of the internalization of PEVs can potentially represent novel therapeutic tools. Both platelets and PEVs contain a significant number of different types of molecules, and their omics assessment and integration with clinical data using computational approaches have the potential to detect early disease development and monitor drug treatments.
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Affiliation(s)
- Annalisa Contursi
- Systems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University Medical School, Chieti, Italy
| | - Stefania Tacconelli
- Systems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy
| | - Sara Di Berardino
- Systems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University Medical School, Chieti, Italy
| | - Alessandra De Michele
- Systems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University Medical School, Chieti, Italy
| | - Paola Patrignani
- Systems Pharmacology and Translational Therapeutics Laboratory, at the Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Science, "G. d'Annunzio" University Medical School, Chieti, Italy.
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12
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Wang Z, Zhang Y, Li X. Mitigation of Oxidative Stress in Idiopathic Pulmonary Fibrosis Through Exosome-Mediated Therapies. Int J Nanomedicine 2024; 19:6161-6176. [PMID: 38911503 PMCID: PMC11193999 DOI: 10.2147/ijn.s453739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 05/01/2024] [Indexed: 06/25/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) poses a formidable clinical challenge, characterized by the thickening of alveolar septa and the onset of pulmonary fibrosis. The pronounced activation of oxidative stress emerges as a pivotal hallmark of inflammation. Traditional application of exogenous antioxidants proves inadequate in addressing oxidative stress, necessitating exploration into strategies to augment their antioxidant efficacy. Exosomes, nano-sized extracellular vesicles harboring a diverse array of bioactive factors, present as promising carriers with the potential to meet this challenge. Recent attention has been directed towards the clinical applications of exosomes in IPF, fueling the impetus for this comprehensive review. We have compiled fresh insights into the role of exosomes in modulating oxidative stress in IPF and delved into their potential as carriers for regulating endogenous reactive oxygen species generation. This review endeavors to bridge the divide between exosome research and IPF, traversing from bedside to bench. Through the synthesis of recent findings, we propose exosomes as a novel and promising strategy for improving the outcomes of IPF therapy.
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Affiliation(s)
- Zaiyan Wang
- Department of Pulmonary and Critical Care Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, People’s Republic of China
| | - Yuan Zhang
- Department of Pulmonary and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China
| | - Xiaoning Li
- Department of Geriatric Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, People’s Republic of China
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13
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Zhang C, Ma J, Zhang X, Zhou D, Cao Z, Qiao L, Chen G, Yang L, Ding BS. Processing of angiocrine alarmin IL-1α in endothelial cells promotes lung and liver fibrosis. Int Immunopharmacol 2024; 134:112176. [PMID: 38723369 DOI: 10.1016/j.intimp.2024.112176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/21/2024] [Accepted: 04/27/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND Fibrosis results from excessive scar formation after tissue injury. Injured cells release alarmins such as interleukin 1 (IL-1) α and β as primary mediators initiating tissue repair. However, how alarmins from different cell types differentially regulate fibrosis remains to be explored. METHODS Here, we used tissue specific knockout strategy to illustrate a unique contribution of endothelial cell-derived IL-1α to lung and liver fibrosis. The two fibrotic animal model triggered by bleomycin and CCl4 were used to study the effects of endothelial paracrine/angiocrine IL-1α in fibrotic progression. Human umbilical vein endothelial cells (HUVEC) were performed to explore the production of angiocrine IL-1α at both transcriptional and post-transcriptional levels in vitro. RESULTS We found that endothelial paracrine/angiocrine IL-1α primarily promotes lung and liver fibrosis during the early phase of organ repair. By contrast, myeloid cell-specific ablation of IL-1α in mice resulted in little influence on fibrosis, suggesting the specific pro-fibrotic role of IL-1α from endothelial cell but not macrophage. In vitro study revealed a coordinated regulation of IL-1α production in human primary endothelial cells at both transcriptional and post-transcriptional levels. Specifically, the transcription of IL-1α is regulated by RIPK1, and after caspase-8 (CASP8) cleaves the precursor form of IL-1α, its secretion is triggered by ion channel Pannexin 1 upon CASP8 cleavage. CONCLUSIONS Endothelial cell-produced IL-1α plays a unique role in promoting organ fibrosis. Furthermore, the release of this angiocrine alarmin relies on a unique molecular mechanism involving RIPK1, CASP8, and ion channel Pannexin 1.
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Affiliation(s)
- Chunxue Zhang
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Jie Ma
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Xu Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China
| | - Dengcheng Zhou
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Zhongwei Cao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China
| | - Lina Qiao
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China.
| | - Guo Chen
- Department of Anesthesiology, The Research Units of West China(2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, China.
| | - Liming Yang
- Department of Pathophysiology, Harbin Medical University, Harbin 150081, China.
| | - Bi-Sen Ding
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life Sciences, Sichuan University, Chengdu 610041, China.
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14
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He X, Tang B, Zou P, Song Z, Liu J, Pi Z, Xiao Y, Xiao R. m6A RNA methylation: The latent string-puller in fibrosis. Life Sci 2024; 346:122644. [PMID: 38614300 DOI: 10.1016/j.lfs.2024.122644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/21/2024] [Accepted: 04/10/2024] [Indexed: 04/15/2024]
Abstract
Fibrosis is a pathological phenomenon characterized by the aberrant accumulation of extracellular matrix (ECM) in tissues. Fibrosis is a universally age-related disease involving that many organs and is the final stage of many chronic inflammatory diseases, which often threaten the patient's health. Undoubtedly, fibrosis has become a serious economic and health burden worldwide, However, the pathogenesis of fibrosis is complex. Further, the key molecules still remain to be unraveled. Hence, so far, there have been no effective treatments designed against the key targets of fibrosis. The methylation modification on the nitrogen atom at position 6 of adenine (m6A) is the most common mRNA modification in mammals. There is increasing evidence that m6A is actively involved in the pathogenesis of fibrosis. This review aims to highlight m6A-associated mechanisms and functions in several organic fibrosis, which implies that m6A is universal and critical for fibrosis and summarize the outlook of m6A in the treatment of fibrosis. This may light up the unknown aspects of this condition for researchers interested to explore fibrosis further.
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Affiliation(s)
- Xinglan He
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Bingsi Tang
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Puyu Zou
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Zehong Song
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Jiani Liu
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Zixin Pi
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yangfan Xiao
- Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, China; Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China.
| | - Rong Xiao
- Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Medical Epigenetics, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan.
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15
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Goltseva YD, Dergilev KV, Boldyreva MA, Parfyonova EV, Beloglazova IB. TGFβ1 Regulates Cellular Composition of In Vitro Cardiac Perivascular Niche Based on Cardiospheres. Bull Exp Biol Med 2024; 177:115-123. [PMID: 38963596 DOI: 10.1007/s10517-024-06142-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Indexed: 07/05/2024]
Abstract
The cardiac perivascular niche is a cellular microenvironment of a blood vessel. The principles of niche regulation are still poorly understood. We studied the effect of TGFβ1 on cells forming the cardiac perivascular niche using 3D cell culture (cardiospheres). Cardiospheres contained progenitor (c-Kit), endothelial (CD31), and mural (αSMA) cells, basement membrane proteins (laminin) and extracellular matrix proteins (collagen I, fibronectin). TGFβ1 treatment decreased the length of CD31+ microvasculature, VE cadherin protein level, and proportion of NG2+ cells, and increased proportion of αSMA+ cells and transgelin/SM22α protein level. We supposed that this effect is related to the stabilizing function of TGFβ1 on vascular cells: decreased endothelial cell proliferation, as shown for HUVEC, and activation of mural cell differentiation.
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Affiliation(s)
- Yu D Goltseva
- National Medical Research Centre of Cardiology named after academician E. I. Chazov, Moscow, Russia.
| | - K V Dergilev
- National Medical Research Centre of Cardiology named after academician E. I. Chazov, Moscow, Russia
| | - M A Boldyreva
- National Medical Research Centre of Cardiology named after academician E. I. Chazov, Moscow, Russia
| | - E V Parfyonova
- National Medical Research Centre of Cardiology named after academician E. I. Chazov, Moscow, Russia
| | - I B Beloglazova
- National Medical Research Centre of Cardiology named after academician E. I. Chazov, Moscow, Russia
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16
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Mehdizadeh M, Naud P, Abu-Taha IH, Hiram R, Xiong F, Xiao J, Saljic A, Kamler M, Vuong-Robillard N, Thorin E, Ferbeyre G, Tardif JC, Sirois MG, Tanguay JF, Dobrev D, Nattel S. The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology. Cardiovasc Res 2024; 120:506-518. [PMID: 38181429 PMCID: PMC11060482 DOI: 10.1093/cvr/cvae003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/21/2023] [Accepted: 12/12/2023] [Indexed: 01/07/2024] Open
Abstract
AIMS Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. CONCLUSION Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.
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Affiliation(s)
- Mozhdeh Mehdizadeh
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
- Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada
| | - Patrice Naud
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
- Department of Medicine, Université de Montréal, Pavillon Roger-Gaudry, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada
| | - Issam H Abu-Taha
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany
| | - Roddy Hiram
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
- Department of Medicine, Université de Montréal, Pavillon Roger-Gaudry, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada
| | - Feng Xiong
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
| | - Jiening Xiao
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
| | - Arnela Saljic
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Norregade 10, P.O. Box 2177, Copenhagen, Denmark
| | - Markus Kamler
- Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center Essen, University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany
| | - Nhung Vuong-Robillard
- Department of Biochemistry, Université de Montréal, CRCHUM, 900 Saint Denis St, Montreal, Quebec H2X 0A9, Canada
| | - Eric Thorin
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
- Department of Surgery, Université de Montréal, Pavillon Roger-Gaudry, Montreal, Quebec H3C 3J7, Canada
| | - Gerardo Ferbeyre
- Department of Biochemistry, Université de Montréal, CRCHUM, 900 Saint Denis St, Montreal, Quebec H2X 0A9, Canada
| | - Jean-Claude Tardif
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
| | - Martin G Sirois
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Pavillon Roger-GaudryOffice S-436, 2900 boulevard Édouard-Montpetit, Montreal, Quebec H3T 1J4, Canada
| | - Jean Francois Tanguay
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
| | - Dobromir Dobrev
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
| | - Stanley Nattel
- Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
- Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada
- Department of Medicine, Université de Montréal, Pavillon Roger-Gaudry, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada
- Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany
- Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Pavillon Roger-GaudryOffice S-436, 2900 boulevard Édouard-Montpetit, Montreal, Quebec H3T 1J4, Canada
- IHU Liryc and Fondation Bordeaux Université, 166 cours de l’Argonne, Bordeaux 33000, France
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Vo Q, Benam KH. Advancements in preclinical human-relevant modeling of pulmonary vasculature on-chip. Eur J Pharm Sci 2024; 195:106709. [PMID: 38246431 PMCID: PMC10939731 DOI: 10.1016/j.ejps.2024.106709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 01/05/2024] [Accepted: 01/18/2024] [Indexed: 01/23/2024]
Abstract
Preclinical human-relevant modeling of organ-specific vasculature offers a unique opportunity to recreate pathophysiological intercellular, tissue-tissue, and cell-matrix interactions for a broad range of applications. Lung vasculature is particularly important due to its involvement in genesis and progression of rare, debilitating disorders as well as common chronic pathologies. Here, we provide an overview of the latest advances in the development of pulmonary vascular (PV) models using emerging microfluidic tissue engineering technology Organs-on-Chips (so-called PV-Chips). We first review the currently reported PV-Chip systems and their key features, and then critically discuss their major limitations in reproducing in vivo-seen and disease-relevant cellularity, localization, and microstructure. We conclude by presenting latest efforts to overcome such technical and biological limitations and future directions.
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Affiliation(s)
- Quoc Vo
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Kambez H Benam
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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18
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Liu J, Yu X, Braucht A, Smith S, Wang C. N-Cadherin Targeted Melanin Nanoparticles Reverse the Endothelial-Mesenchymal Transition in Vascular Endothelial Cells to Potentially Slow the Progression of Atherosclerosis and Cancer. ACS NANO 2024; 18:8229-8247. [PMID: 38427686 DOI: 10.1021/acsnano.3c12281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/03/2024]
Abstract
Endothelial-mesenchymal transition (EndoMT) of vascular endothelial cells has recently been considered as a key player in the early progression of a variety of vascular and nonvascular diseases, including atherosclerosis, cancer, and organ fibrosis. However, current strategies attempting to identify pharmacological inhibitors to block the regulatory pathways of EndoMT suffer from poor selectivity, unwanted side effects, and a heterogeneous response from endothelial cells with different origins. Furthermore, EndoMT inhibitors focus on preventing EndoMT, leaving the endothelial cells that have already undergone EndoMT unresolved. Here, we report the design of a simple but powerful nanoparticle system (i.e., N-cadherin targeted melanin nanoparticles) to convert cytokine-activated, mesenchymal-like endothelial cells back to their original endothelial phenotype. We term this process "Reversed EndoMT" (R-EndoMT). R-EndoMT allows the impaired endothelial barriers to recover their quiescence and intactness, with significantly reduced leukocyte and cancer cell adhesion and transmigration, which could potentially stop atheromatous plaque formation and cancer metastasis in the early stages. R-EndoMT is achieved on different endothelial cell types originating from arteries, veins, and capillaries, independent of activating cytokines. We reveal that N-cadherin targeted melanin nanoparticles reverse EndoMT by downregulating an N-cadherin dependent RhoA activation pathway. Overall, this approach offers a different prospect to treat multiple EndoMT-associated diseases by designing nanoparticles to reverse the phenotypical transition of endothelial cells.
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Affiliation(s)
- Jinyuan Liu
- Nanoscience and Biomedical Engineering, South Dakota School of Mines and Technology, 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
- BioSystems Networks & Translational Research (BioSNTR), 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
| | - Xiao Yu
- Nanoscience and Biomedical Engineering, South Dakota School of Mines and Technology, 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
- BioSystems Networks & Translational Research (BioSNTR), 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
| | - Annaliese Braucht
- Nanoscience and Biomedical Engineering, South Dakota School of Mines and Technology, 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
- BioSystems Networks & Translational Research (BioSNTR), 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
| | - Steve Smith
- Nanoscience and Biomedical Engineering, South Dakota School of Mines and Technology, 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
- BioSystems Networks & Translational Research (BioSNTR), 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
| | - Congzhou Wang
- Nanoscience and Biomedical Engineering, South Dakota School of Mines and Technology, 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
- BioSystems Networks & Translational Research (BioSNTR), 501 E St Joseph Street, Rapid City, South Dakota 57701, United States
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19
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Altrieth A, Kenney J, Nelson D, Suarez E, Gellatly V, Gabunia S, Larsen M. Single-Cell Transcriptomic Analysis of Salivary Gland Endothelial Cells. J Dent Res 2024; 103:269-278. [PMID: 38411696 PMCID: PMC10985389 DOI: 10.1177/00220345231219987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024] Open
Abstract
Vascular endothelial cells have important tissue-specific functions in fibrosis and regeneration. In the salivary gland, endothelial cells are required for proper development, but their roles within adult glands are largely unknown. To identify ligand-receptor interactions between endothelial cells and other cell types that may be important during fibrosis and regeneration, we used a reversible ductal ligation injury. To induce injury, a clip was applied to the primary ducts for 14 d, and to induce a regenerative response, the clip was subsequently removed for 5 d. To identify endothelial cell-produced factors, we used single-cell RNA sequencing of stromal-enriched cells from adult female submandibular and sublingual salivary glands. Transcriptional profiles of homeostatic salivary gland endothelial cells were compared to endothelial cells of other organs. Salivary gland endothelial cells expressed many unique genes and displayed the highest overlap in gene expression with other fenestrated endothelial cells from the colon, small intestine, and kidney. Comparison of the 14-d ligated, mock-ligated, and 5-d deligated stromal-enriched transcripts and lineage tracing revealed that endothelial cells retain their identity following ligation and recovery from injury. CellChat and NATMI were used to predict changes in ligand-receptor interactions from endothelial cells to other cells in response to ligation and deligation. CellChat and NATMI predicted that after ligation, interactions with fibroblasts, epithelial cells, and glial cells were increased, and following deligation, interactions with pericyte, glia, fibroblasts, and immune cells were increased. Some of the highest-ranked interactions predicted in ligated compared to mock endothelial cells were between glial cells via Col4a2-Cd93 and Jag2-Notch1, as well as epithelial cells via Pecam1-Cd38, while in deligated compared to ligated endothelial cells, the top interactions were between fibroblasts via Ntf3-Ntrk2, glial cells via Hspg2-Itgb1, and pericytes via Jam2-F11r. Understanding salivary gland endothelial cell signaling will inform future endothelial cell-based regenerative therapies.
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Affiliation(s)
- A.L. Altrieth
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA
- Department of Pathology & Laboratory Medicine, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
| | - J. Kenney
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
| | - D.A. Nelson
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
| | - E.G. Suarez
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
| | - V. Gellatly
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA
| | - S. Gabunia
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
| | - M. Larsen
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, NY, USA
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY, USA
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20
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Tan Y, Zhang M, Kong Y, Zhang F, Wang Y, Huang Y, Song W, Li Z, Hou L, Liang L, Guo X, Liu Q, Feng Y, Zhang C, Fu X, Huang S. Fibroblasts and endothelial cells interplay drives hypertrophic scar formation: Insights from in vitro and in vivo models. Bioeng Transl Med 2024; 9:e10630. [PMID: 38435816 PMCID: PMC10905555 DOI: 10.1002/btm2.10630] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 10/23/2023] [Accepted: 11/24/2023] [Indexed: 03/05/2024] Open
Abstract
Hypertrophic scar formation is influenced by the intricate interplay between fibroblasts and endothelial cells. In this study, we investigated this relationship using in vitro and in vivo models. Clinical observations revealed distinct morphological changes and increased vascularity at pathological scar sites. Further analysis using OCTA, immunohistochemistry, and immunofluorescence confirmed the involvement of angiogenesis in scar formation. Our indirect co-culture systems demonstrated that endothelial cells enhance the proliferation and migration of fibroblasts through the secretion of cytokines including VEGF, PDGF, bFGF, and TGF-β. Additionally, a suspended co-culture multicellular spheroid model revealed molecular-level changes associated with extracellular matrix remodeling, cellular behaviors, inflammatory response, and pro-angiogenic activity. Furthermore, KEGG pathway analysis identified the involvement of TGF-β, IL-17, Wnt, Notch, PI3K-Akt, and MAPK pathways in regulating fibroblasts activity. These findings underscore the critical role of fibroblasts-endothelial cells crosstalk in scar formation and provide potential targets for therapeutic intervention. Understanding the molecular mechanisms underlying this interplay holds promise for the development of innovative approaches to treat tissue injuries and diseases.
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Affiliation(s)
- Yaxin Tan
- College of GraduateTianjin Medical UniversityTianjinPR China
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Mengde Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Yi Kong
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Fanliang Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Yuzhen Wang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Yuyan Huang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Wei Song
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Zhao Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Linhao Hou
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Liting Liang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Xu Guo
- College of GraduateTianjin Medical UniversityTianjinPR China
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Qinghua Liu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Yu Feng
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Chao Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Xiaobing Fu
- College of GraduateTianjin Medical UniversityTianjinPR China
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
| | - Sha Huang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research DepartmentPLA General Hospital and PLA Medical CollegeBeijingPR China
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21
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Goligorsky MS. Permissive role of vascular endothelium in fibrosis: focus on the kidney. Am J Physiol Cell Physiol 2024; 326:C712-C723. [PMID: 38223932 PMCID: PMC11193458 DOI: 10.1152/ajpcell.00526.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 01/09/2024] [Accepted: 01/09/2024] [Indexed: 01/16/2024]
Abstract
Fibrosis, the morphologic end-result of a plethora of chronic conditions and the scorch for organ function, has been thoroughly investigated. One aspect of its development and progression, namely the permissive role of vascular endothelium, has been overshadowed by studies into (myo)fibroblasts and TGF-β; thus, it is the subject of the present review. It has been established that tensile forces of the extracellular matrix acting on cells are a prerequisite for mechanochemical coupling, leading to liberation of TGF-β and formation of myofibroblasts. Increased tensile forces are prompted by elevated vascular permeability in response to diverse stressors, resulting in the exudation of fibronectin, fibrinogen/fibrin, and other proteins, all stiffening the extracellular matrix. These processes lead to the development of endothelial cells dysfunction, endothelial-to-mesenchymal transition, premature senescence of endothelial cells, perturbation of blood flow, and gradual obliteration of microvasculature, leaving behind "string" vessels. The resulting microvascular rarefaction is not only a constant companion of fibrosis but also an adjunct mechanism of its progression. The deepening knowledge of the above chain of pathogenetic events involving endothelial cells, namely increased permeability-stiffening of the matrix-endothelial dysfunction-microvascular rarefaction-tissue fibrosis, may provide a roadmap for therapeutic interventions deemed to curtail and reverse fibrosis.
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Affiliation(s)
- Michael S Goligorsky
- Department of Medicine, New York Medical College, Touro University, Valhalla, New York, United States
- Department of Pharmacology, New York Medical College, Touro University, Valhalla, New York, United States
- Department of Physiology, New York Medical College, Touro University, Valhalla, New York, United States
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22
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Zhou X, Zhang C, Yang S, Yang L, Luo W, Zhang W, Zhang X, Chao J. Macrophage-derived MMP12 promotes fibrosis through sustained damage to endothelial cells. JOURNAL OF HAZARDOUS MATERIALS 2024; 461:132733. [PMID: 37816293 DOI: 10.1016/j.jhazmat.2023.132733] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 09/16/2023] [Accepted: 10/04/2023] [Indexed: 10/12/2023]
Abstract
Macrophages are essential for the maintenance of endothelial cell function. However, the potential impact and mechanisms of crosstalk between macrophages and endothelial cells during silicosis progression remain unexplored. To fill this knowledge gap, a mouse model of silicosis was established. Single cell sequencing, spatial transcriptome sequencing, western blotting, immunofluorescence staining, tube-forming and wound healing assays were used to explore the effects of silicon dioxide on macrophage-endothelial interactions. To investigate the mechanism of macrophage-mediated fibrosis, MMP12 was specifically inactivated using siRNA and pharmacological approaches, and macrophages were depleted using disodium chlorophosphite liposomes. Compared to the normal saline group, the silica dust group showed altered macrophage-endothelial interactions. Matrix metalloproteinase family member MMP12 was identified as a key mediator of the altered function of macrophage-endothelial interactions after silica exposure, which was accompanied by pro-inflammatory macrophage activation and fibrotic progression. By using ablation strategies, macrophage-derived MMP12 was shown to mediate endothelial cell dysfunction by accumulating on the extracellular matrix. During the inflammatory phase of silicosis, MMP12 secreted by pro-inflammatory macrophages caused decreased endothelial cell viability, reduced migration, decreased trans-endothelial resistance and increased permeability; while during the fibrotic phase, macrophage-derived MMP12 sustained endothelial cell injury through accumulation on the extracellular matrix.
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Affiliation(s)
- Xinbei Zhou
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Cong Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Shaoqi Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Liliang Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Wei Luo
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China
| | - Wei Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Xinxin Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Jie Chao
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China; Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China; School of Medicine, Xizang Minzu University, Xianyang, Shanxi, 712082, China.
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23
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Jimenez SA, Piera-Velazquez S. Cellular Transdifferentiation: A Crucial Mechanism of Fibrosis in Systemic Sclerosis. Curr Rheumatol Rev 2024; 20:388-404. [PMID: 37921216 DOI: 10.2174/0115733971261932231025045400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/13/2023] [Accepted: 07/27/2023] [Indexed: 11/04/2023]
Abstract
Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology with a highly complex pathogenesis that despite extensive investigation is not completely understood. The clinical and pathologic manifestations of the disease result from three distinct processes: 1) Severe and frequently progressive tissue fibrosis causing exaggerated and deleterious accumulation of interstitial collagens and other extracellular matrix molecules in the skin and various internal organs; 2) extensive fibroproliferative vascular lesions affecting small arteries and arterioles causing tissue ischemic alterations; and 3) cellular and humoral immunity abnormalities with the production of numerous autoantibodies, some with very high specificity for SSc. The fibrotic process in SSc is one of the main causes of disability and high mortality of the disease. Owing to its essentially universal presence and the severity of its clinical effects, the mechanisms involved in the development and progression of tissue fibrosis have been extensively investigated, however, despite intensive investigation, the precise molecular mechanisms have not been fully elucidated. Several recent studies have suggested that cellular transdifferentiation resulting in the phenotypic conversion of various cell types into activated myofibroblasts may be one important mechanism. Here, we review the potential role that cellular transdifferentiation may play in the development of severe and often progressive tissue fibrosis in SSc.
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Affiliation(s)
- Sergio A Jimenez
- Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia 19107, USA
| | - Sonsoles Piera-Velazquez
- Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia 19107, USA
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24
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Abstract
PURPOSE OF REVIEW Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity and mortality rates. Growing evidence indicates that common cellular and molecular mechanisms may drive fibrosis of diverse cause and affecting different organs. The scope of this review is to highlight recent findings in support for an important role of vascular endothelial cells in the pathogenesis of fibrosis, with a special focus on systemic sclerosis as a prototypic multisystem fibrotic disorder. RECENT FINDINGS Although transition of fibroblasts to chronically activated myofibroblasts is widely considered the central profibrotic switch, the endothelial cell involvement in development and progression of fibrosis has been increasingly recognized over the last few years. Endothelial cells can contribute to the fibrotic process either directly by acting as source of myofibroblasts through endothelial-to-myofibroblast transition (EndMT) and concomitant microvascular rarefaction, or indirectly by becoming senescent and/or secreting a variety of profibrotic and proinflammatory mediators with consequent fibroblast activation and recruitment of inflammatory/immune cells that further promote fibrosis. SUMMARY An in-depth understanding of the mechanisms underlying EndMT or the acquisition of a profibrotic secretory phenotype by endothelial cells will provide the rationale for novel endothelial cell reprogramming-based therapeutic approaches to prevent and/or treat fibrosis.
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Affiliation(s)
- Eloisa Romano
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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25
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Mimouni M, Lajoix AD, Desmetz C. Experimental Models to Study Endothelial to Mesenchymal Transition in Myocardial Fibrosis and Cardiovascular Diseases. Int J Mol Sci 2023; 25:382. [PMID: 38203553 PMCID: PMC10779210 DOI: 10.3390/ijms25010382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Fibrosis is a common feature of cardiovascular diseases and targets multiple organs, such as the heart and vessels. Endothelial to mesenchymal transition is a complex, vital process that occurs during embryonic formation and plays a crucial role in cardiac development. It is also a fundamental process implicated in cardiac fibrosis and repair, but also in other organs. Indeed, in numerous cardiovascular diseases, the endothelial-to-mesenchymal transition has been shown to be involved in the generation of fibroblasts that are able to produce extracellular matrix proteins such as type I collagen. This massive deposition results in tissue stiffening and organ dysfunction. To advance our understanding of this process for the development of new specific diagnostic and therapeutic strategies, it is essential to develop relevant cellular and animal models of this process. In this review, our aim was to gain an in-depth insight into existing in vitro and in vivo models of endothelial to mesenchymal transition in cardiovascular diseases with a focus on cardiac fibrosis. We discuss important parameters impacting endothelial to mesenchymal transition, and we give perspectives for the development of relevant models to decipher the underlying mechanisms and ultimately find new treatments specific to fibrosis happening in cardiovascular diseases.
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Affiliation(s)
- Mohammed Mimouni
- Biocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34000 Montpellier, France
| | - Anne-Dominique Lajoix
- Biocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34000 Montpellier, France
| | - Caroline Desmetz
- Biocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34000 Montpellier, France
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26
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Chavkin NW, Vippa T, Jung C, McDonnell S, Hirschi KK, Gokce N, Walsh K. Obesity accelerates endothelial-to-mesenchymal transition in adipose tissues of mice and humans. Front Cardiovasc Med 2023; 10:1264479. [PMID: 37795485 PMCID: PMC10546194 DOI: 10.3389/fcvm.2023.1264479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/07/2023] [Indexed: 10/06/2023] Open
Abstract
Introduction Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue. Methods Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP +. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals. Results Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFβ signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-β1, IFN-γ, and TNF-α exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT. Discussion These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity..
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Affiliation(s)
- Nicholas W. Chavkin
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Tanvi Vippa
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Changhee Jung
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Stephanie McDonnell
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, United States
| | - Karen K. Hirschi
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, United States
- Department of Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, United States
| | - Noyan Gokce
- Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, United States
| | - Kenneth Walsh
- Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, United States
- Hematovascular Biology Center, University of Virginia School of Medicine, Charlottesville, VA, United States
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27
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Li N, Zhang T, Zhu L, Sun L, Shao G, Gao J. Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease. Mol Pharm 2023; 20:4354-4372. [PMID: 37566627 DOI: 10.1021/acs.molpharmaceut.3c00268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of human death worldwide. Exosomes act as endogenous biological vectors; they possess advantages of low immunogenicity and low safety risks, also providing tissue selectivity, including the inherent targeting the to heart. Therefore, exosomes not only have been applied as biomarkers for diagnosis and therapeutic outcome confirmation but also showed potential as drug carriers for cardiovascular targeting delivery. This review aims to summarize the progress and challenges of exosomes as novel biomarkers, especially many novel exosomal noncoding RNAs (ncRNAs), and also provides an overview of the improved targeting functions of exosomes by unique engineered approaches, the latest developed administration methods, and the therapeutic effects of exosomes used as the biocarriers of medications for cardiovascular disease treatment. Also, the possible therapeutic mechanisms and the potentials for transferring exosomes to the clinic for CVD treatment are discussed. The advances, in vivo and in vitro applications, modifications, mechanisms, and challenges summarized in this review will provide a general understanding of this promising strategy for CVD treatment.
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Affiliation(s)
- Ni Li
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Tianyuan Zhang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Linwen Zhu
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
| | - Lebo Sun
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
| | - Guofeng Shao
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
| | - Jianqing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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28
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Rosa I, Romano E, Fioretto BS, El Aoufy K, Bellando-Randone S, Matucci-Cerinic M, Manetti M. Lymphatic Endothelial-to-Myofibroblast Transition: A Potential New Mechanism Underlying Skin Fibrosis in Systemic Sclerosis. Cells 2023; 12:2195. [PMID: 37681927 PMCID: PMC10486460 DOI: 10.3390/cells12172195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/29/2023] [Accepted: 08/31/2023] [Indexed: 09/09/2023] Open
Abstract
At present, only a few reports have addressed the possible contribution of the lymphatic vascular system to the pathogenesis of systemic sclerosis (SSc). Based on the evidence that blood vascular endothelial cells can undertake the endothelial-to-myofibroblast transition (EndMT) contributing to SSc-related skin fibrosis, we herein investigated whether the lymphatic endothelium might represent an additional source of profibrotic myofibroblasts through a lymphatic EndMT (Ly-EndMT) process. Skin sections from patients with SSc and healthy donors were immunostained for the lymphatic endothelial cell-specific marker lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in combination with α-smooth muscle actin (α-SMA) as the main marker of myofibroblasts. Commercial human adult dermal lymphatic microvascular endothelial cells (HdLy-MVECs) were challenged with recombinant human transforming growth factor-β1 (TGFβ1) or serum from SSc patients and healthy donors. The expression of lymphatic endothelial cell/myofibroblast markers was measured by quantitative real-time PCR, Western blotting and immunofluorescence. Collagen gel contraction assay was performed to assess myofibroblast-like cell contractile ability. Lymphatic endothelial cells in intermediate stages of the Ly-EndMT process (i.e., coexpressing LYVE-1 and α-SMA) were found exclusively in the fibrotic skin of SSc patients. The culturing of HdLy-MVECs with SSc serum or profibrotic TGFβ1 led to the acquisition of a myofibroblast-like morphofunctional phenotype, as well as the downregulation of lymphatic endothelial cell-specific markers and the parallel upregulation of myofibroblast markers. In SSc, the Ly-EndMT might represent a previously overlooked pathogenetic process bridging peripheral microlymphatic dysfunction and skin fibrosis development.
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Affiliation(s)
- Irene Rosa
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (I.R.); (B.S.F.)
| | - Eloisa Romano
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (K.E.A.); (S.B.-R.)
| | - Bianca Saveria Fioretto
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (I.R.); (B.S.F.)
| | - Khadija El Aoufy
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (K.E.A.); (S.B.-R.)
- Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50141 Florence, Italy
| | - Silvia Bellando-Randone
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (K.E.A.); (S.B.-R.)
- Division of Rheumatology, Azienda Ospedaliero-Universitaria Careggi (AOUC), 50141 Florence, Italy
| | - Marco Matucci-Cerinic
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, 20132 Milan, Italy;
| | - Mirko Manetti
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; (I.R.); (B.S.F.)
- Imaging Platform, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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29
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Lurje I, Gaisa NT, Weiskirchen R, Tacke F. Mechanisms of organ fibrosis: Emerging concepts and implications for novel treatment strategies. Mol Aspects Med 2023; 92:101191. [PMID: 37236017 DOI: 10.1016/j.mam.2023.101191] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023]
Abstract
Fibrosis, or tissue scarring, develops as a pathological deviation from the physiological wound healing response and can occur in various organs such as the heart, lung, liver, kidney, skin, and bone marrow. Organ fibrosis significantly contributes to global morbidity and mortality. A broad spectrum of etiologies can cause fibrosis, including acute and chronic ischemia, hypertension, chronic viral infection (e.g., viral hepatitis), environmental exposure (e.g., pneumoconiosis, alcohol, nutrition, smoking) and genetic diseases (e.g., cystic fibrosis, alpha-1-antitrypsin deficiency). Common mechanisms across organs and disease etiologies involve a sustained injury to parenchymal cells that triggers a wound healing response, which becomes deregulated in the disease process. A transformation of resting fibroblasts into myofibroblasts with excessive extracellular matrix production constitutes the hallmark of disease, however, multiple other cell types such as immune cells, predominantly monocytes/macrophages, endothelial cells, and parenchymal cells form a complex network of profibrotic cellular crosstalk. Across organs, leading mediators include growth factors like transforming growth factor-β and platelet-derived growth factor, cytokines like interleukin-10, interleukin-13, interleukin-17, and danger-associated molecular patterns. More recently, insights into fibrosis regression and resolution of chronic conditions have deepened our understanding of beneficial, protective effects of immune cells, soluble mediators and intracellular signaling. Further in-depth insights into the mechanisms of fibrogenesis can provide the rationale for therapeutic interventions and the development of targeted antifibrotic agents. This review gives insight into shared responses and cellular mechanisms across organs and etiologies, aiming to paint a comprehensive picture of fibrotic diseases in both experimental settings and in human pathology.
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Affiliation(s)
- Isabella Lurje
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nadine T Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Mourad O, Mastikhina O, Khan S, Sun X, Hatkar R, Williams K, Nunes SS. Antisenescence Therapy Improves Function in a Human Model of Cardiac Fibrosis-on-a-Chip. ACS MATERIALS AU 2023; 3:360-370. [PMID: 38090129 PMCID: PMC10347691 DOI: 10.1021/acsmaterialsau.3c00009] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/14/2023] [Accepted: 04/17/2023] [Indexed: 02/12/2024]
Abstract
Cardiac fibrosis is a significant contributor to heart failure and is characterized by abnormal ECM deposition and impaired contractile function. We have previously developed a model of cardiac fibrosis via TGF-β treatment of engineered microtissues using heart-on-a-chip technology which incorporates human induced pluripotent stem cell-derived cardiomyocytes and cardiac fibroblasts. Here, we describe that these cardiac fibrotic tissues expressed markers associated with cellular senescence via transcriptomic analysis. Treatment of fibrotic tissues with the senolytic drugs dasatinib and quercetin (D+Q) led to an improvement of contractile function, reduced passive tension, and downregulated senescence-related gene expression, an outcome we were previously unable to achieve using standard-of-care drugs. The improvement in functional parameters was also associated with a reduction in fibroblast density, though no changes in absolute collagen deposition were observed. This study demonstrates the benefit of senolytic treatment for cardiac fibrosis in a human-relevant model, supporting data in animal models, and will enable the further elucidation of cell-specific effects of senolytics and how they impact cardiac fibrosis and senescence.
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Affiliation(s)
- Omar Mourad
- Toronto
General Hospital Research Institute, University
Health Network, Toronto, Canada M5G 2C4
- Institute
of Biomedical Engineering, University of
Toronto, Toronto, Canada M5S 3G9
| | - Olya Mastikhina
- Toronto
General Hospital Research Institute, University
Health Network, Toronto, Canada M5G 2C4
- Institute
of Biomedical Engineering, University of
Toronto, Toronto, Canada M5S 3G9
| | - Safwat Khan
- Toronto
General Hospital Research Institute, University
Health Network, Toronto, Canada M5G 2C4
- Institute
of Biomedical Engineering, University of
Toronto, Toronto, Canada M5S 3G9
| | - Xuetao Sun
- Toronto
General Hospital Research Institute, University
Health Network, Toronto, Canada M5G 2C4
| | - Rupal Hatkar
- Toronto
General Hospital Research Institute, University
Health Network, Toronto, Canada M5G 2C4
- Institute
of Biomedical Engineering, University of
Toronto, Toronto, Canada M5S 3G9
| | - Kenneth Williams
- Toronto
General Hospital Research Institute, University
Health Network, Toronto, Canada M5G 2C4
- Laboratory
of Medicine and Pathobiology, University
of Toronto, Toronto, Canada M5S 1A8
| | - Sara S. Nunes
- Toronto
General Hospital Research Institute, University
Health Network, Toronto, Canada M5G 2C4
- Institute
of Biomedical Engineering, University of
Toronto, Toronto, Canada M5S 3G9
- Ajmera
Transplant Center, University Health Network, Toronto, Canada M5G 2C4
- Laboratory
of Medicine and Pathobiology, University
of Toronto, Toronto, Canada M5S 1A8
- Heart
& Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada M5S 3H2
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31
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Altrieth AL, Suarez E, Nelson DA, Gabunia S, Larsen M. Single-cell Transcriptomic Analysis of Salivary Gland Endothelial Cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.22.545817. [PMID: 37425911 PMCID: PMC10327062 DOI: 10.1101/2023.06.22.545817] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Vascular endothelial cells have important functions in fibrosis via direct and indirect methods and in regeneration through secretion of tissue-specific, paracrineacting angiocrine factors. In the salivary gland, endothelial cells are required for proper development, but their roles within adult glands are largely unknown. The goal of this work was to identify ligand-receptor interactions between endothelial cells and other cell types that are important during homeostasis, fibrosis, and regeneration. To model salivary gland fibrosis and regeneration, we utilized a reversible ductal ligation. To induce injury, a clip was applied to the primary ducts for 14 days, and to induce a regenerative response, the clip was subsequently removed for 5 days. To identify endothelial cell-produced factors, we used single-cell RNA-sequencing of stromal-enriched cells from adult submandibular and sublingual salivary glands. Transcriptional profiles of homeostatic salivary gland endothelial cells were compared to endothelial cells of other organs. Salivary gland endothelial cells were found to express unique genes and displayed the highest overlap in gene expression with other fenestrated endothelial cells from the colon, small intestine, and kidney. Comparison of the 14-day ligated, mock ligated, and 5-day deligated stromal-enriched transcripts and lineage tracing were used to identify evidence for a partial endoMT phenotype, which was observed in a small number of endothelial cell subsets with ligation. CellChat was used to predict changes in ligand-receptor interactions in response to ligation and deligation. CellChat predicted that after ligation, endothelial cells are sources of protein tyrosine phosphatase receptor type m, tumor necrosis factor ligand superfamily member 13, and myelin protein zero signaling and targets for tumor necrosis factor signaling. Following deligation, CellChat predicted that endothelial cells are sources of chemokine (C-X-C motif) and EPH signaling to promote regenerative responses. These studies will inform future endothelial cell-based regenerative therapies.
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Affiliation(s)
- Amber L. Altrieth
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, New York, USA
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, Department of Biological Sciences, University at Albany, State University of New York, Albany, New York, USA
| | - Emily Suarez
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, New York, USA
| | - Deirdre A. Nelson
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, New York, USA
| | - Sergo Gabunia
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, New York, USA
| | - Melinda Larsen
- Department of Biological Sciences and The RNA Institute, University at Albany, State University of New York, Albany, New York, USA
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, Department of Biological Sciences, University at Albany, State University of New York, Albany, New York, USA
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Chandiran K, Cauley LS. The diverse effects of transforming growth factor-β and SMAD signaling pathways during the CTL response. Front Immunol 2023; 14:1199671. [PMID: 37426662 PMCID: PMC10327426 DOI: 10.3389/fimmu.2023.1199671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/12/2023] [Indexed: 07/11/2023] Open
Abstract
Cytotoxic T lymphocytes (CTLs) play an important role in defense against infections with intracellular pathogens and anti-tumor immunity. Efficient migration is required to locate and destroy infected cells in different regions of the body. CTLs accomplish this task by differentiating into specialized subsets of effector and memory CD8 T cells that traffic to different tissues. Transforming growth factor-beta (TGFβ) belongs to a large family of growth factors that elicit diverse cellular responses via canonical and non-canonical signaling pathways. Canonical SMAD-dependent signaling pathways are required to coordinate changes in homing receptor expression as CTLs traffic between different tissues. In this review, we discuss the various ways that TGFβ and SMAD-dependent signaling pathways shape the cellular immune response and transcriptional programming of newly activated CTLs. As protective immunity requires access to the circulation, emphasis is placed on cellular processes that are required for cell-migration through the vasculature.
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Affiliation(s)
- Karthik Chandiran
- School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, Kerala, India
| | - Linda S. Cauley
- Department of Immunology, UCONN Health, Farmington, CT, United States
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Wang J, Li T, Zhou Y, Wang X, Carvalho V, Ni C, Li W, Wang Q, Chen Y, Shang Z, Qiu S, Sun Z. Genetic lineage tracing reveals stellate cells as contributors to myofibroblasts in pancreas and islet fibrosis. iScience 2023; 26:106988. [PMID: 37378313 PMCID: PMC10291507 DOI: 10.1016/j.isci.2023.106988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/18/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Pancreatic stellate cells (PSCs) are suggested to play an important role in the development of pancreas and islet fibrosis. However, the precise contributions and solid in vivo evidence of PSCs to the fibrogenesis remain to be elucidated. Here, we developed a novel fate-tracing strategy for PSCs by vitamin A administration in Lrat-cre; Rosa26-tdTomato transgenic mouse. The results showed that stellate cells give rise to 65.7% of myofibroblasts in cerulein-induced pancreatic exocrine fibrosis. In addition, stellate cells in islets increase and contribute partly to myofibroblasts pool in streptozocin-induced acute or chronic islet injury and fibrosis. Furthermore, we substantiated the functional contribution of PSCs to fibrogenesis of pancreatic exocrine and islet in PSCs ablated mice. We also found stellate cells' genetic ablation can improve pancreatic exocrine but not islet fibrosis. Together, our data indicates that stellate cells are vital/partial contributors to myofibroblasts in pancreatic exocrine/islet fibrosis.
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Affiliation(s)
- Jinbang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Tingting Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yunting Zhou
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Vladmir Carvalho
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Chengming Ni
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Wei Li
- Department of Endocrinology, Suzhou Hospital of Anhui Medical University, Suzhou, China
| | - Qianqian Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Zhanjia Shang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Shanhu Qiu
- Department of General Practice, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
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Liu J, Gao D, Ding Q, Zhang B, Zhu W, Shi Y. Sparganii Rhizoma alleviates pulmonary fibrosis by inhibiting fibroblasts differentiation and epithelial-mesenchymal transition mediated by TGF-β1/ Smad2/3 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 309:116305. [PMID: 36878395 DOI: 10.1016/j.jep.2023.116305] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/12/2023] [Accepted: 02/19/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pulmonary fibrosis (PF), a lethal lung disease, can lead to structural destruction of the alveoli until death. Sparganii Rhizoma (SR), primarily distributed in East Asia, has been used clinically for hundreds of years against organ fibrosis and inflammation. AIM OF THE STUDY We intended to verify the effect of SR alleviate PF and further explore mechanisms. METHODS Murine model of PF was established by endotracheal infusion of bleomycin. We detected the anti-PF effect of SR through lung coefficient, hydroxyproline content, lung function and pathological staining. Then, we used Western Blot and RT-PCR to verify the mechanism. In vitro experiments, MRC-5 and BEAS-2B were induced to phenotypic transformation by TGF-β1 and then RT-PCR, WB and IF were conducted to verify the effect of SR. RESULTS SR significantly reduced BLM-induced PF in mice, improved lung function, slowed the degree of lung tissue lesions, and reduced collagen deposition. SR alleviated PF by inhibiting fibroblasts differentiation and epithelial-mesenchymal transition. In vivo studies explored the mechanism and found that it was related to TGF-β1/Smad2/3 pathway. CONCLUSIONS Our research proved SR could effectively treat PF, providing a fresh idea and approach for the treatment of PF with traditional Chinese medicine.
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Affiliation(s)
- Jing Liu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Dongyang Gao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Qi Ding
- Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, 518118, China.
| | - Binbin Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Wenxiang Zhu
- Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, 518118, China.
| | - Yuanyuan Shi
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China; Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, 518118, China.
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Feng J, Wu Y. Endothelial-to-Mesenchymal Transition: Potential Target of Doxorubicin-Induced Cardiotoxicity. Am J Cardiovasc Drugs 2023; 23:231-246. [PMID: 36841924 DOI: 10.1007/s40256-023-00573-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/02/2023] [Indexed: 02/27/2023]
Abstract
The use of chemotherapeutic agents is becoming more frequent as the proportion of new oncology patients increases worldwide, with prolonged survival after treatment. As one of the most popular chemotherapy drugs, doxorubicin plays a substantial role in the treatment of tumors. Unfortunately, the use of doxorubicin is associated with several adverse effects, particularly severe cardiotoxicity that can be life-threatening, which greatly limits its clinical use. For decades, scientists have tried to explore many cardioprotective agents and therapeutic approaches, but their efficacy remains controversial, and some drugs have even brought about significant adverse effects. The concrete molecular mechanism of doxorubicin-induced cardiotoxicity is still to be unraveled, yet endothelial damage is gradually being identified as an important mechanism triggering the development and progression of doxorubicin-induced cardiotoxicity. Endothelial-to-mesenchymal transition (EndMT), a fundamental process regulating morphogenesis in multicellular organisms, is recognized to be associated with endothelial damage repair and acts as an important factor in the progression of cardiovascular diseases, tumors, and rheumatic immune diseases. Mounting evidence suggests that endothelial-mesenchymal transition may play a non-negligible role in doxorubicin-induced cardiotoxicity. In this paper, we reviewed the molecular mechanisms and signaling pathways of EndMT and outlined the molecular mechanisms of doxorubicin-induced cardiotoxicity and the current therapeutic advances. Furthermore, we summarized the basic principles of doxorubicin-induced endothelial-mesenchymal transition that lead to endothelial dysfunction and cardiotoxicity, aiming to provide suggestions or new ideas for the prevention and treatment of doxorubicin-induced endothelial and cardiac injury.
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Affiliation(s)
- Jie Feng
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yanqing Wu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
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Dolivo DM, Sun LS, Rodrigues AE, Galiano RD, Mustoe TA, Hong SJ. Epidermal Potentiation of Dermal Fibrosis: Lessons from Occlusion and Mucosal Healing. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:510-519. [PMID: 36740181 DOI: 10.1016/j.ajpath.2023.01.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/05/2023]
Abstract
Fibrotic skin conditions, such as hypertrophic and keloid scars, frequently result from injury to the skin and as sequelae to surgical procedures. The development of skin fibrosis may lead to patient discomfort, limitation in range of motion, and cosmetic disfigurement. Despite the frequency of skin fibrosis, treatments that seek to address the root causes of fibrosis are lacking. Much research into fibrotic pathophysiology has focused on dermal pathology, but less research has been performed to understand aberrations in fibrotic epidermis, leading to an incomplete understanding of dermal fibrosis. The literature on occlusion, a treatment modality known to reduce dermal fibrosis, in part through accelerating wound healing and regulating aberrant epidermal inflammation that otherwise drives fibrosis in the dermis, is reviewed. There is a focus on epidermal-dermal crosstalk, which contributes to the development and maintenance of dermal fibrosis, an underemphasized interplay that may yield novel strategies for treatment if understood in more detail.
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Affiliation(s)
- David M Dolivo
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Lauren S Sun
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Adrian E Rodrigues
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Robert D Galiano
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Thomas A Mustoe
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Seok Jong Hong
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
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The Function and Therapeutic Potential of lncRNAs in Cardiac Fibrosis. BIOLOGY 2023; 12:biology12020154. [PMID: 36829433 PMCID: PMC9952806 DOI: 10.3390/biology12020154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023]
Abstract
Cardiac fibrosis remains an unresolved problem in cardiovascular diseases. Fibrosis of the myocardium plays a key role in the clinical outcomes of patients with heart injuries. Moderate fibrosis is favorable for cardiac structure maintaining and contractile force transmission, whereas adverse fibrosis generally progresses to ventricular remodeling and cardiac systolic or diastolic dysfunction. The molecular mechanisms involved in these processes are multifactorial and complex. Several molecular mechanisms, such as TGF-β signaling pathway, extracellular matrix (ECM) synthesis and degradation, and non-coding RNAs, positively or negatively regulate myocardial fibrosis. Long noncoding RNAs (lncRNAs) have emerged as significant mediators in gene regulation in cardiovascular diseases. Recent studies have demonstrated that lncRNAs are crucial in genetic programming and gene expression during myocardial fibrosis. We summarize the function of lncRNAs in cardiac fibrosis and their contributions to miRNA expression, TGF-β signaling, and ECMs synthesis, with a particular attention on the exosome-derived lncRNAs in the regulation of adverse fibrosis as well as the mode of action of lncRNAs secreted into exosomes. We also discuss how the current knowledge on lncRNAs can be applied to develop novel therapeutic strategies to prevent or reverse cardiac fibrosis.
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The Carthamus tinctorius L. and Lepidium apetalum Willd. Drug Pair Inhibits EndMT through the TGF β1/Snail Signaling Pathway in the Treatment of Myocardial Fibrosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2023; 2023:6018375. [PMID: 36686974 PMCID: PMC9851799 DOI: 10.1155/2023/6018375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 12/22/2022] [Accepted: 12/28/2022] [Indexed: 01/13/2023]
Abstract
Background Myocardial fibrosis (MF) is an essential pathological factor for heart failure. Previous studies have shown that the combination of Carthamus tinctorius L. and Lepidium apetalum Willd. (C-L), two types of Chinese herbal medicine, can ameliorate MF after myocardial infarction (MI) in rats and inhibit the activation of myocardial fibroblasts. However, the mechanism of C-L in the treatment of MF remains unclear. Methods A rat model of MF with left anterior descending coronary ligation-induced MI was first established. Then, the effects of C-L on cardiac function, MF, and endothelial-to-mesenchymal transition (EndMT) were evaluated by the left ventricular ejection fraction (LVEF), serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, Masson's trichrome staining, and immunohistochemical and immunofluorescence staining. Next, a hypoxia-induced cardiac microvascular endothelial cell (CMEC) model was established to observe the effects of C-L on EndMT. The supernatant of CMECs was collected and used to culture cardiac fibroblasts (CFs) and observe the effects of CMEC paracrine factors on CFs. Results Animal experiments indicated that C-L improves the cardiac function of rats after MI, inhibits the progression of EndMT and MF, and downregulates TGFβ1, Snail, and CTGF expression. Cell experiments showed that drug-loaded serum containing C-L inhibits the EndMT of CMECs under hypoxic conditions. The culture supernatant of CMECs grown under hypoxic conditions significantly activated CFs. After treatment with C-L, the activating factor for CFs in hypoxic CMEC culture supernatant was substantially downregulated, and the effect of the culture supernatant on CF activation was also reduced. However, TGFβ1 agonists inhibited the effects of C-L on CMECs and CFs. Conclusion Our data demonstrated that by regulating the TGFβ1/Snail pathway, C-L inhibits EndMT of CMECs and reduces the release of CF-activating factors in cells undergoing EndMT.
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39
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Xing C, Bao L, Li W, Fan H. Progress on role of ion channels of cardiac fibroblasts in fibrosis. Front Physiol 2023; 14:1138306. [PMID: 36969589 PMCID: PMC10033868 DOI: 10.3389/fphys.2023.1138306] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/27/2023] [Indexed: 03/29/2023] Open
Abstract
Cardiac fibrosis is defined as excessive deposition of extracellular matrix (ECM) in pathological conditions. Cardiac fibroblasts (CFs) activated by injury or inflammation differentiate into myofibroblasts (MFs) with secretory and contractile functions. In the fibrotic heart, MFs produce ECM which is composed mainly of collagen and is initially involved in maintaining tissue integrity. However, persistent fibrosis disrupts the coordination of excitatory contractile coupling, leading to systolic and diastolic dysfunction, and ultimately heart failure. Numerous studies have demonstrated that both voltage- and non-voltage-gated ion channels alter intracellular ion levels and cellular activity, contributing to myofibroblast proliferation, contraction, and secretory function. However, an effective treatment strategy for myocardial fibrosis has not been established. Therefore, this review describes the progress made in research related to transient receptor potential (TRP) channels, Piezo1, Ca2+ release-activated Ca2+ (CRAC) channels, voltage-gated Ca2+ channels (VGCCs), sodium channels, and potassium channels in myocardial fibroblasts with the aim of providing new ideas for treating myocardial fibrosis.
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Endothelial-cell-mediated mechanism of coronary microvascular dysfunction leading to heart failure with preserved ejection fraction. Heart Fail Rev 2023; 28:169-178. [PMID: 35266091 PMCID: PMC9902427 DOI: 10.1007/s10741-022-10224-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2022] [Indexed: 02/07/2023]
Abstract
Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is growing worldwide, its complex pathophysiology has yet to be fully elucidated, and multiple hypotheses have all failed to produce a viable target for therapeutic action or provide effective treatment. Cardiac remodeling has long been considered an important mechanism of HFpEF. Strong evidence has been reported over the past years that coronary microvascular dysfunction (CMD), manifesting as structural and functional abnormalities of coronary microvasculature, also contributes to the evolution of HFpEF. However, the mechanisms of CMD are still not well understood and need to be studied further. Coronary microvascular endothelial cells (CMECs) are one of the most abundant cell types in the heart by number and active players in cardiac physiology and pathology. CMECs are not only important cellular mediators of cardiac vascularization but also play an important role in disease pathophysiology by participating in the inception and progression of cardiac remodeling. CMECs are also actively involved in the pathogenesis of CMD. Numerous studies have confirmed that CMD is closely related to cardiac remodeling. ECs may serve a critical function in mediating the connection between CMD and HFpEF. It follows that CMECs participate in the mechanism of CMD leading to HFpEF. In this review article, we focus on the role of CMD in the pathogenesis of HFpEF resulting from cardiac remodeling and highlight the subsequent complexity of the EC-mediated correlation between CMD and HFpEF.
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Proteomic Insights into Cardiac Fibrosis: From Pathophysiological Mechanisms to Therapeutic Opportunities. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248784. [PMID: 36557919 PMCID: PMC9781843 DOI: 10.3390/molecules27248784] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022]
Abstract
Cardiac fibrosis is a common pathophysiologic process in nearly all forms of heart disease which refers to excessive deposition of extracellular matrix proteins by cardiac fibroblasts. Activated fibroblasts are the central cellular effectors in cardiac fibrosis, and fibrotic remodelling can cause several cardiac dysfunctions either by reducing the ejection fraction due to a stiffened myocardial matrix, or by impairing electric conductance. Recently, there is a rising focus on the proteomic studies of cardiac fibrosis for pathogenesis elucidation and potential biomarker mining. This paper summarizes the current knowledge of molecular mechanisms underlying cardiac fibrosis, discusses the potential of imaging and circulating biomarkers available to recognize different phenotypes of this lesion, reviews the currently available and potential future therapies that allow individualized management in reversing progressive fibrosis, as well as the recent progress on proteomic studies of cardiac fibrosis. Proteomic approaches using clinical specimens and animal models can provide the ability to track pathological changes and new insights into the mechanisms underlining cardiac fibrosis. Furthermore, spatial and cell-type resolved quantitative proteomic analysis may also serve as a minimally invasive method for diagnosing cardiac fibrosis and allowing for the initiation of prophylactic treatment.
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Beloglazova I, Zubkova E, Dergilev K, Goltseva Y, Parfyonova Y. New Insight on 2D In Vitro Angiogenesis Models: All That Stretches Is Not a Tube. Cells 2022; 11:cells11203278. [PMID: 36291145 PMCID: PMC9600603 DOI: 10.3390/cells11203278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/30/2022] [Accepted: 10/15/2022] [Indexed: 11/16/2022] Open
Abstract
Highlights Abstract A Matrigel-based tube formation assay is a simple and widely accepted 2D angiogenesis model in vitro. Extracellular matrix (EM) proteins and growth factors (GFs) from MatrigelTM exclusively trigger endothelial cell (EC) tubular network (ETN) formation. Co-culture of ECs with mesenchymal stromal cells (MSCs) is another and more reliable in vitro angiogenesis assay. MSCs modulate ETN formation through intercellular interactions and as a supplier of EM and GFs. The aim of the present study was to compare the expression profile of ECs in both models. We revealed upregulation of the uPA, uPAR, Jagged1, and Notch2 genes in dividing/migrating ECs and for ECs in both experimental models at 19 h. The expression of endothelial–mesenchymal transition genes largely increased in co-cultured ECs whereas Notch and Hippo signaling pathway genes were upregulated in ECs on MatrigelTM. We showed that in the co-culture model, basement membrane (BM) deposition is limited only to cell-to-cell contacts in contrast to MatrigelTM, which represents by itself fully pre-assembled BM matrix. We suggest that ETN in a co-culture model is still in a dynamic process due to immature BM whereas ECs in the MatrigelTM assay seem to be at the final stage of ETN formation.
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Affiliation(s)
- Irina Beloglazova
- Laboratory of Angiogenesis, Chazov National Medical Research Center of Cardiology, Moscow 121552, Russia
- Correspondence:
| | - Ekaterina Zubkova
- Laboratory of Angiogenesis, Chazov National Medical Research Center of Cardiology, Moscow 121552, Russia
| | - Konstantin Dergilev
- Laboratory of Angiogenesis, Chazov National Medical Research Center of Cardiology, Moscow 121552, Russia
| | - Yulia Goltseva
- Laboratory of Angiogenesis, Chazov National Medical Research Center of Cardiology, Moscow 121552, Russia
| | - Yelena Parfyonova
- Laboratory of Angiogenesis, Chazov National Medical Research Center of Cardiology, Moscow 121552, Russia
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Lomonosov Moscow State University, Moscow 119192, Russia
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Cornuault L, Rouault P, Duplàa C, Couffinhal T, Renault MA. Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction: What are the Experimental Proofs? Front Physiol 2022; 13:906272. [PMID: 35874523 PMCID: PMC9304560 DOI: 10.3389/fphys.2022.906272] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) has been recognized as the greatest single unmet need in cardiovascular medicine. Indeed, the morbi-mortality of HFpEF is high and as the population ages and the comorbidities increase, so considerably does the prevalence of HFpEF. However, HFpEF pathophysiology is still poorly understood and therapeutic targets are missing. An unifying, but untested, theory of the pathophysiology of HFpEF, proposed in 2013, suggests that cardiovascular risk factors lead to a systemic inflammation, which triggers endothelial cells (EC) and coronary microvascular dysfunction. This cardiac small vessel disease is proposed to be responsible for cardiac wall stiffening and diastolic dysfunction. This paradigm is based on the fact that microvascular dysfunction is highly prevalent in HFpEF patients. More specifically, HFpEF patients have been shown to have decreased cardiac microvascular density, systemic endothelial dysfunction and a lower mean coronary flow reserve. Importantly, impaired coronary microvascular function has been associated with the severity of HF. This review discusses evidence supporting the causal role of endothelial dysfunction in the pathophysiology of HFpEF in human and experimental models.
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Wu Y, Lin X, Hong H, Fung YL, Cao X, Tse JKY, Li TH, Chan TF, Tian XY. Endothelium-targeted delivery of PPARδ by adeno-associated virus serotype 1 ameliorates vascular injury induced by hindlimb ischemia in obese mice. Biomed Pharmacother 2022; 151:113172. [PMID: 35644115 DOI: 10.1016/j.biopha.2022.113172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/13/2022] [Accepted: 05/22/2022] [Indexed: 11/28/2022] Open
Abstract
Diabetic vasculopathy is a major health problem worldwide. Peripheral arterial disease (PAD), and in its severe form, critical limb ischemia is a major form of diabetic vasculopathy with limited treatment options. Existing literature suggested an important role of PPARδ in vascular homeostasis. It remains elusive for using PPARδ as a potential therapeutic target due to mostly the side effects of PPARδ agonists. To explore the roles of PPARδ in endothelial homeostasis, endothelial cell (EC) selective Ppard knockout and controlled mice were subjected to hindlimb ischemia (HLI) injury. The muscle ECs were sorted for single-cell RNA sequencing (scRNA-seq) analysis. HLI was also performed in high fat diet (HFD)-induced obese mice to examine the function of PPARδ in obese mice with delayed vascular repair. Adeno-associated virus type 1 (AAV1) carrying ICAM2 promoter to target endothelium for overexpressing PPARδ was injected into the injured muscles of normal chow- and HFD-fed obese mice before HLI surgery was performed. scRNA-seq analysis of ECs in ischemic muscles revealed a pivotal role of PPARδ in endothelial homeostasis. PPARδ expression was diminished both after HLI injury, and also in obese mice, which showed further delayed vascular repair. Endothelium-targeted delivery of PPARδ by AAV1 improved perfusion recovery, increased capillary density, restored endothelial integrity, suppressed vascular inflammation, and promoted muscle regeneration in ischemic hindlimbs of both lean and obese mice. Our study indicated the effectiveness of endothelium-targeted PPARδ overexpression for restoring functional vasculature after ischemic injury, which might be a promising option of gene therapy to treat PAD and CLI.
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Affiliation(s)
- Yalan Wu
- Chinese University of Hong Kong, Hong Kong, China; School of Biomedical Sciences, Faculty of Medicine, Hong Kong, China; Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China
| | - Xiao Lin
- School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Huiling Hong
- Chinese University of Hong Kong, Hong Kong, China; School of Biomedical Sciences, Faculty of Medicine, Hong Kong, China; Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China
| | - Yee Lok Fung
- Chinese University of Hong Kong, Hong Kong, China; School of Biomedical Sciences, Faculty of Medicine, Hong Kong, China; Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China
| | - Xiaoyun Cao
- Chinese University of Hong Kong, Hong Kong, China; School of Biomedical Sciences, Faculty of Medicine, Hong Kong, China; Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China
| | - Joyce Ka Yu Tse
- School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Tsz Ho Li
- School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Ting Fung Chan
- Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China; School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Xiao Yu Tian
- Chinese University of Hong Kong, Hong Kong, China; School of Biomedical Sciences, Faculty of Medicine, Hong Kong, China; Shenzhen Research Institute, Chinese University of Hong Kong, Shenzhen, China.
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Zhao F, Satyanarayana G, Zhang Z, Zhao J, Ma XL, Wang Y. Endothelial Autophagy in Coronary Microvascular Dysfunction and Cardiovascular Disease. Cells 2022; 11:2081. [PMID: 35805165 PMCID: PMC9265562 DOI: 10.3390/cells11132081] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 02/06/2023] Open
Abstract
Coronary microvascular dysfunction (CMD) refers to a subset of structural and/or functional disorders of coronary microcirculation that lead to impaired coronary blood flow and eventually myocardial ischemia. Amid the growing knowledge of the pathophysiological mechanisms and the development of advanced tools for assessment, CMD has emerged as a prevalent cause of a broad spectrum of cardiovascular diseases (CVDs), including obstructive and nonobstructive coronary artery disease, diabetic cardiomyopathy, and heart failure with preserved ejection fraction. Of note, the endothelium exerts vital functions in regulating coronary microvascular and cardiac function. Importantly, insufficient or uncontrolled activation of endothelial autophagy facilitates the pathogenesis of CMD in diverse CVDs. Here, we review the progress in understanding the pathophysiological mechanisms of autophagy in coronary endothelial cells and discuss their potential role in CMD and CVDs.
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Affiliation(s)
- Fujie Zhao
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | | | - Zheng Zhang
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Jianli Zhao
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Xin-Liang Ma
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Yajing Wang
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
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Graham C, Sethu P. Myocardial Fibrosis: Cell Signaling and In Vitro Modeling. CARDIOVASCULAR SIGNALING IN HEALTH AND DISEASE 2022:287-321. [DOI: 10.1007/978-3-031-08309-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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47
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Zhang Y, Zhu Z, Wang T, Dong Y, Fan Y, Sun D. TGF-β1-containing exosomes from cardiac microvascular endothelial cells mediate cardiac fibroblast activation under high glucose conditions. Biochem Cell Biol 2021; 99:693-699. [PMID: 34726968 DOI: 10.1139/bcb-2020-0624] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Cardiac fibroblast (CF)-mediated extracellular matrix (ECM) remodeling is the key pathological basis for the occurrence and development of diabetic cardiomyopathy (DCM); its specific regulatory mechanisms have been widely studied but remain unclear. Exosomes are a type of stable signal transmission medium, and exosome-mediated cell-cell interactions play an important role in DCM. Endothelial cells form an important barrier between circulation and cardiomyocytes, in addition to being an important endocrine organ of the heart and an initial target for hyperglycemia, a key aspect in the development of DCM. We previously showed that exosomes derived from cardiac microvascular endothelial cells (CMECs) under high glucose conditions can be taken up by cardiomyocytes and regulate autophagy, apoptosis, and glucose metabolism. Consequently, in the present study, we focused on how exosomes mediate the interaction between CMECs and CFs. Surprisingly, exosomes derived from CMECs under high glucose were rich in TGF-β1 mRNA, which significantly promoted the activation of CFs. Additionally, exosomes derived from CMECs under high glucose conditions aggravated perivascular and interstitial fibrosis in mice treated with streptozotocin. Herein, we demonstrated for the first time the capacity of exosomes, released by CMECs under high glucose, to mediate fibroblast activation through TGF-β1 mRNA, which may be potentially beneficial in the development of exosome-targeted therapies to control DCM.
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Affiliation(s)
- Yan Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhengru Zhu
- Department of Otolaryngology Head and Neck Surgery, First Hospital of Lanzhou University, Lanzhou, China
| | - Tingting Wang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yuan Dong
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yanhong Fan
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Dongdong Sun
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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van den Berg NWE, Kawasaki M, Fabrizi B, Nariswari FA, Verduijn AC, Neefs J, Wesselink R, Al‐Shama RFM, van der Wal AC, de Boer OJ, Aten J, Driessen AHG, Jongejan A, de Groot JR. Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation. Clin Transl Med 2021; 11:e558. [PMID: 34841686 PMCID: PMC8567047 DOI: 10.1002/ctm2.558] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Improved understanding of the interconnectedness of structural remodeling processes in atrial fibrillation (AF) in patients could identify targets for future therapies. METHODS We present transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF, and persistent AF (total n = 64). RNA expression levels were validated in the same and an independent cohort with qPCR. Biological processes were assessed with histological and immunohistochemical analyses. RESULTS In AF patients, epicardial cell gene expression decreased, contrasting with an upregulation of epithelial-to-mesenchymal transition (EMT) and mesenchymal cell gene expression. Immunohistochemistry demonstrated thickening of the epicardium and an increased proportion of (myo)fibroblast-like cells in the myocardium, supporting enhanced EMT in AF. We furthermore report an upregulation of endothelial cell proliferation, angiogenesis, and endothelial signaling. EMT and endothelial cell proliferation concurred with increased interstitial (myo)fibroblast-like cells and extracellular matrix gene expression including enhanced tenascin-C, thrombospondins, biglycan, and versican. Morphological analyses discovered increased and redistributed glycosaminoglycans and collagens in the atria of AF patients. Signaling pathways, including cell-matrix interactions, PI3K-AKT, and Notch signaling that could regulate mesenchymal cell activation, were upregulated. CONCLUSION Our results suggest that EMT and endothelial cell proliferation work in concert and characterize the (myo)fibroblast recruitment and ECM remodeling of AF. These processes could guide future research toward the discovery of targets for AF therapy.
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Affiliation(s)
- Nicoline W. E. van den Berg
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Makiri Kawasaki
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Benedetta Fabrizi
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Fransisca A. Nariswari
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Arianne C. Verduijn
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Jolien Neefs
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Robin Wesselink
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Rushd F. M. Al‐Shama
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Allard C. van der Wal
- Department of Clinical PathologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Onno J. de Boer
- Department of Clinical PathologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Jan Aten
- Department of Clinical PathologyAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Antoine H. G. Driessen
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
| | - Aldo Jongejan
- Department of Epidemiology & Data ScienceAmsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Joris R. de Groot
- Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular SciencesAmsterdam UMC, University of Amsterdam, Heart CenterAmsterdamThe Netherlands
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Akinbote A, Beltran-Sastre V, Cherubini M, Visone R, Hajal C, Cobanoglu D, Haase K. Classical and Non-classical Fibrosis Phenotypes Are Revealed by Lung and Cardiac Like Microvascular Tissues On-Chip. Front Physiol 2021; 12:735915. [PMID: 34690810 PMCID: PMC8528192 DOI: 10.3389/fphys.2021.735915] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 08/31/2021] [Indexed: 11/13/2022] Open
Abstract
Fibrosis, a hallmark of many cardiac and pulmonary diseases, is characterized by excess deposition of extracellular matrix proteins and increased tissue stiffness. This serious pathologic condition is thought to stem majorly from local stromal cell activation. Most studies have focused on the role of fibroblasts; however, the endothelium has been implicated in fibrosis through direct and indirect contributions. Here, we present a 3D vascular model to investigate vessel-stroma crosstalk in normal conditions and following induced fibrosis. Human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) are co-cultured with (and without) primary human cardiac and lung fibroblasts (LFs) in a microfluidic device to generate perfusable microvasculature in cardiac- and pulmonary-like microenvironments. Endothelial barrier function, vascular morphology, and matrix properties (stiffness and diffusivity) are differentially impacted by the presence of stromal cells. These vessels (with and without stromal cells) express inflammatory cytokines, which could induce a wound-healing state. Further treatment with transforming growth factor-β (TGF-β) induced varied fibrotic phenotypes on-chip, with LFs resulting in increased stiffness, lower MMP activity, and increased smooth muscle actin expression. Taken together, our work demonstrates the strong impact of stromal-endothelial interactions on vessel formation and extravascular matrix regulation. The role of TGF-β is shown to affect co-cultured microvessels differentially and has a severe negative impact on the endothelium without stromal cell support. Our human 3D in vitro model has the potential to examine anti-fibrotic therapies on patient-specific hiPSCs in the future.
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Affiliation(s)
- Akinola Akinbote
- European Molecular Biology Laboratory, Barcelona, Spain.,Heidelberg University, Faculty of Biosciences, Heidelberg, Germany
| | | | | | - Roberta Visone
- Politecnico di Milano, Department of Electronics, Information, and Bioengineering, Milan Italy.,Massachusetts Institute of Technology, Department of Mechanical Engineering, Cambridge, MA, United States
| | - Cynthia Hajal
- Massachusetts Institute of Technology, Department of Mechanical Engineering, Cambridge, MA, United States
| | - Defne Cobanoglu
- European Molecular Biology Laboratory, Barcelona, Spain.,Heidelberg University, Faculty of Biosciences, Heidelberg, Germany
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50
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Yao L, Shao W, Chen Y, Wang S, Huang D. Suppression of ADAM8 attenuates angiotensin II-induced cardiac fibrosis and endothelial-mesenchymal transition via inhibiting TGF-β1/Smad2/Smad3 pathways. Exp Anim 2021; 71:90-99. [PMID: 34615811 PMCID: PMC8828410 DOI: 10.1538/expanim.21-0064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Endothelial-to-mesenchymal transition (EndMT) is involved in cardiac fibrosis induced by angiotensin II (Ang II). A disintegrin and metalloproteinase 8 (ADAM8), a member of ADAMs family, participates in cell adhesion, proteolysis and various signaling. However, its effects on the development of cardiac fibrosis remain completely unknown. This study aimed to reveal whether ADAM8 aggravates cardiac fibrosis induced by Ang II in vivo and in vitro. The C57BL/6J mice or cardiac endothelial cells were subjected to Ang II infusion to induce fibrosis. The results showed that systolic blood pressure and diastolic blood pressure were significantly increased under Ang II infusion, and ADAM8 was up-regulated. ADAM8 inhibition attenuated Ang II-induced cardiac dysfunction. ADAM8 knockdown suppressed Ang II-induced cardiac fibrosis as evidenced by the down-regulation of CTGF, collagen I, and collagen III. In addition, the endothelial marker (VE-cadherin) was decreased, whilst mesenchymal markers (α-SMA and FSP1) were increased following Ang II infusion. However, ADAM8 repression inhibited Ang II-induced EndMT. Moreover, ADAM8 silencing repressed the activation of TGF-β1/Smad2/Smad3 pathways. Consistent with the results in vivo, we also found the inhibitory effects of ADAM8 inhibition on EndMT in vitro. All data suggest that ADAM8 promotes Ang II-induced cardiac fibrosis and EndMT via activating TGF-β1/Smad2/Smad3 pathways.
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Affiliation(s)
- Lixia Yao
- Department of Geriatrics, Hebei General Hospital
| | - Weihua Shao
- Department of Geriatrics, Hebei General Hospital
| | - Yan Chen
- Department of Anesthesiology, Children's Hospital of Hebei Province
| | - Suxing Wang
- Department of Geriatrics, Hebei General Hospital
| | - Dai Huang
- Department of Ultrasound, Hebei General Hospital
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