|
1
|
Yin D, Zhao C. Multi-omics analysis reveals the cerebral sex-specific responses to chronic hypoxia in yellow catfish (Pelteobagrus fulvidraco). COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2025; 54:101401. [PMID: 39700741 DOI: 10.1016/j.cbd.2024.101401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/12/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024]
Abstract
Hypoxia disrupts multiple physiological processes, including metabolism, immunity, and reproduction in teleosts. The brain plays a critical role in adapting to environmental changes, regulating the endocrine system, and controlling reproduction. The present study investigated the sex-specific cerebral responses to chronic hypoxia through an integrated analysis of the transcriptome, proteome, and metabolome of yellow catfish. Common cerebral responses in both females and males included activation of the HIF signaling pathway, angiogenesis, and improved oxygen delivery by red blood cells. Reproductive defects were indicated by the downregulation of gh1, cga, and tshb in both sexes. Thyroid hormone homeostasis was more severely disrupted by hypoxia in females than in males, accompanied by a significant decrease in the level of VTG in the female brain. Damaged brain function was evidenced by the highly enriched pathways of "cytokine-cytokine receptor interaction" and "ECM-receptor interaction," and the blood-brain barrier (BBB) also appeared to be disrupted in female fish. In the male brain, reproductive-related genes or proteins, including prl, lepr, and AVP, were specifically decreased. Dysfunction in the male brain was also indicated by the enrichment of pathways such as "cytokine-cytokine receptor interaction" and "neuroactive ligand-receptor interaction," based on differentially expressed genes (DEGs) and proteins (DEPs). Additionally, chronic hypoxia appeared to inhibit cerebral amino acid metabolism in males. In summary, our results offer insight into understanding the sex-specific cerebral responses induced by chronic hypoxia in teleosts.
Collapse
Affiliation(s)
- Danqing Yin
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong; Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Hong Kong
| | - Cheng Zhao
- College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, China.
| |
Collapse
|
|
2
|
Yang SH, Gan J, Xu HR, Shi JX, Wang J, Zhang X. The BMP Signaling Pathway: Bridging Maternal-Fetal Crosstalk in Early Pregnancy. Reprod Sci 2025; 32:1427-1445. [PMID: 39821798 DOI: 10.1007/s43032-024-01777-4] [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: 10/26/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025]
Abstract
The maintenance of early pregnancy is a complex and distinctive process, primarily characterized by critical reproductive events such as embryo implantation, trophoblasts differentiation, decidualization, and extravillous trophoblasts (EVTs) invasion etc. However, dysregulation of these essential reproductive processes can result in various pregnancy complications, including recurrent miscarriage, preeclampsia, and fetal growth restriction etc. Notably, these complications exhibit an interconnected regulatory network that suggests shared underlying pathophysiological mechanisms. Meanwhile, the role of the BMP signaling pathway in sustaining early pregnancy is increasingly being investigated and elucidated. In this review, we have clarified the specific molecular mechanisms which are fundamental to essential reproductive processes and summarize an overview of animal models associated with BMP signaling molecules. In addition, we present a novel perspective on several contentious viewpoints regarding the functional roles of BMP ligands. Therefore, we anticipated a comprehensive understanding of the precise ways in which the BMP signaling pathway affects reproductive events during early pregnancy could provide new perspectives and approaches for preventing and addressing early pregnancy complications.
Collapse
Affiliation(s)
- Shu-Han Yang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai, 200237, China
| | - Jie Gan
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai, 200237, China
| | - Hao-Ran Xu
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai, 200237, China
| | - Jia-Xin Shi
- Institute of Pathology, Medical Faculty, RWTH Aachen University, Aachen, 52074, Germany
| | - Jian Wang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai, 200237, China.
| | - Xuan Zhang
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Medical School, Fudan University, Shanghai, 200237, China.
| |
Collapse
|
|
3
|
Dobariya KH, Goyal D, Kumar H. Molecular signature-based labeling techniques for vascular endothelial cells. Acta Histochem 2025; 127:152222. [PMID: 39644518 DOI: 10.1016/j.acthis.2024.152222] [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: 07/13/2024] [Revised: 11/14/2024] [Accepted: 11/26/2024] [Indexed: 12/09/2024]
Abstract
Vascular endothelial cells (VECs) play a crucial role in the development and maintenance of vascular biology specific to the tissue types. Molecular signature-based labeling and imaging of VECs help researchers understand potential mechanisms linking VECs to disease pathology, serving as valuable biomarkers in clinical settings and trials. Labeling techniques involve selectively tagging or marking VECs for visualization. Immunolabeled employs antibodies that specifically bind to VECs markers, while fluorescent tracers or dyes can directly label VECs for imaging. Some techniques use specific carbohydrate residues on cell surface, while others employ endothelial-specific promoters to express fluorescent proteins. Additionally, VEC can be labeled with contrast agents, radiolabeled tracers, and nanoparticles. The choice of labeling technique depends on study context, including whether it involves animal models, in vitro cell cultures, or clinical applications. Herein, we discussed the various labeling methods utilized to label VECs and the techniques to visualize them.
Collapse
Affiliation(s)
- Krutika H Dobariya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Divya Goyal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India.
| |
Collapse
|
|
4
|
Xu X, Fu J, Yang G, Chen Z, Chen S, Yuan G. Dentin sialoprotein acts as an angiogenic factor through association with the membrane receptor endoglin. J Biol Chem 2025; 301:108279. [PMID: 39922489 PMCID: PMC11910139 DOI: 10.1016/j.jbc.2025.108279] [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: 08/04/2024] [Revised: 01/04/2025] [Accepted: 01/23/2025] [Indexed: 02/10/2025] Open
Abstract
Dentin sialophosphoprotein (DSPP) is highly expressed by odontoblasts, the cell type responsible for dentin formation. DSPP therefore has been extensively studied as a regulator of dentinogenesis. Besides defective dentinogenesis in teeth, Dspp-deficient mice also display reduced blood vessels in the transition zone of femurs. However, the exact role and underlying mechanisms of DSPP in the process of blood vessel formation remain enigmatic. Here, we show that dentin sialoprotein (DSP), the NH2-terminal cleavage product of DSPP, promotes the migration and capillary-like structure formation of human umbilical vein endothelial cells (HUVECs) as well as the migration and endothelial differentiation of human dental pulp stem cells (DPSCs). Further experiments demonstrate that endoglin (ENG), a membrane receptor associated with angiogenesis, can be co-immunoprecipitated by DSP. Flow cytometry assays show that HUVECs and DPSCs, two cell types with endogenous ENG expression, display obvious binding signals of supplemented DSP protein, but human embryonic kidney 293T (HEK293T) cells, a cell type without endogenous ENG expression, do not. Pretreatment with an anti-ENG antibody or knockdown of ENG inhibits the binding of DSP to DPSCs, while ENG overexpression enhances binding signals of DSP to HEK293T cells. Meanwhile, multiple experiments demonstrate that knockdown of ENG impairs DSP-induced migration and endothelial differentiation of DPSCs. Therefore, ENG is essential for the angiogenic effects of DSP. Moreover, Dspp-deficient mice exhibit defective capillary formation in molars, supporting the positive role of DSP in blood vessel development. Collectively, these findings identify that DSP acts as an angiogenic factor through association with ENG.
Collapse
Affiliation(s)
- Ximin Xu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China
| | - Jing Fu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China
| | - Guobin Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Zhi Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Shuo Chen
- Department of Developmental Dentistry, School of Dentistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Guohua Yuan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China.
| |
Collapse
|
|
5
|
Ejlalidiz M, Mehri-Ghahfarrokhi A, Saberiyan M. Identification of hub genes and pathways in Uterine corpus endometrial carcinoma (UCEC): A comprehensive in silico study. Biochem Biophys Rep 2024; 40:101860. [PMID: 39552710 PMCID: PMC11565547 DOI: 10.1016/j.bbrep.2024.101860] [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: 10/09/2024] [Accepted: 10/27/2024] [Indexed: 11/19/2024] Open
Abstract
Background Uterine corpus endometrial carcinoma (UCEC), derived from the endometrium, is the most common type of endometrial malignasis. This gynecological malignancy is very common all over the world, especially in developed countries and shows a potentially rising trend correlated with the increase in obese women. Methods Differentially Expressed Genes (DEGs) analysis was conducted on GSE7305 and GSE25628 datasets from the Gene Expression Omnibus (GEO). DEGs were identified using GEO2R (adjusted p-value <0.05, |logFC| > 1). Pathway analysis employed KEGG and Gene Ontology databases, while protein-protein interactions were analyzed using Cytoscape and Gephi. GEPIA was used for target gene validation. Results We have identified 304 common DEGs and 78 hub genes using GEO and PPI analysis, respectively. The GO and KEGG pathways analysis revealed enrichment of DEGs in extracellular matrix structural constituent, extracellular space, cell adhesion, and ECM-receptor interaction. GEPIA analysis identified three genes, ENG, GNG4, and ECT2, whose expression significantly differed between normal and tumor samples. Conclusion This analysis study identified the hub genes and associated pathways involved in the pathogenesis of UCEC. The identified hub genes exhibit remarkable potential as diagnostic biomarkers, providing a significant opportunity for early diagnosis and more effective therapeutic approaches for UCEC.
Collapse
Affiliation(s)
- Mahsa Ejlalidiz
- Medical Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ameneh Mehri-Ghahfarrokhi
- Clinical Research Developmental Unit, Hajar Hospital, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammadreza Saberiyan
- Department of Medical Genetics, School of Medical Sciences, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| |
Collapse
|
|
6
|
Testa AM, Vignozzi L, Corallo D, Aveic S, Viola A, Allegra M, Angioni R. Hypoxic Human Microglia Promote Angiogenesis Through Extracellular Vesicle Release. Int J Mol Sci 2024; 25:12508. [PMID: 39684220 DOI: 10.3390/ijms252312508] [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: 11/09/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Microglia, the brain-resident immune cells, orchestrate neuroinflammatory responses and are crucial in the progression of neurological diseases, including ischemic stroke (IS), which accounts for approximately 85% of all strokes worldwide. Initially deemed detrimental, microglial activation has been shown to perform protective functions in the ischemic brain. Besides their effects on neurons, microglia play a role in promoting post-ischemic angiogenesis, a pivotal step for restoring oxygen and nutrient supply. However, the molecular mechanisms underlying microglia-endothelial cell interactions remain largely unresolved, particularly in humans. Using both in vitro and in vivo models, we investigated the angiogenic signature and properties of extracellular vesicles (EVs) released by human microglia upon hypoxia-reperfusion stimulation. EVs were isolated and characterized in terms of their size, concentration, and protein content. Their angiogenic potential was evaluated using endothelial cell assays and a zebrafish xenograft model. The in vivo effects were further assessed in a mouse model of ischemic stroke. Our findings identified key proteins orchestrating the pro-angiogenic functions of human microglial EVs under hypoxic conditions. In vitro assays demonstrated that hypoxic EVs (hypEVs) promoted endothelial cell migration and tube formation. In vivo, hypEVs induced vessel sprouting in zebrafish and increased microvessel density in the perilesional area of mice following ischemic stroke.
Collapse
Affiliation(s)
- Alessandra Maria Testa
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy
- Laboratory of Immunity, Inflammation and Angiogenesis, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padua, Italy
| | - Livia Vignozzi
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy
| | - Diana Corallo
- Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padua, Italy
| | - Sanja Aveic
- Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padua, Italy
| | - Antonella Viola
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy
| | - Manuela Allegra
- Laboratory of Neuronal Circuits in Developmental Disorders, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padua, Italy
- Neuroscience Institute, National Research Council, 35131 Padua, Italy
| | - Roberta Angioni
- Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy
- Laboratory of Immunity, Inflammation and Angiogenesis, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35127 Padua, Italy
| |
Collapse
|
|
7
|
Mangoni AA, Zinellu A. A systematic review and meta-analysis of the endothelial-immune candidate biomarker endoglin in rheumatic diseases. Clin Exp Med 2024; 25:4. [PMID: 39535678 PMCID: PMC11561007 DOI: 10.1007/s10238-024-01519-5] [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: 08/20/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Existing challenges in accurately diagnosing various rheumatic diseases (RDs) have stimulated the search for novel biomarkers to aid clinical evaluation and monitoring. We conducted a systematic review and meta-analysis of studies investigating the candidate biomarker endoglin (CD105), a transmembrane glycoprotein expressed in endothelial, myeloid, and lymphoid cells, in RD patients and healthy controls. We searched PubMed, Scopus, and Web of Science from inception to 10 August 2024 to identify relevant studies. We evaluated the risk of bias using the JBI Critical Appraisal Checklist and the certainty of evidence using GRADE (PROSPERO registration number: CRD42023581008). Overall, circulating endoglin concentrations were significantly higher in RD patients compared to controls (13 studies; standard mean difference, SMD = 0.64, 95% CI 0.13 to 1.14, p = 0.014; low certainty of evidence). The effect size of the between-group differences in endoglin concentrations was not significantly associated with age, male-to-female ratio, year of publication, number of participants, or mean RD duration. By contrast, the effect size was statistically significant in studies conducted in the European region (p = 0.033), involving patients with systemic sclerosis (p = 0.032), and measuring serum (p = 0.019). The results of this systematic review and meta-analysis suggest the potential pathophysiological role of endoglin in RDs. This, however, requires further investigation in prospective studies, particularly in patients with systemic sclerosis.
Collapse
Affiliation(s)
- Arduino A Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, and Flinders Medical Centre, Bedford Park, Adelaide, SA, 5042, Australia.
- Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia.
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| |
Collapse
|
|
8
|
Jeong JY, Bafor AE, Freeman BH, Chen PR, Park ES, Kim E. Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition. Biomedicines 2024; 12:1795. [PMID: 39200259 PMCID: PMC11351371 DOI: 10.3390/biomedicines12081795] [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: 06/26/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).
Collapse
Affiliation(s)
| | | | | | | | | | - Eunhee Kim
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (J.Y.J.); (A.E.B.); (B.H.F.); (P.R.C.); (E.S.P.)
| |
Collapse
|
|
9
|
Gerrits T, Dijkstra KL, Bruijn JA, Scharpfenecker M, Bijkerk R, Baelde HJ. Antisense oligonucleotide-mediated terminal intron retention of endoglin: A potential strategy to inhibit renal interstitial fibrosis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167186. [PMID: 38642778 DOI: 10.1016/j.bbadis.2024.167186] [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: 01/04/2024] [Revised: 04/15/2024] [Accepted: 04/17/2024] [Indexed: 04/22/2024]
Abstract
TGF-β is considered an important cytokine in the development of interstitial fibrosis in chronic kidney disease. The TGF-β co-receptor endoglin (ENG) tends to be upregulated in kidney fibrosis. ENG has two membrane bound isoforms generated via alternative splicing. Long-ENG was shown to enhance the extent of renal fibrosis in an unilateral ureteral obstruction mouse model, while short-ENG inhibited renal fibrosis. Here we aimed to achieve terminal intron retention of endoglin using antisense-oligo nucleotides (ASOs), thereby shifting the ratio towards short-ENG to inhibit the TGF-β1-mediated pro-fibrotic response. We isolated mRNA from kidney biopsies of patients with chronic allograft disease (CAD) (n = 12) and measured total ENG and short-ENG mRNA levels. ENG mRNA was upregulated 2.3 fold (p < 0.05) in kidneys of CAD patients compared to controls, while the percentage short-ENG of the total ENG mRNA was significantly lower (1.8 fold; p < 0.05). Transfection of ASOs that target splicing regulatory sites of ENG into TK173 fibroblasts led to higher levels of short-ENG (2 fold; p < 0.05). In addition, we stimulated these cells with TGF-β1 and measured a decrease in upregulation of ACTA2, COL1A1 and FN1 mRNA levels, and protein expression of αSMA, collagen type I, and fibronectin. These results show a potential for ENG ASOs as a therapy to reduce interstitial fibrosis in CKD.
Collapse
Affiliation(s)
- Tessa Gerrits
- Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands.
| | - Kyra L Dijkstra
- Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands
| | - Jan Anthonie Bruijn
- Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands
| | - Marion Scharpfenecker
- Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands
| | - Roel Bijkerk
- Department of Nephrology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands
| | - Hans J Baelde
- Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands
| |
Collapse
|
|
10
|
Iida M, Crossman BE, Kostecki KL, Glitchev CE, Kranjac CA, Crow MT, Adams JM, Liu P, Ong I, Yang DT, Kang I, Salgia R, Wheeler DL. MerTK Drives Proliferation and Metastatic Potential in Triple-Negative Breast Cancer. Int J Mol Sci 2024; 25:5109. [PMID: 38791148 PMCID: PMC11121248 DOI: 10.3390/ijms25105109] [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: 02/21/2024] [Revised: 04/29/2024] [Accepted: 05/02/2024] [Indexed: 05/26/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG's role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients.
Collapse
Affiliation(s)
- Mari Iida
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Bridget E. Crossman
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Kourtney L. Kostecki
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Christine E. Glitchev
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Carlene A. Kranjac
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Madisen T. Crow
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Jillian M. Adams
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
| | - Peng Liu
- Departments of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA; (P.L.); (I.O.)
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Irene Ong
- Departments of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA; (P.L.); (I.O.)
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - David T. Yang
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Irene Kang
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; (I.K.); (R.S.)
| | - Ravi Salgia
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA; (I.K.); (R.S.)
| | - Deric L. Wheeler
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA; (M.I.); (B.E.C.); (K.L.K.); (C.E.G.); (C.A.K.); (M.T.C.); (J.M.A.)
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA
| |
Collapse
|
|
11
|
Chen M, Huang X, Wang C, Wang S, Jia L, Li L. Endogenous retroviral solo-LTRs in human genome. Front Genet 2024; 15:1358078. [PMID: 38606358 PMCID: PMC11007075 DOI: 10.3389/fgene.2024.1358078] [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: 12/21/2023] [Accepted: 03/04/2024] [Indexed: 04/13/2024] Open
Abstract
Human endogenous retroviruses (HERVs) are derived from the infection and integration of exogenetic retroviruses. HERVs account for 8% of human genome, and the majority of HERVs are solitary LTRs (solo-LTRs) due to homologous recombination. Multiple findings have showed that solo-LTRs could provide an enormous reservoir of transcriptional regulatory sequences involved in diverse biological processes, especially carcinogenesis and cancer development. The link between solo-LTRs and human diseases still remains poorly understood. This review focuses on the regulatory modules of solo-LTRs, which contribute greatly to the diversification and evolution of human genes. More importantly, although inactivating mutations, insertions and deletions have been identified in solo-LTRs, the inherited regulatory elements of solo-LTRs initiate the expression of chimeric lncRNA transcripts, which have been reported to play crucial roles in human health and disease. These findings provide valuable insights into the evolutionary and functional mechanisms underlying the presence of HERVs in human genome. Taken together, in this review, we will present evidences showing the regulatory and encoding capacity of solo-LTRs as well as the significant impact on various aspects of human biology.
Collapse
Affiliation(s)
- Mingyue Chen
- National 111 Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering, Hubei University of Technology, Wuhan, Hubei, China
| | - Xiaolong Huang
- National 111 Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering, Hubei University of Technology, Wuhan, Hubei, China
| | - Chunlei Wang
- Department of Microbiology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, China
- Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| | - Shibo Wang
- National 111 Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering, Hubei University of Technology, Wuhan, Hubei, China
| | - Lei Jia
- Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| | - Lin Li
- Department of Virology, Beijing Institute of Microbiology and Epidemiology, Beijing, China
- State Key Laboratory of Pathogen and Biosecurity, Beijing, China
| |
Collapse
|
|
12
|
Sun C, Xie K, Yang L, Cai S, Wang M, Zhu Y, Tao B, Zhu Y. HDAC6 Enhances Endoglin Expression through Deacetylation of Transcription Factor SP1, Potentiating BMP9-Induced Angiogenesis. Cells 2024; 13:490. [PMID: 38534334 PMCID: PMC10969049 DOI: 10.3390/cells13060490] [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: 01/09/2024] [Revised: 03/01/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
Histone deacetylase 6 (HDAC6) plays a crucial role in the acetylation of non-histone proteins and is notably implicated in angiogenesis, though its underlying mechanisms were previously not fully understood. This study conducted transcriptomic and proteomic analyses on vascular endothelial cells with HDAC6 knockdown, identifying endoglin (ENG) as a key downstream protein regulated by HDAC6. This protein is vital for maintaining vascular integrity and plays a complex role in angiogenesis, particularly in its interaction with bone morphogenetic protein 9 (BMP9). In experiments using human umbilical vein endothelial cells (HUVECs), the pro-angiogenic effects of BMP9 were observed, which diminished following the knockdown of HDAC6 and ENG. Western blot analysis revealed that BMP9 treatment increased SMAD1/5/9 phosphorylation, a process hindered by HDAC6 knockdown, correlating with reduced ENG expression. Mechanistically, our study indicates that HDAC6 modulates ENG transcription by influencing promoter activity, leading to increased acetylation of transcription factor SP1 and consequently altering its transcriptional activity. Additionally, the study delves into the structural role of HDAC6, particularly its CD2 domain, in regulating SP1 acetylation and subsequently ENG expression. In conclusion, the present study underscores the critical function of HDAC6 in modulating SP1 acetylation and ENG expression, thereby significantly affecting BMP9-mediated angiogenesis. This finding highlights the potential of HDAC6 as a therapeutic target in angiogenesis-related processes.
Collapse
Affiliation(s)
- Chen Sun
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; (C.S.); (K.X.); (L.Y.); (S.C.); (M.W.)
- State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Avenida WaiLong, Taipa, Macau 999078, China;
| | - Kuifang Xie
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; (C.S.); (K.X.); (L.Y.); (S.C.); (M.W.)
| | - Lejie Yang
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; (C.S.); (K.X.); (L.Y.); (S.C.); (M.W.)
| | - Shengyang Cai
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; (C.S.); (K.X.); (L.Y.); (S.C.); (M.W.)
| | - Mingjie Wang
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; (C.S.); (K.X.); (L.Y.); (S.C.); (M.W.)
| | - Yizhun Zhu
- State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Avenida WaiLong, Taipa, Macau 999078, China;
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 200433, China
| | - Beibei Tao
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; (C.S.); (K.X.); (L.Y.); (S.C.); (M.W.)
| | - Yichun Zhu
- Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China; (C.S.); (K.X.); (L.Y.); (S.C.); (M.W.)
| |
Collapse
|
|
13
|
Rajan R, Hanifah M, Mariappan V, Anand M, Balakrishna Pillai A. Soluble Endoglin and Syndecan-1 levels predicts the clinical outcome in COVID-19 patients. Microb Pathog 2024; 188:106558. [PMID: 38272329 DOI: 10.1016/j.micpath.2024.106558] [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: 11/02/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
Endothelial instability is reported to be involved in the pathogenesis of COVID-19. The mechanism that regulates the endothelial dysfunction and disease virulence is not known. Studies on proteins that are released into circulation by activated endothelial cells may provide some means to understand the disease manifestation. The study investigated the circulating levels of two molecules Endoglin (Eng) and Syndecan-1 (SDC-1) that are presumed to be involved in the maintenance of endothelial integrity and their association with hypercoagulation marker in COVID-19 patients. The serum levels of Eng, SDC-1, D-mer were evaluated using ELISA at the time of admission (DOA) and day 7 post-admission among COVID-19 patients (N = 39 with 17 moderate and 22 severe cases). Compared to the time of admission, there was an increase in sEng and sSDC1 levels in all COVID-19 cases on day 7 post admission. The serum levels of sEng and sSDC-1 was significantly (P ≤ 0.001 & P ≤ 0.01 respectively) elevated in severe cases including the four deceased group compared to moderate cases on day 7 post admission. Further, the study molecules showed a strong positive association (P ≤ 0.001) with the hypercoagulation marker D-mer. The results show an early shedding of the endothelial proteins sEng and sSDC-1 into circulation as a host response to the viral infection during the febrile phase of infection. Increased levels of sEng and sSDC-1 along with D-mer could be beneficial in predicting COVID-19 disease severity.
Collapse
Affiliation(s)
- Remya Rajan
- Department of General Medicine, Mahatma Gandhi Medical College and Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India.
| | - Mohamed Hanifah
- Department of General Medicine, Mahatma Gandhi Medical College and Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India.
| | - Vignesh Mariappan
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India.
| | - Monica Anand
- Department of General Medicine, Mahatma Gandhi Medical College and Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India.
| | - Agieshkumar Balakrishna Pillai
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607 402, India.
| |
Collapse
|
|
14
|
Ahuja S, Zaheer S. Multifaceted TGF-β signaling, a master regulator: From bench-to-bedside, intricacies, and complexities. Cell Biol Int 2024; 48:87-127. [PMID: 37859532 DOI: 10.1002/cbin.12097] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/08/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Physiological embryogenesis and adult tissue homeostasis are regulated by transforming growth factor-β (TGF-β), an evolutionarily conserved family of secreted polypeptide factors, acting in an autocrine and paracrine manner. The role of TGF-β in inflammation, fibrosis, and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, especially fibrosis and cancer, overexpressed TGF-β causes extracellular matrix deposition, epithelial-mesenchymal transition, cancer-associated fibroblast formation, and/or angiogenesis. In this review article, we have tried to dive deep into the mechanism of action of TGF-β in inflammation, fibrosis, and carcinogenesis. As TGF-β and its downstream signaling mechanism are implicated in fibrosis and carcinogenesis blocking this signaling mechanism appears to be a promising avenue. However, targeting TGF-β carries substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. There is a need for careful dosing of TGF-β drugs for therapeutic use and patient selection.
Collapse
Affiliation(s)
- Sana Ahuja
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| |
Collapse
|
|
15
|
Sharma S, Ehrlich M, Zhang M, Blobe GC, Henis YI. NRP1 interacts with endoglin and VEGFR2 to modulate VEGF signaling and endothelial cell sprouting. Commun Biol 2024; 7:112. [PMID: 38242992 PMCID: PMC10799020 DOI: 10.1038/s42003-024-05798-2] [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: 06/19/2023] [Accepted: 01/09/2024] [Indexed: 01/21/2024] Open
Abstract
Endothelial cells express neuropilin 1 (NRP1), endoglin (ENG) and vascular endothelial growth factor receptor 2 (VEGFR2), which regulate VEGF-A-mediated vascular development and angiogenesis. However, the link between complex formation among these receptors with VEGF-A-induced signaling and biology is yet unclear. Here, we quantify surface receptor interactions by IgG-mediated immobilization of one receptor, and fluorescence recovery after photobleaching (FRAP) measurements of the mobility of another coexpressed receptor. We observe stable ENG/NRP1, ENG/VEGFR2, and NRP1/VEGFR2 complexes, which are enhanced by VEGF-A. ENG augments NRP1/VEGFR2 interactions, suggesting formation of tripartite complexes bridged by ENG. Effects on signaling are measured in murine embryonic endothelial cells expressing (MEEC+/+) or lacking (MEEC-/-) ENG, along with NRP1 and/or ENG overexpression or knockdown. We find that optimal VEGF-A-mediated phosphorylation of VEGFR2 and Erk1/2 requires ENG and NRP1. ENG or NRP1 increase VEGF-A-induced sprouting, becoming optimal in cells expressing all three receptors, and both processes are inhibited by a MEK1/2 inhibitor. We propose a model where the maximal potency of VEGF-A involves a tripartite complex where ENG bridges VEGFR2 and NRP1, providing an attractive therapeutic target for modulation of VEGF-A signaling and biological responses.
Collapse
Affiliation(s)
- Swati Sharma
- Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Marcelo Ehrlich
- Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
| | - Manqi Zhang
- Department of Medicine, Duke University Medical Center, Durham, NC, 27708, USA
| | - Gerard C Blobe
- Department of Medicine, Duke University Medical Center, Durham, NC, 27708, USA
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA
| | - Yoav I Henis
- Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
| |
Collapse
|
|
16
|
Hong X, Luo AC, Doulamis I, Oh N, Im GB, Lin CY, del Nido PJ, Lin RZ, Melero-Martin JM. Photopolymerizable Hydrogel for Enhanced Intramyocardial Vascular Progenitor Cell Delivery and Post-Myocardial Infarction Healing. Adv Healthc Mater 2023; 12:e2301581. [PMID: 37611321 PMCID: PMC10840685 DOI: 10.1002/adhm.202301581] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/08/2023] [Indexed: 08/25/2023]
Abstract
Cell transplantation success for myocardial infarction (MI) treatment is often hindered by low engraftment due to washout effects during myocardial contraction. A clinically viable biomaterial that enhances cell retention can optimize intramyocardial cell delivery. In this study, a therapeutic cell delivery method is developed for MI treatment utilizing a photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. Human vascular progenitor cells, capable of forming functional vasculatures upon transplantation, are combined with an in situ photopolymerization approach and injected into the infarcted zones of mouse hearts. This strategy substantially improves acute cell retention and promotes long-term post-MI cardiac healing, including stabilized cardiac functions, preserved viable myocardium, and reduced cardiac fibrosis. Additionally, engrafted vascular cells polarize recruited bone marrow-derived neutrophils toward a non-inflammatory phenotype via transforming growth factor beta (TGFβ) signaling, fostering a pro-regenerative microenvironment. Neutrophil depletion negates the therapeutic benefits generated by cell delivery in ischemic hearts, highlighting the essential role of non-inflammatory, pro-regenerative neutrophils in cardiac remodeling. In conclusion, this GelMA hydrogel-based intramyocardial vascular cell delivery approach holds promise for enhancing the treatment of acute myocardial infarction.
Collapse
Affiliation(s)
- Xuechong Hong
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Allen Chilun Luo
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Ilias Doulamis
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Nicholas Oh
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Gwang-Bum Im
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Chun-Yen Lin
- Department of Lymphoma and Myeloma, The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Pedro J. del Nido
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Ruei-Zeng Lin
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Juan M. Melero-Martin
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| |
Collapse
|
|
17
|
Barone L, Gallazzi M, Rossi F, Papait R, Raspanti M, Zecca PA, Buonarrivo L, Bassani B, Bernardini G, Bruno A, Gornati R. Human Dental Pulp Mesenchymal Stem Cell-Derived Soluble Factors Combined with a Nanostructured Scaffold Support the Generation of a Vascular Network In Vivo. NANOMATERIALS (BASEL, SWITZERLAND) 2023; 13:2479. [PMID: 37686988 PMCID: PMC10489993 DOI: 10.3390/nano13172479] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 08/28/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023]
Abstract
Among all strategies directed at developing new tools to support re-vascularization of damaged tissues, the use of pro-angiogenic soluble factors, derived from mesenchymal stem cells (MSCs), appears a promising approach for regenerative medicine. Here, we compared the feasibility of two devices, generated by coupling soluble factors of human dental pulp mesenchymal stem cells (DPSCs), with a nanostructured scaffold, to support angiogenesis once transplanted in mice. DPSCs were obtained from impacted wisdom tooth removal, usually considered surgical waste material. After 28 days, we verified the presence of active blood vessels inside the scaffold through optical and scansion electron microscopy. The mRNA expression of surface antigens related to macrophage polarization (CD68, CD80, CD86, CD163, CD206), as well as pro-angiogenic markers (CD31, CD34, CD105, Angpt1, Angpt2, CDH5) was evaluated by real-time PCR. Our results demonstrate the capability of DPSC-scaffold and DPSC soluble factors-scaffold to support angiogenesis, similarly to adipose stem cells, whereas the absence of blood vessels was found in the scaffold grafted alone. Our results provide evidence that DPSC-conditioned medium can be proposed as a cell-free preparation able to support angiogenesis, thus, providing a relevant tool to overcome the issues and restrictions associated with the use of cells.
Collapse
Affiliation(s)
- Ludovica Barone
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (L.B.); (F.R.); (R.P.); (L.B.); (G.B.)
| | - Matteo Gallazzi
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, 20138 Milan, Italy; (M.G.); (B.B.)
| | - Federica Rossi
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (L.B.); (F.R.); (R.P.); (L.B.); (G.B.)
| | - Roberto Papait
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (L.B.); (F.R.); (R.P.); (L.B.); (G.B.)
| | - Mario Raspanti
- Department of Medicine and Innovative Technology, University of Insubria, 21100 Varese, Italy; (M.R.); (P.A.Z.)
| | - Piero Antonio Zecca
- Department of Medicine and Innovative Technology, University of Insubria, 21100 Varese, Italy; (M.R.); (P.A.Z.)
| | - Luca Buonarrivo
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (L.B.); (F.R.); (R.P.); (L.B.); (G.B.)
| | - Barbara Bassani
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, 20138 Milan, Italy; (M.G.); (B.B.)
| | - Giovanni Bernardini
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (L.B.); (F.R.); (R.P.); (L.B.); (G.B.)
| | - Antonino Bruno
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (L.B.); (F.R.); (R.P.); (L.B.); (G.B.)
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, 20138 Milan, Italy; (M.G.); (B.B.)
| | - Rosalba Gornati
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; (L.B.); (F.R.); (R.P.); (L.B.); (G.B.)
| |
Collapse
|
|
18
|
Wu M, Yu Z, Matar DY, Karvar M, Chen Z, Ng B, Aoki S, Haug V, Orgill DP, Panayi AC. Human Amniotic Membrane Promotes Angiogenesis in an Oxidative Stress Chronic Diabetic Murine Wound Model. Adv Wound Care (New Rochelle) 2023; 12:301-315. [PMID: 35293255 DOI: 10.1089/wound.2022.0005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective: The development of animal models, which adequately replicate the pathophysiology of chronic wounds, has been challenging. In this study, we utilized an oxidative stress (OS) murine model, which was previously developed by our group, to study the effect of a human amniotic membrane (AM) on chronic wound healing. Approach: Forty-five diabetic (genetically obese leptin receptor-deficient mice [db/db]) mice were separated into three groups. Thirty mice received an OS regimen and a 1 - × 1 cm2 full-thickness excisional dorsal wound. The wounds were either covered with AM and occlusive dressing (db/dbOS-AM) or occlusive dressing only (db/dbOS). Fifteen mice did not receive the OS regimen, and were covered with AM and occlusive dressing (db/db-AM). The wounds were photographed, and tissue was harvested at various time points. Results: Vascular density was higher in the AM-treated groups (db/dbOS-AM: 34 ± 12; db/db-AM: 37 ± 14; vs. db/dbOS: 19 ± 9 cluster of differentiation 31 [CD31+]/high power field [HPF] photograph; p = 0.04 and p = 0.003). Vessel maturity was lowest in the db/dbOS group (21% ± 4%; vs. db/dbOS-AM: 38% ± 10%, p = 0.004; db/db-AM: 40% ± 11%, p = 0.0005). Leukocyte infiltration was higher in the AM groups (db/dbOS-AM: 15 ± 4; db/db-AM: 16 ± 4 vs. db/dbOS: 8 ± 3 lymphocyte common antigen [CD45+]/HPF; p = 0.005 and p = 0.06). AM upregulated various proangiogenic factors, including vascular endothelial growth factor (VEGF), and downregulated genes involved in chronicity, such as osteopontin, as visualized through proteome analysis and western blotting. Cell death was lower in the AM groups (db/dbOS-AM: 28 ± 10, db/db-AM: 7 ± 5 vs. db/dbOS: 17% ± 9% Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL+]; p = 0.03 and p < 0.0001). Innovation: This study offers new insight on the mechanisms of action of human AM in chronic wound healing. Conclusion: AM treatment promoted healing in mice with complex chronic wounds. The AM stimulated angiogenesis through upregulation of proangiogenic factors, improving the wound milieu by increasing leukocyte and growth factor delivery and decreasing cell death.
Collapse
Affiliation(s)
- Mengfan Wu
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Plastic Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Zhen Yu
- Department of Ophthalmology, Shenzhen Eye Hospital, Shenzhen Key Ophthalmic Laboratory, Jinan University, Shenzhen, China
- Angiogenesis Laboratory, Ophthalmology Department, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA
| | - Dany Y Matar
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Biology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Mehran Karvar
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Ziyu Chen
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Brian Ng
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, Missouri, USA
| | - Shimpo Aoki
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Valentin Haug
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Dennis P Orgill
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Adriana C Panayi
- Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
19
|
Chen Z, Yu H, Chen X, Chen W, Song W, Li Z. Mutual regulation between glycosylation and transforming growth factor-β isoforms signaling pathway. Int J Biol Macromol 2023; 236:123818. [PMID: 36858092 DOI: 10.1016/j.ijbiomac.2023.123818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/18/2023] [Accepted: 02/19/2023] [Indexed: 03/02/2023]
Abstract
Transforming growth factor-beta (TGF-β) superfamily members orchestrate a wide breadth of biological processes. Through Sma and Mad (Smad)-related dependent or noncanonical pathways, TGF-β members involve in the occurrence and development of many diseases such as cancers, fibrosis, autoimmune diseases, cardiovascular diseases and brain diseases. Glycosylation is one kind of the most common posttranslational modifications on proteins or lipids. Abnormal protein glycosylation can lead to protein malfunction and biological process disorder, thereby causing serious diseases. Previously, researchers commonly make comprehensive systematic overviews on the roles of TGF-β signaling in a specific disease or biological process. In recent years, more and more evidences associate glycosylation modification with TGF-β signaling pathway, and we can no longer disengage and ignore the roles of glycosylation from TGF-β signaling to make investigation. In this review, we provide an overview of current findings involved in glycosylation within TGF-βs and theirs receptors, and the interaction effects between glycosylation and TGF-β subfamily signaling, concluding that there is an intricate mutual regulation between glycosylation and TGF-β signaling, hoping to present the glycosylation regulatory patterns that concealed in TGF-βs signaling pathways.
Collapse
Affiliation(s)
- Zhuo Chen
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Hanjie Yu
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Xiangqin Chen
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Wentian Chen
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Wanghua Song
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Zheng Li
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, PR China.
| |
Collapse
|
|
20
|
Sheikh AM, Yano S, Tabassum S, Mitaki S, Michikawa M, Nagai A. Alzheimer's Amyloid β Peptide Induces Angiogenesis in an Alzheimer's Disease Model Mouse through Placental Growth Factor and Angiopoietin 2 Expressions. Int J Mol Sci 2023; 24:ijms24054510. [PMID: 36901941 PMCID: PMC10003449 DOI: 10.3390/ijms24054510] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/22/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Increased angiogenesis, especially the pathological type, has been documented in Alzheimer's disease (AD) brains, and it is considered to be activated due to a vascular dysfunction-mediated hypoxic condition. To understand the role of the amyloid β (Aβ) peptide in angiogenesis, we analyzed its effects on the brains of young APP transgenic AD model mice. Immunostaining results revealed that Aβ was mainly localized intracellularly, with very few immunopositive vessels, and there was no extracellular deposition at this age. Solanum tuberosum lectin staining demonstrated that compared to their wild-type littermates, the vessel number was only increased in the cortex of J20 mice. CD105 staining also showed an increased number of new vessels in the cortex, some of which were partially positive for collagen4. Real-time PCR results demonstrated that placental growth factor (PlGF) and angiopoietin 2 (AngII) mRNA were increased in both the cortex and hippocampus of J20 mice compared to their wild-type littermates. However, vascular endothelial growth factor (VEGF) mRNA did not change. Immunofluorescence staining confirmed the increased expression of PlGF and AngII in the cortex of the J20 mice. Neuronal cells were positive for PlGF and AngII. Treatment of a neural stem cell line (NMW7) with synthetic Aβ1-42 directly increased the expression of PlGF and AngII, at mRNA levels, and AngII at protein levels. Thus, these pilot data indicate that pathological angiogenesis exists in AD brains due to the direct effects of early Aβ accumulation, suggesting that the Aβ peptide regulates angiogenesis through PlGF and AngII expression.
Collapse
Affiliation(s)
- Abdullah Md. Sheikh
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
- Correspondence: (A.M.S.); (A.N.); Tel.: +81-0853-20-2306 (A.M.S.); +81-0853-20-2198 (A.N.)
| | - Shozo Yano
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Shatera Tabassum
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Shingo Mitaki
- Department of Neurology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
| | - Makoto Michikawa
- Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
| | - Atsushi Nagai
- Department of Laboratory Medicine, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
- Department of Neurology, Shimane University School of Medicine, 89-1 Enya Cho, Izumo 693-8501, Japan
- Correspondence: (A.M.S.); (A.N.); Tel.: +81-0853-20-2306 (A.M.S.); +81-0853-20-2198 (A.N.)
| |
Collapse
|
|
21
|
Fioretto BS, Rosa I, Matucci-Cerinic M, Romano E, Manetti M. Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review. Int J Mol Sci 2023; 24:ijms24044097. [PMID: 36835506 PMCID: PMC9965592 DOI: 10.3390/ijms24044097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease.
Collapse
Affiliation(s)
- Bianca Saveria Fioretto
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Irene Rosa
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Marco Matucci-Cerinic
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, 20132 Milan, Italy
| | - Eloisa Romano
- Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Mirko Manetti
- Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
- Imaging Platform, Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
- Correspondence:
| |
Collapse
|
|
22
|
Litwiniuk-Kosmala M, Makuszewska M, Czesak M. Endoglin in head and neck neoplasms. Front Med (Lausanne) 2023; 10:1115212. [PMID: 36844233 PMCID: PMC9950573 DOI: 10.3389/fmed.2023.1115212] [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: 12/03/2022] [Accepted: 01/27/2023] [Indexed: 02/12/2023] Open
Abstract
Tumors of the head and neck region form a heterogeneous group of pathologies, including various benign lesions and malignant neoplasms. Endoglin, also known as CD105, is an accessory receptor for transforming growth factor beta (TGF-β), that regulates angiogenesis, both under physiological and pathological conditions. It is highly expressed in proliferating endothelial cells. Therefore, it is considered as a marker of tumor-related angiogenesis. In this review we discuss the role of endoglin as a possible marker of carcinogenesis, as well as a potential target for antibody-based therapies in the neoplasms of the head and neck region.
Collapse
Affiliation(s)
| | - Maria Makuszewska
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Małgorzata Czesak
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland
| |
Collapse
|
|
23
|
Systemic Cytokines in Retinopathy of Prematurity. J Pers Med 2023; 13:jpm13020291. [PMID: 36836525 PMCID: PMC9966226 DOI: 10.3390/jpm13020291] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/09/2023] Open
Abstract
Retinopathy of prematurity (ROP), a vasoproliferative vitreoretinal disorder, is the leading cause of childhood blindness worldwide. Although angiogenic pathways have been the main focus, cytokine-mediated inflammation is also involved in ROP etiology. Herein, we illustrate the characteristics and actions of all cytokines involved in ROP pathogenesis. The two-phase (vaso-obliteration followed by vasoproliferation) theory outlines the evaluation of cytokines in a time-dependent manner. Levels of cytokines may even differ between the blood and the vitreous. Data from animal models of oxygen-induced retinopathy are also valuable. Although conventional cryotherapy and laser photocoagulation are well established and anti-vascular endothelial growth factor agents are available, less destructive novel therapeutics that can precisely target the signaling pathways are required. Linking the cytokines involved in ROP to other maternal and neonatal diseases and conditions provides insights into the management of ROP. Suppressing disordered retinal angiogenesis via the modulation of hypoxia-inducible factor, supplementation of insulin-like growth factor (IGF)-1/IGF-binding protein 3 complex, erythropoietin, and its derivatives, polyunsaturated fatty acids, and inhibition of secretogranin III have attracted the attention of researchers. Recently, gut microbiota modulation, non-coding RNAs, and gene therapies have shown promise in regulating ROP. These emerging therapeutics can be used to treat preterm infants with ROP.
Collapse
|
|
24
|
Itoh F, Watabe T. TGF-β signaling in lymphatic vascular vessel formation and maintenance. Front Physiol 2022; 13:1081376. [PMID: 36589453 PMCID: PMC9799095 DOI: 10.3389/fphys.2022.1081376] [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: 10/27/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
Transforming growth factor (TGF)-β and its family members, including bone morphogenetic proteins (BMPs), nodal proteins, and activins, are implicated in the development and maintenance of various organs. Here, we review its role in the lymphatic vascular system (the secondary vascular system in vertebrates), which plays a crucial role in various physiological and pathological processes, participating in the maintenance of the normal tissue fluid balance, immune cell trafficking, and fatty acid absorption in the gut. The lymphatic system is associated with pathogenesis in multiple diseases, including lymphedema, inflammatory diseases, and tumor metastasis. Lymphatic vessels are composed of lymphatic endothelial cells, which differentiate from blood vascular endothelial cells (BECs). Although TGF-β family signaling is essential for maintaining blood vessel function, little is known about the role of TGF-β in lymphatic homeostasis. Recently, we reported that endothelial-specific depletion of TGF-β signaling affects lymphatic function. These reports suggest that TGF-β signaling in lymphatic endothelial cells maintains the structure of lymphatic vessels and lymphatic homeostasis, and promotes tumor lymphatic metastasis. Suppression of TGF-β signaling in lymphatic endothelial cells may therefore be effective in inhibiting cancer metastasis. We highlight recent advances in understanding the roles of TGF-β signaling in the formation and maintenance of the lymphatic system.
Collapse
Affiliation(s)
- Fumiko Itoh
- Laboratory of Stem Cells Regulations, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan,*Correspondence: Fumiko Itoh, ; Tetsuro Watabe,
| | - Tetsuro Watabe
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan,*Correspondence: Fumiko Itoh, ; Tetsuro Watabe,
| |
Collapse
|
|
25
|
Negre-Salvayre A, Swiader A, Salvayre R, Guerby P. Oxidative stress, lipid peroxidation and premature placental senescence in preeclampsia. Arch Biochem Biophys 2022; 730:109416. [PMID: 36179910 DOI: 10.1016/j.abb.2022.109416] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/19/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022]
Abstract
Accelerated placental senescence is associated with preeclampsia (PE) and other pregnancy complications. It is characterized by an accelerated decline in placental function due to the accumulation of senescence patterns such as telomere shortening, mitochondrial dysfunction, oxidative damages, increased expression of phosphorylated (serine-139) histone γ-H2AX, a sensitive marker of double-stranded DNA breaks, accumulation of cross-linked ubiquitinated proteins and sirtuin inhibition. Among the lipid oxidation products generated by the peroxidation of polyunsaturated fatty acids, aldehydes such as acrolein, 4-hydroxy-2-nonenal, 4-oxo-2-nonenal, are present in the blood and placenta from PE-affected women and could contribute to PE pathogenesis and accelerated placental aging. In this review we summarize the current knowledge on premature placental senescence and the role of oxidative stress and lipid oxidation-derived aldehydes in this process, as well as their links with PE pathogenesis. The interest of developing (or not) new therapeutic strategies targeting lipid peroxidation is discussed, the objective being a better understanding of accelerated placental aging in PE pathophysiology, and the prevention of PE bad outcomes.
Collapse
Affiliation(s)
| | | | | | - Paul Guerby
- lnfinity, CNRS, Inserm UMR 1291, University Toulouse III and Gynecology/Obstetrics Department, Paule-de-Viguier Hospital, Toulouse, France
| |
Collapse
|
|
26
|
Puerto-Camacho P, Díaz-Martín J, Olmedo-Pelayo J, Bolado-Carrancio A, Salguero-Aranda C, Jordán-Pérez C, Esteban-Medina M, Álamo-Álvarez I, Delgado-Bellido D, Lobo-Selma L, Dopazo J, Sastre A, Alonso J, Grünewald TGP, Bernabeu C, Byron A, Brunton VG, Amaral AT, Álava ED. Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell–Matrix Interactions. Int J Mol Sci 2022; 23:ijms23158657. [PMID: 35955799 PMCID: PMC9369355 DOI: 10.3390/ijms23158657] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/14/2022] [Accepted: 07/22/2022] [Indexed: 01/26/2023] Open
Abstract
Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell–matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.
Collapse
Affiliation(s)
- Pilar Puerto-Camacho
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
| | - Juan Díaz-Martín
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Joaquín Olmedo-Pelayo
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Alfonso Bolado-Carrancio
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Carmen Salguero-Aranda
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Carmen Jordán-Pérez
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
| | - Marina Esteban-Medina
- Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocío, 41013 Seville, Spain
| | - Inmaculada Álamo-Álvarez
- Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocío, 41013 Seville, Spain
| | - Daniel Delgado-Bellido
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
| | - Laura Lobo-Selma
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Joaquín Dopazo
- Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocío, 41013 Seville, Spain
| | - Ana Sastre
- Unidad Hemato-oncología Pediátrica, Hospital Infantil Universitario La Paz, 28046 Madrid, Spain
| | - Javier Alonso
- Unidad Hemato-oncología Pediátrica, Hospital Infantil Universitario La Paz, 28046 Madrid, Spain
- Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III (IIER-ISCIII), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/1009; CIBERER-ISCIII), 28029 Madrid, Spain
| | - Thomas G. P. Grünewald
- Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Hopp-Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Carmelo Bernabeu
- Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain
| | - Adam Byron
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
- Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Valerie G. Brunton
- Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Ana Teresa Amaral
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
- Correspondence: (A.T.A.); (E.D.Á.)
| | - Enrique De Álava
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Molecular Pathology of Sarcomas, 41013 Seville, Spain
- Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, 41009 Seville, Spain
- Correspondence: (A.T.A.); (E.D.Á.)
| |
Collapse
|
|
27
|
Santos-Gomes J, Gandra I, Adão R, Perros F, Brás-Silva C. An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers. Front Cardiovasc Med 2022; 9:924873. [PMID: 35911521 PMCID: PMC9333554 DOI: 10.3389/fcvm.2022.924873] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.
Collapse
Affiliation(s)
- Joana Santos-Gomes
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Inês Gandra
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Rui Adão
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Frédéric Perros
- Paris-Porto Pulmonary Hypertension Collaborative Laboratory (3PH), UMR_S 999, INSERM, Université Paris-Saclay, Paris, France
- Université Paris–Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France
| | - Carmen Brás-Silva
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
- Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal
| |
Collapse
|
|
28
|
Li L, Zhong L, Tang C, Gan L, Mo T, Na J, He J, Huang Y. CD105: tumor diagnosis, prognostic marker and future tumor therapeutic target. Clin Transl Oncol 2022; 24:1447-1458. [PMID: 35165838 DOI: 10.1007/s12094-022-02792-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/21/2022] [Indexed: 02/06/2023]
Abstract
Cancer is one of the diseases with the highest morbidity and mortality rates worldwide, and its therapeutic options are inadequate. The endothelial glycoprotein, also known as CD105, is a type I transmembrane glycoprotein located on the surface of the cell membranes and it is one of the transforming growth factor-β (TGF-β) receptor complexes. It regulates the responses associated with binding to transforming growth factor β1 egg (Activin-A), bone morphogenetic protein 2 (BMP-2), and bone morphogenetic protein 7 (BMP-7). Additionally, it is involved in the regulation of angiogenesis. This glycoprotein is indispensable in the treatment of tumor angiogenesis, and it also plays a leading role in tumor angiogenesis therapy. Therefore, CD105 is considered to be a novel therapeutic target. In this study, we explored the significance of CD105 in the diagnosis, treatment and prognosis of various tumors, and provided evidence for the effect and mechanism of CD105 on tumors.
Collapse
Affiliation(s)
- Lan Li
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Liping Zhong
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Chao Tang
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Lu Gan
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Tong Mo
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jintong Na
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jian He
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yong Huang
- National Center for International Research of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China.
- Guangxi Medical University, Nanning, 530021, Guangxi, China.
| |
Collapse
|
|
29
|
Ortega MA, Fraile-Martínez O, García-Montero C, Sáez MA, Álvarez-Mon MA, Torres-Carranza D, Álvarez-Mon M, Bujan J, García-Honduvilla N, Bravo C, Guijarro LG, De León-Luis JA. The Pivotal Role of the Placenta in Normal and Pathological Pregnancies: A Focus on Preeclampsia, Fetal Growth Restriction, and Maternal Chronic Venous Disease. Cells 2022; 11:cells11030568. [PMID: 35159377 PMCID: PMC8833914 DOI: 10.3390/cells11030568] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 12/01/2022] Open
Abstract
The placenta is a central structure in pregnancy and has pleiotropic functions. This organ grows incredibly rapidly during this period, acting as a mastermind behind different fetal and maternal processes. The relevance of the placenta extends far beyond the pregnancy, being crucial for fetal programming before birth. Having integrative knowledge of this maternofetal structure helps significantly in understanding the development of pregnancy either in a proper or pathophysiological context. Thus, the aim of this review is to summarize the main features of the placenta, with a special focus on its early development, cytoarchitecture, immunology, and functions in non-pathological conditions. In contraposition, the role of the placenta is examined in preeclampsia, a worrisome hypertensive disorder of pregnancy, in order to describe the pathophysiological implications of the placenta in this disease. Likewise, dysfunction of the placenta in fetal growth restriction, a major consequence of preeclampsia, is also discussed, emphasizing the potential clinical strategies derived. Finally, the emerging role of the placenta in maternal chronic venous disease either as a causative agent or as a consequence of the disease is equally treated.
Collapse
Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
- Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28801 Alcalá de Henares, Madrid, Spain
- Correspondence: ; Tel.: +34-91-885-4540; Fax: +34-91-885-4885
| | - Oscar Fraile-Martínez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
| | - Cielo García-Montero
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
| | - Miguel A. Sáez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
- Pathological Anatomy Service, Central University Hospital of Defence-UAH, 28047 Madrid, Spain
| | - Miguel Angel Álvarez-Mon
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
| | - Diego Torres-Carranza
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
- Immune System Diseases-Rheumatology and Oncology Service, University Hospital Príncipe de Asturias, CIBEREHD, 28801 Alcalá de Henares, Madrid, Spain
| | - Julia Bujan
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; (O.F.-M.); (C.G.-M.); (M.A.S.); (M.A.Á.-M.); (D.T.-C.); (M.Á.-M.); (J.B.); (N.G.-H.)
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
| | - Coral Bravo
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (C.B.); (J.A.D.L.-L.)
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Luis G. Guijarro
- Ramón y Cajal Institute of Healthcare Research (IRYCIS), 28034 Madrid, Spain;
- Unit of Biochemistry and Molecular Biology (CIBEREHD), Department of System Biology, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
| | - Juan A. De León-Luis
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (C.B.); (J.A.D.L.-L.)
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| |
Collapse
|
|
30
|
Margioula-Siarkou G, Margioula-Siarkou C, Petousis S, Margaritis K, Vavoulidis E, Gullo G, Alexandratou M, Dinas K, Sotiriadis A, Mavromatidis G. The role of endoglin and its soluble form in pathogenesis of preeclampsia. Mol Cell Biochem 2022; 477:479-491. [PMID: 34783962 DOI: 10.1007/s11010-021-04294-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 11/04/2021] [Indexed: 12/21/2022]
Abstract
Preeclampsia remains till today a leading cause of maternal and fetal morbidity and mortality. Pathophysiology of the disease is not yet fully elucidated, though it is evident that it revolves around placenta. Cellular ischemia in the preeclamptic placenta creates an imbalance between angiogenic and anti-angiogenic factors in maternal circulation. Endoglin, a transmembrane co-receptor of transforming growth factor β (TGF-β) demonstrating angiogenic effects, is involved in a variety of angiogenesis-dependent diseases with endothelial dysfunction, including preeclampsia. Endoglin expression is up-regulated in preeclamptic placentas, through mechanisms mainly induced by hypoxia, oxidative stress and oxysterol-mediated activation of liver X receptors. Overexpression of endoglin results in an increase of its soluble form in maternal circulation. Soluble endoglin represents the extracellular domain of membrane endoglin, cleaved by the action of metalloproteinases, predominantly matrix metalloproteinase-14. Released in circulation, soluble endoglin interferes in TGF-β1 and activin receptor-like kinase 1 signaling pathways and inhibits endothelial nitric oxide synthase activation, consequently deranging angiogenesis and promoting vasoconstriction. Due to these properties, soluble endoglin actively contributes to the impaired placentation observed in preeclampsia, as well as to the pathogenesis and manifestation of its clinical signs and symptoms, especially hypertension and proteinuria. The significant role of endoglin and soluble endoglin in pathophysiology of preeclampsia could have prognostic, diagnostic and therapeutic perspectives. Further research is essential to extensively explore the potential use of these molecules in the management of preeclampsia in clinical settings.
Collapse
Affiliation(s)
- Georgia Margioula-Siarkou
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54624, Thessaloniki, Greece.
| | - Chrysoula Margioula-Siarkou
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54624, Thessaloniki, Greece
| | - Stamatios Petousis
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54624, Thessaloniki, Greece
| | - Kosmas Margaritis
- 2nd Department of Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleftherios Vavoulidis
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54624, Thessaloniki, Greece
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, IVF Unit, Villa Sofia Cervello Hospital, University of Palermo, Palermo, Italy
| | - Maria Alexandratou
- Department of Radiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Dinas
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54624, Thessaloniki, Greece
| | - Alexandros Sotiriadis
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54624, Thessaloniki, Greece
| | - Georgios Mavromatidis
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Konstantinoupoleos 49, 54624, Thessaloniki, Greece
| |
Collapse
|
|
31
|
Genetics and Vascular Biology of Brain Vascular Malformations. Stroke 2022. [DOI: 10.1016/b978-0-323-69424-7.00012-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
|
|
32
|
Erol Deniz M, Deniz A, Mendilcioglu I, Sanhal CY, Ozdem S, Kucukcetin IO, Kandemir H. Serial measurement of soluble endoglin for risk assessment at the diagnosis of fetal growth restriction. Int J Clin Pract 2021; 75:e14840. [PMID: 34528351 DOI: 10.1111/ijcp.14840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/05/2021] [Accepted: 09/10/2021] [Indexed: 11/29/2022] Open
Abstract
AIM In this study, we aimed to investigate the soluble endoglin (sEng) levels in pregnant women with fetal growth restriction (FGR) and to examine the possible relation of the sEng levels with the time remaining to delivery and maternal and fetal complications. METHODS A total of 42 pregnant women diagnosed with FGR were retrospectively reviewed. Using the maternal blood samples it is at the collected 24-37 gestational weeks, the sEng levels were measured. Fetal biometry measurements, umbilical artery, uterine artery, middle cerebral artery Doppler indices were documented. RESULTS Of all patients, 17 (40%) were diagnosed with early-onset FGR, while 25 (60%) were diagnosed with late-onset FGR. Abnormal Doppler findings were present in 25 (60%) patients. Of 42 newborns, 18 (42%) were hospitalised in the neonatal unit. The mean sEng level calculated by taking the average of the first and second blood samples was 63.24 ± 49.83 ng/mL. There was no statistically significant difference in the mean sEng levels between those who gave birth within four, three, and two weeks after the diagnosis of FGR and those who did not. There was a positive significant correlation between the mean sEng levels and systolic blood pressure (r = 0.319, P = .04). CONCLUSIONS We did not find a statistically significant relationship between the sEng level and the time remaining to the time of delivery in pregnant women with FGR. We found no statistically significant difference in sEng level between the groups in pregnant women with fetuses with FGR with or without maternal and fetal complications.
Collapse
Affiliation(s)
- Merve Erol Deniz
- Clinic of Obstetrics and Gynecology, Manavgat State Hospital, Antalya, Turkey
| | - Alparslan Deniz
- Department of Obstetrics and Gynecology, Alanya Alaaddin Keykubat University, Alanya, Turkey
| | - Inanc Mendilcioglu
- Department of Obstetrics and Gynecology, Akdeniz University, Antalya, Turkey
| | - Cem Yasar Sanhal
- Department of Obstetrics and Gynecology, Akdeniz University, Antalya, Turkey
| | - Sebahat Ozdem
- Department of Biochemistry, Akdeniz University, Antalya, Turkey
| | | | - Hülya Kandemir
- Department of Obstetrics and Gynecology, Akdeniz University, Antalya, Turkey
| |
Collapse
|
|
33
|
Hariprabu KNG, Sathya M, Vimalraj S. CRISPR/Cas9 in cancer therapy: A review with a special focus on tumor angiogenesis. Int J Biol Macromol 2021; 192:913-930. [PMID: 34655593 DOI: 10.1016/j.ijbiomac.2021.10.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022]
Abstract
Tumor angiogenesis is a critical target for cancer treatment and its inhibition has become a common anticancer approach following chemotherapy. However, due to the simultaneous activation of different compensatory molecular mechanisms that enhance tumor angiogenesis, clinically authorized anti-angiogenic medicines are ineffective. Additionally, medications used to treat cancer have an effect on normal body cells; nonetheless, more research is needed to create new cancer therapeutic techniques. With advances in molecular biology, it is now possible to use gene-editing technology to alter the genome and study the functional changes resulting from genetic manipulation. With the development of CRISPR/Cas9 technology, it has become a very powerful tool for altering the genomes of many organisms. It was determined that CRISPR/Cas9, which first appeared in bacteria as a part of an adaptive immune system, could be used, in modified forms, to alter genomes and function. In conclusion, CRISPR/Cas9 could be a major step forward to cancer management by providing patients with an effective method for dealing with cancers by dissecting the carcinogenesis pathways, identifying new biologic targets, and perhaps arming cancer cells with drugs. Hence, this review will discuss the current applications of CRISPR/Cas9 technology in tumor angiogenesis research for the purpose of cancer treatment.
Collapse
Affiliation(s)
| | - Muthusamy Sathya
- Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India
| | - Selvaraj Vimalraj
- Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India.
| |
Collapse
|
|
34
|
Secondary Cerebellar Cortex Injury in Albino Male Rats after MCAO: A Histological and Biochemical Study. Biomedicines 2021; 9:biomedicines9091267. [PMID: 34572453 PMCID: PMC8468751 DOI: 10.3390/biomedicines9091267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 01/17/2023] Open
Abstract
The present study focused on secondary injury following the middle cerebral artery (MCA) occlusion in rats not linked to the MCA’s feeding zone. This entity has been very rarely studied. Additionally, this study investigated the rates of expression of five fundamental angiogenic biomarkers called endoglin, vascular endothelial growth factors-A (VEGF-A), endothelin-1 (ET-1), 2granulocyte colony-stimulating factor (G-CSF), and angiopoietin-using the MCA occlusion (MCAO) model. The random allocation of twelve adult male albino rats was in two groups. As a sham control group, six rats were used. This group was subjected to a sham operation without MCAO. The MCAO group consisted of six rats that were subjected to MCAO operation. After three days, the rats were sacrificed. The cerebellar specimens were immediately processed for light microscopic examination. An angiogenic biomarkers multiplex assay from multiplex was used to assess endoglin levels, VEGF-A, ET-1, angiopoietin-2, and G-CSF in serum samples. Hematoxylin and eosin-stained sections showed that the cerebellar cortex of rats of the MCAO group was more affected than the sham control group. Furthermore, Nissl stain and immunohistochemical analysis revealed an apparent increase in the number of positive immunoreactive in the cerebellar cortex and an evident decrease in Nissl granules in Purkinje cells of the MCAO rats, in contrast to the control rats. In addition, there was a significant increase in angiogenic factors VEGF-A, ET-1, angiopoietin-2, and endoglin. Interestingly, there was an increase in the G-CSF but a non-significant in the MCAO rats compared to the control rats. Furthermore, there was a significant correlation between the angiopoietin-2 and ET-1, and between G-CSF and ET-1. VEGF-A also exhibited significant positive correlations with the G-CSF serum level parameter, Endoglin, and ET-1. Rats subjected to MCAO are a suitable model to study secondary injury away from MCA’s feeding zone. Additionally, valuable insights into the association and interaction between altered angiogenic factors and acute ischemic stroke induced by MCAO in rats.
Collapse
|
|
35
|
Huang K, Castiaux A, Podicheti R, Rusch DB, Martin RS, Baker LA. A Hybrid Nanofiber/Paper Cell Culture Platform for Building a 3D Blood-brain Barrier Model. SMALL METHODS 2021; 5:2100592. [PMID: 34541301 PMCID: PMC8445000 DOI: 10.1002/smtd.202100592] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Indexed: 05/16/2023]
Abstract
The blood brain barrier (BBB) protects the central nervous system from toxins and pathogens in the blood by regulating permeation of molecules through the barrier interface. In vitro BBB models described to date reproduce some aspects of BBB functionality, but also suffer from incomplete phenotypic expression of brain endothelial traits, difficulty in reproducibility and fabrication, or overall cost. To address these limitations, we describe a three-dimensional (3D) BBB model based on a hybrid paper/nanofiber scaffold. The cell culture platform utilizes lens paper as a framework to accommodate 3D culture of astrocytes. An electrospun nanofiber layer is coated onto one face of the paper to mimic the basement membrane and support growth of an organized two-dimensional layer of endothelial cells (ECs). Human induced pluripotent stem cell-derived ECs and astrocytes are co-cultured to develop a human BBB model. Morphological and spatial organization of model are validated with confocal microscopy. Measurements of transendothelial resistance and permeability demonstrate the BBB model develops a high-quality barrier and responds to hyperosmolar treatments. RNA-sequencing shows introduction of astrocytes both regulates EC tight junction proteins and improves endothelial phenotypes related to vasculogenesis. This model shows promise as a model platform for future in vitro studies of the BBB.
Collapse
Affiliation(s)
- Kaixiang Huang
- Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana 47405, USA
| | - Andre Castiaux
- Department of Chemistry and Center for Additive Manufacturing, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103, USA
| | - Ram Podicheti
- Center for Genomics and Bioinformatics, Indiana University Bloomington, 1001 East Third St., Bloomington, Indiana 47405, USA
| | - Douglas B Rusch
- Center for Genomics and Bioinformatics, Indiana University Bloomington, 1001 East Third St., Bloomington, Indiana 47405, USA
| | - R Scott Martin
- Department of Chemistry and Center for Additive Manufacturing, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103, USA
| | - Lane A Baker
- Department of Chemistry, Indiana University Bloomington, 800 E. Kirkwood Avenue, Bloomington, Indiana 47405, USA
| |
Collapse
|
|
36
|
Schlecht A, Vallon M, Wagner N, Ergün S, Braunger BM. TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain. Biomolecules 2021; 11:biom11091360. [PMID: 34572573 PMCID: PMC8464756 DOI: 10.3390/biom11091360] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/07/2021] [Accepted: 09/10/2021] [Indexed: 12/13/2022] Open
Abstract
Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain.
Collapse
|
|
37
|
Tang H, Zhang X, Xue G, Xu F, Wang Q, Yang P, Hong B, Xu Y, Huang Q, Liu J, Zuo Q. The biology of bone morphogenetic protein signaling pathway in cerebrovascular system. Chin Neurosurg J 2021; 7:36. [PMID: 34465399 PMCID: PMC8408949 DOI: 10.1186/s41016-021-00254-0] [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: 07/02/2020] [Accepted: 07/08/2021] [Indexed: 11/30/2022] Open
Abstract
Bone morphogenetic protein belongs to transcription growth factor superfamily β; bone morphogenetic protein signal pathway regulates cell proliferation, differentiation, and apoptosis among different tissues. Cerebrovascular system supplies sufficient oxygen and blood into brain to maintain its normal function. The disorder of cerebrovascular system will result into serious cerebrovascular diseases, which is gradually becoming a major threat to human health in modern society. In recent decades, many studies have revealed the underlying biology and mechanism of bone morphogenetic protein signal pathway played in cerebrovascular system. This review will discuss the relationship between the two aspects, aiming to provide new perspective for non-invasive treatment and basic research of cerebrovascular diseases.
Collapse
Affiliation(s)
- Haishuang Tang
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China.,Naval Medical Center of PLA, Naval Military Medical University, Shanghai, 200050, People's Republic of China
| | - Xiaoxi Zhang
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China
| | - Gaici Xue
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China
| | - Fengfeng Xu
- Naval Medical Center of PLA, Naval Military Medical University, Shanghai, 200050, People's Republic of China
| | - Qingsong Wang
- Department of Cardiology, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Pengfei Yang
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China
| | - Bo Hong
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China
| | - Yi Xu
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China
| | - Qinghai Huang
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China
| | - Jianmin Liu
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China.
| | - Qiao Zuo
- Department of Neurosurgery, Changhai Hospital, Naval Military Medical University, 168 Changhai Road, Shanghai, 200433, People's Republic of China.
| |
Collapse
|
|
38
|
FOXA1 promotes prostate cancer angiogenesis by inducing multiple pro-angiogenic factors expression. J Cancer Res Clin Oncol 2021; 147:3225-3243. [PMID: 34258652 DOI: 10.1007/s00432-021-03730-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 07/05/2021] [Indexed: 01/04/2023]
Abstract
PURPOSE FOXA1, as a pioneering transcription factor, has been shown to drive prostate cancer progression. Previous studies showed that FOXA1 expression in prostate cancer was positively associated with cancer angiolymphatic invasion and metastasis. However, the mechanism underlying the correlation between FOXA1 and prostate cancer angiolymphatic invasion and metastasis remains largely unclear. METHODS Herein, we set out to investigate the role of FOXA1 in the interactions between prostate cancer cells and endothelial cells. Endothelial cells' phenotypes were assessed through CCK-8 assay, Transwell migration assay, and tube formation assay. The angiogenic factors acting on endothelial cells mediated by FOXA1were characterized by RNA-seq, qPCR array, angiogenesis cytokines array, and ELISA assay. The impact of FOXA1 on tumor angiogenesis was examined in a xenograft model in nude mice. The effect of FOXA1 on prostate cancer angiogenesis was validated on a primary prostate cancer tissue microarray. RESULTS FOXA1 expression in prostate cancer cells promoted endothelial cell proliferation, migration, and tube formation in vitro. Mechanistically, FOXA1 increased pro-angiogenic factors production, including EGF, Endothelin-1, and Endoglin. Moreover, in vivo study showed that FOXA1 facilitated tumor angiogenesis. Furthermore, clinical samples investigation indicated that FOXA1 enhanced prostate cancer angiogenesis. CONCLUSION Overall, these findings illustrated a tumor angiogenesis-promoting role of FOXA1 in prostate cancer.
Collapse
|
|
39
|
Search for Novel Plasma Membrane Proteins as Potential Biomarkers in Human Mesenchymal Stem Cells Derived from Dental Pulp, Adipose Tissue, Bone Marrow, and Hair Follicle. J Membr Biol 2021; 254:409-422. [PMID: 34230997 DOI: 10.1007/s00232-021-00190-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/07/2021] [Indexed: 10/20/2022]
Abstract
One of the drawbacks preventing the use of mesenchymal stem cells (MSCs) in clinical practice is the heterogeneous nature of their cultures. MSC cultures are not homogeneously formed by the MSCs and may contain non-mesenchymal cell types. Therefore, prior to use in clinics or research, complete characterization of MSCs should be performed to demonstrate the existence or absence of proper stem cell markers, many of which are happened to be cell-surface proteins. Unfortunately, the success of MSC characterization studies is limited due to the low specificity of the currently available cell-surface markers. Therefore, in this study, we aimed to investigate the plasma membrane (PM) proteins of MSCs isolated from human dental pulp (DP), adipose tissue (AT), bone marrow (BM), and hair follicle (HF) with the hope of proposing novel putative specific MSC markers. Differential-velocity centrifugation was used to enrich PM proteins. The isolated proteins were then identified by nLC-MS/MS and subjected to bioinformatics analysis. Proteins that were unique to each MSC type (CD9, CD10, CD63 for DP-MSCs; CD26, CD81, CD201, CD364 for AT-MSCs; Cd49a, CD49d for HF-MSCs; CD49e, CD56, CD92, CD97, CD156b, CD156c, CD220, CD221, CD298, CD315 for BM-MSCs) and common to all four MSC types (CD13, CD29, CD44, CD51, CD59, CD73, CD90) were identified. Uncharacterized proteins that have transmembrane (TM) domains were also detected. Some of the proteins identified in this study were the putative cell-surface markers that might be used for characterization of MSCs.
Collapse
|
|
40
|
Momoi Y, Nishida J, Miyakuni K, Kuroda M, Kubota SI, Miyazono K, Ehata S. Heterogenous expression of endoglin marks advanced renal cancer with distinct tumor microenvironment fitness. Cancer Sci 2021; 112:3136-3149. [PMID: 34091990 PMCID: PMC8353946 DOI: 10.1111/cas.15007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/04/2021] [Accepted: 05/19/2021] [Indexed: 12/15/2022] Open
Abstract
Intratumoral heterogeneity, including in clear cell renal cell carcinoma, is a potential cause of drug resistance and metastatic cancer progression. We specified the heterogeneous population marked by endoglin (also known as CD105) in a preclinical model of clear cell renal cell carcinoma progression. Highly malignant derivatives of human clear cell renal cell carcinoma OS‐RC‐2 cells were established as OS5Ks by serial orthotopic inoculation in our previous study. Expression of both ENG (encoding endoglin) mRNA and protein were heterogeneously upregulated in OS5Ks, and the endoglin‐positive (ENG+) population exhibited growth dependency on endoglin in anchorage‐independent cultures. Despite the function of endoglin as a type III receptor, transforming growth factor β and bone morphogenetic protein‐9 signaling were unlikely to contribute to the proliferative phenotype. Although endoglin has been proposed as a marker for renal cancer‐initiating cells, the OS5K‐3 ENG+ population did not enrich other reported cancer‐initiating cell markers or differentiate into the ENG– population. Mouse tumor inoculation models revealed that the tumor‐forming capabilities of OS5K‐3 ENG+ and ENG– cells in vivo were highly dependent on the microenvironment, with the renal microenvironment most preferable to ENG+ cells. In conclusion, the renal microenvironment, rather than the hypothesized ENG+ cell‐centered hierarchy, maintains cellular heterogeneity in clear cell renal cell carcinoma. Therefore, the effect of the microenvironment should be considered when evaluating the proliferative capability of renal cancer cells in the experimental settings.
Collapse
Affiliation(s)
- Yusaku Momoi
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Jun Nishida
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kosuke Miyakuni
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Masafumi Kuroda
- International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Bunkyo-ku, Japan
| | - Shimpei I Kubota
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kohei Miyazono
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Shogo Ehata
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan.,Environmental Science Center, The University of Tokyo, Bunkyo-ku, Japan
| |
Collapse
|
|
41
|
SARS-CoV-2, Endothelial Dysfunction, and the Renin-Angiotensin System (RAS): A Potentially Dangerous Triad for the Development of Pre-Eclampsia. REPRODUCTIVE MEDICINE 2021. [DOI: 10.3390/reprodmed2020010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
SARS-CoV-2 represents the greatest epidemiological, clinical, and social challenge the human being has had to face in this century. SARS-CoV-2 is not merely a respiratory virus, as its target cells range from upper airway respiratory cells to pulmonary cells but also and above all to the cardiovascular cells, such as pericytes and endothelial cells. Indeed, the pathology related to SARS-CoV-2, COVID-19, may be defined as a thromboinflammatory syndrome in its most severe form, characterized by sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulopathy (DIC), which is prevalent in individuals already presenting a chronic level of inflammation (e.g., obese individuals, elderly) and hypertension. Pregnancy is not only an inflammatory-prone condition but is characterized by a consistent rearrangement of the blood circulation and coagulation profile. Cardiac output increases while arterial systolic and diastolic pressure decrease, regardless of the activation of the RAS system. ACE2, the SARS-CoV-2 entry receptor into the host cells, which transforms Ang II in Ang 1–7, is highly expressed in endothelial, smooth muscle cells and pericytes of placental villi, regulating blood pressure and fetal development. Pre-eclampsia is a pregnancy disorder characterized by hypertension and low levels of ACE2, endothelial dysfunction, and a high production of pro-inflammatory cytokines, resembling COVID-19 manifestations. Whereas pre-eclampsia and COVID-19 have overlapping clinical features, a role for SARS-CoV-2 as a leading cause of pre-eclampsia in COVID-19 positive pregnant women has not been clarified yet. In this mini-review, we will explore the possibility of the existence of such a link, focusing on the role of endothelial dysfunction and RAS in both pre-eclampsia and SARS-CoV-2-induced COVID-19 pathogenesis.
Collapse
|
|
42
|
Sier VQ, van der Vorst JR, Quax PHA, de Vries MR, Zonoobi E, Vahrmeijer AL, Dekkers IA, de Geus-Oei LF, Smits AM, Cai W, Sier CFM, Goumans MJTH, Hawinkels LJAC. Endoglin/CD105-Based Imaging of Cancer and Cardiovascular Diseases: A Systematic Review. Int J Mol Sci 2021; 22:4804. [PMID: 33946583 PMCID: PMC8124553 DOI: 10.3390/ijms22094804] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Molecular imaging of pathologic lesions can improve efficient detection of cancer and cardiovascular diseases. A shared pathophysiological feature is angiogenesis, the formation of new blood vessels. Endoglin (CD105) is a coreceptor for ligands of the Transforming Growth Factor-β (TGF-β) family and is highly expressed on angiogenic endothelial cells. Therefore, endoglin-based imaging has been explored to visualize lesions of the aforementioned diseases. This systematic review highlights the progress in endoglin-based imaging of cancer, atherosclerosis, myocardial infarction, and aortic aneurysm, focusing on positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), near-infrared fluorescence (NIRF) imaging, and ultrasound imaging. PubMed was searched combining the following subjects and their respective synonyms or relevant subterms: "Endoglin", "Imaging/Image-guided surgery". In total, 59 papers were found eligible to be included: 58 reporting about preclinical animal or in vitro models and one ex vivo study in human organs. In addition to exact data extraction of imaging modality type, tumor or cardiovascular disease model, and tracer (class), outcomes were described via a narrative synthesis. Collectively, the data identify endoglin as a suitable target for intraoperative and diagnostic imaging of the neovasculature in tumors, whereas for cardiovascular diseases, the evidence remains scarce but promising.
Collapse
Affiliation(s)
- Vincent Q. Sier
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.Q.S.); (J.R.v.d.V.); (P.H.A.Q.); (M.R.d.V.); (E.Z.); (A.L.V.)
| | - Joost R. van der Vorst
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.Q.S.); (J.R.v.d.V.); (P.H.A.Q.); (M.R.d.V.); (E.Z.); (A.L.V.)
| | - Paul H. A. Quax
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.Q.S.); (J.R.v.d.V.); (P.H.A.Q.); (M.R.d.V.); (E.Z.); (A.L.V.)
| | - Margreet R. de Vries
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.Q.S.); (J.R.v.d.V.); (P.H.A.Q.); (M.R.d.V.); (E.Z.); (A.L.V.)
| | - Elham Zonoobi
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.Q.S.); (J.R.v.d.V.); (P.H.A.Q.); (M.R.d.V.); (E.Z.); (A.L.V.)
- Edinburgh Molecular Imaging Ltd. (EMI), Edinburgh EH16 4UX, UK
| | - Alexander L. Vahrmeijer
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.Q.S.); (J.R.v.d.V.); (P.H.A.Q.); (M.R.d.V.); (E.Z.); (A.L.V.)
| | - Ilona A. Dekkers
- Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
| | - Lioe-Fee de Geus-Oei
- Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
- Biomedical Photonic Imaging Group, University of Twente, 7500 AE Enschede, The Netherlands
| | - Anke M. Smits
- Department of Cell & Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (A.M.S.); (M.J.T.H.G.)
| | - Weibo Cai
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, WI 53705, USA;
| | - Cornelis F. M. Sier
- Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.Q.S.); (J.R.v.d.V.); (P.H.A.Q.); (M.R.d.V.); (E.Z.); (A.L.V.)
- Percuros B.V., 2333 CL Leiden, The Netherlands
| | - Marie José T. H. Goumans
- Department of Cell & Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (A.M.S.); (M.J.T.H.G.)
| | - Lukas J. A. C. Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
| |
Collapse
|
|
43
|
Elmasry K, Habib S, Moustafa M, Al-Shabrawey M. Bone Morphogenetic Proteins and Diabetic Retinopathy. Biomolecules 2021; 11:biom11040593. [PMID: 33919531 PMCID: PMC8073699 DOI: 10.3390/biom11040593] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Bone morphogenetic proteins (BMPs) play an important role in bone formation and repair. Recent studies underscored their essential role in the normal development of several organs and vascular homeostasis in health and diseases. Elevated levels of BMPs have been linked to the development of cardiovascular complications of diabetes mellitus. However, their particular role in the pathogenesis of microvascular dysfunction associated with diabetic retinopathy (DR) is still under-investigated. Accumulated evidence from our and others’ studies suggests the involvement of BMP signaling in retinal inflammation, hyperpermeability and pathological neovascularization in DR and age-related macular degeneration (AMD). Therefore, targeting BMP signaling in diabetes is proposed as a potential therapeutic strategy to halt the development of microvascular dysfunction in retinal diseases, particularly in DR. The goal of this review article is to discuss the biological functions of BMPs, their underlying mechanisms and their potential role in the pathogenesis of DR in particular.
Collapse
Affiliation(s)
- Khaled Elmasry
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
- Culver Vision discovery Institute, Augusta University, Augusta, GA 30912, USA;
- Department of Anatomy, Mansoura Faculty of Medicine, Mansoura University, Dakahlia Governorate 35516, Egypt
| | - Samar Habib
- Department of Medical Parasitology, Mansoura Faculty of Medicine, Mansoura University, Dakahlia Governorate 35516, Egypt;
- Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Mohamed Moustafa
- Culver Vision discovery Institute, Augusta University, Augusta, GA 30912, USA;
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Mohamed Al-Shabrawey
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
- Culver Vision discovery Institute, Augusta University, Augusta, GA 30912, USA;
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
- Correspondence: ; Tel.: +1-(706)721-4278 or +1-(706)721-4279
| |
Collapse
|
|
44
|
Chen Z, Chen K, Li J, Shen J, Xu W. Elevated Levels of Endoglin, Endostatin, FGF-α, HGF, and Thrombospondin-2 in Aqueous Humor of nAMD Patients. Ocul Immunol Inflamm 2021; 30:1092-1098. [PMID: 33793358 DOI: 10.1080/09273948.2020.1869785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Purpose: to explore the aqueous cytokine profiles in nAMD patients before and after conbercept therapy.Methods: aqueous levels of 17 cytokines were detected in 20 treatment-naïve nAMD eyes and 20 age- and sex-matched age-related cataract (ARC) eyes. All of the nAMD patients received three intravitreal injections of conbercept. The central macular thickness (CMT) and maximum retinal thickness-3 mm (MRT-3 mm) were measured by SD-OCT. Fundus fluorescein angiography (FA) was used to measure the greatest linear diameter (GLD).Results: Aqueous endoglin, endostatin, FGF-α, HGF, and thrombospondin-2 levels were significantly higher in the nAMD group than those in the ARC group, whether before or after two conbercept injections. In the nAMD group, baseline thrombospondin-2 was positively correlated with GLD. Baseline FGF-α, thrombospondin-2, and VEGF-A were positively correlated with MRT-3 mm. After two conbercept injections, endostatin levels were positively correlated with VEGF-A.Conclusions: Endoglin, endostatin, FGF-α, HGF, and thrombospondin-2 may participate in the pathogenesis of nAMD.
Collapse
Affiliation(s)
- Zhiqing Chen
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Kailin Chen
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.,Department of Head and Neck Surgery, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Jinyu Li
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Junhui Shen
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Wen Xu
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| |
Collapse
|
|
45
|
Bofarid S, Hosman AE, Mager JJ, Snijder RJ, Post MC. Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology. Int J Mol Sci 2021; 22:3471. [PMID: 33801690 PMCID: PMC8038106 DOI: 10.3390/ijms22073471] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/15/2022] Open
Abstract
In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.
Collapse
Affiliation(s)
- Sala Bofarid
- Department of Cardiology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands;
| | - Anna E. Hosman
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands; (A.E.H.); (J.J.M.); (R.J.S.)
| | - Johannes J. Mager
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands; (A.E.H.); (J.J.M.); (R.J.S.)
| | - Repke J. Snijder
- Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands; (A.E.H.); (J.J.M.); (R.J.S.)
| | - Marco C. Post
- Department of Cardiology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands;
- Department of Cardiology, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands
| |
Collapse
|
|
46
|
Xu H, Xie Y, Sun Y, Guo R, Lv D, Li X, Li F, He M, Fan Y, Deng D. Integrated analysis of multiple microarray studies to identify potential pathogenic gene modules in preeclampsia. Exp Mol Pathol 2021; 120:104631. [PMID: 33744280 DOI: 10.1016/j.yexmp.2021.104631] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/15/2021] [Accepted: 03/14/2021] [Indexed: 01/22/2023]
Abstract
BACKGROUND Preeclampsia is a life-threatening hypertensive disorder during pregnancy, while underlying pathogenesis and its diagnosis are incomplete. METHODS In this study, we utilized the Robust Rank Aggregation method to integrate 6 eligible preeclampsia microarray datasets from Gene Expression Omnibus database. We used linear regression to assess the associations between significant differentially expressed genes (DEGs) and blood pressure. Functional annotation, protein-protein interaction, Gene Set Enrichment Analysis (GSEA) and single sample GSEA were employed for investigating underlying pathogenesis in preeclampsia. RESULTS We filtered 52 DEGs and further screened for 5 hub genes (leptin, pappalysin 2, endoglin, fms related receptor tyrosine kinase 1, tripartite motif containing 24) that were positively correlated with both systolic blood pressure and diastolic blood pressure. Receiver operating characteristic indicated that hub genes were potential biomarkers for diagnosis and prognosis in preeclampsia. GSEA for single hub gene revealed that they were all closely related to angiogenesis and estrogen response in preeclampsia. Moreover, single sample GSEA showed that the expression levels of 5 hub genes were correlated with those of immune cells in immunologic microenvironment at maternal-fetal interface. CONCLUSIONS These findings provide new insights into underlying pathogenesis in preeclampsia; 5 hub genes were identified as biomarkers for diagnosis and prognosis in preeclampsia.
Collapse
Affiliation(s)
- Heze Xu
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; The Second Clinical Medicine College, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China
| | - Yin Xie
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanan Sun
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rong Guo
- Department of Software Engineering College, Information and Computer Engineering, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Dan Lv
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuanxuan Li
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fanfan Li
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengzhou He
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yao Fan
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dongrui Deng
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| |
Collapse
|
|
47
|
Bakker W, Dingenouts CKE, Lodder K, Wiesmeijer KC, de Jong A, Kurakula K, Mager HJJ, Smits AM, de Vries MR, Quax PHA, Goumans MJTH. BMP Receptor Inhibition Enhances Tissue Repair in Endoglin Heterozygous Mice. Int J Mol Sci 2021; 22:2010. [PMID: 33670533 PMCID: PMC7922601 DOI: 10.3390/ijms22042010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/02/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a severe vascular disorder caused by mutations in the TGFβ/BMP co-receptor endoglin. Endoglin haploinsufficiency results in vascular malformations and impaired neoangiogenesis. Furthermore, HHT1 patients display an impaired immune response. To date it is not fully understood how endoglin haploinsufficient immune cells contribute to HHT1 pathology. Therefore, we investigated the immune response during tissue repair in Eng+/- mice, a model for HHT1. Eng+/- mice exhibited prolonged infiltration of macrophages after experimentally induced myocardial infarction. Moreover, there was an increased number of inflammatory M1-like macrophages (Ly6Chigh/CD206-) at the expense of reparative M2-like macrophages (Ly6Clow/CD206+). Interestingly, HHT1 patients also showed an increased number of inflammatory macrophages. In vitro analysis revealed that TGFβ-induced differentiation of Eng+/- monocytes into M2-like macrophages was blunted. Inhibiting BMP signaling by treating monocytes with LDN-193189 normalized their differentiation. Finally, LDN treatment improved heart function after MI and enhanced vascularization in both wild type and Eng+/- mice. The beneficial effect of LDN was also observed in the hind limb ischemia model. While blood flow recovery was hampered in vehicle-treated animals, LDN treatment improved tissue perfusion recovery in Eng+/- mice. In conclusion, BMPR kinase inhibition restored HHT1 macrophage imbalance in vitro and improved tissue repair after ischemic injury in Eng+/- mice.
Collapse
Affiliation(s)
- Wineke Bakker
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Calinda K. E. Dingenouts
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Kirsten Lodder
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Karien C. Wiesmeijer
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Alwin de Jong
- Department of Surgery, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (A.d.J.); (M.R.d.V.); (P.H.A.Q.)
| | - Kondababu Kurakula
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | | | - Anke M. Smits
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| | - Margreet R. de Vries
- Department of Surgery, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (A.d.J.); (M.R.d.V.); (P.H.A.Q.)
| | - Paul H. A. Quax
- Department of Surgery, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (A.d.J.); (M.R.d.V.); (P.H.A.Q.)
| | - Marie José T. H. Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; (W.B.); (C.K.E.D.); (K.L.); (K.C.W.); (K.K.); (A.M.S.)
| |
Collapse
|
|
48
|
Hooglugt A, van der Stoel MM, Boon RA, Huveneers S. Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature. Front Oncol 2021; 10:612802. [PMID: 33614496 PMCID: PMC7890025 DOI: 10.3389/fonc.2020.612802] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/07/2020] [Indexed: 12/14/2022] Open
Abstract
Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.
Collapse
Affiliation(s)
- Aukie Hooglugt
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands
| | - Miesje M. van der Stoel
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Reinier A. Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands
- German Center for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Berlin, Germany
- Institute of Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany
| | - Stephan Huveneers
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| |
Collapse
|
|
49
|
Zhang J, Ten Dijke P, Wuhrer M, Zhang T. Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer. Protein Cell 2021; 12:89-106. [PMID: 32583064 PMCID: PMC7862465 DOI: 10.1007/s13238-020-00741-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/29/2020] [Indexed: 12/14/2022] Open
Abstract
Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to uncontrolled cell proliferation, cell-matrix interactions, migration and differentiation, and has been shown to be involved in cancer and other diseases. The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream. This cellular transformation process, which is associated by morphological change, loss of epithelial traits and gain of mesenchymal markers, is triggered by the secreted cytokine transforming growth factor-β (TGF-β). TGF-β bioactivity is carefully regulated, and its effects on cells are mediated by its receptors on the cell surface. In this review, we first provide a brief overview of major types of glycans, namely, N-glycans, O-glycans, glycosphingolipids and glycosaminoglycans that are involved in cancer progression. Thereafter, we summarize studies on how the glycosylation of TGF-β signaling components regulates TGF-β secretion, bioavailability and TGF-β receptor function. Then, we review glycosylation changes associated with TGF-β-induced epithelial-to-mesenchymal transition in cancer. Identifying and understanding the mechanisms by which glycosylation affects TGF-β signaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches.
Collapse
Affiliation(s)
- Jing Zhang
- Oncode Institute and Cell Chemical Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Cell Chemical Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Tao Zhang
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
50
|
Margioula-Siarkou G, Margioula-Siarkou C, Petousis S, Margaritis K, Alexandratou M, Dinas K, Sotiriadis A, Mavromatidis G. Soluble endoglin concentration in maternal blood as a diagnostic biomarker of preeclampsia: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2021; 258:366-381. [PMID: 33529972 DOI: 10.1016/j.ejogrb.2021.01.039] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 01/18/2021] [Accepted: 01/21/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Preeclampsia is a main cause of maternal and fetal morbidity and mortality. Research about maternal circulating diagnostic biomarkers is continuously performed, often with conflicting results that necessitate quantitative synthesis. Objective of this meta-analysis is to examine the value of soluble endoglin as predictor of preeclampsia separately at each pregnancy trimester, therefore exploring its potential usage as diagnostic biomarker in preeclampsia. STUDY DESIGN This systematic review and meta-analysis adhered to PRISMA and MOOSE guidelines. MEDLINE, SCOPUS, Cochrane CENTRAL and ClinicalTrials.gov were searched up to April 20, 2020. Included studies were those comparing soluble endoglin levels in maternal serum or plasma at any pregnancy trimester, between women who subsequently developed preeclampsia and normotensive pregnant women being low-risk for preeclampsia development. Primary outcome was development of preeclampsia, while soluble endoglin levels in 1 st, 2nd and 3rd trimester of pregnancy were examined as possible predictors of preeclampsia. Subgroup analysis was performed regarding time of preeclampsia onset (early, late). Methodological quality of included studies was assessed using Newcastle-Ottawa scale. Overall quality of evidence for primary and secondary outcomes was evaluated using GRADEpro GD tool. RESULTS There were overall 20 studies included in meta-analysis, enrolling 1146 preeclamptic and 1675 normotensive pregnant women. Soluble endoglin concentration (ng/mL) was significantly higher in preeclamptic women during 2nd (8 studies, MD:5.554, 95 %CI:2.671-8.436, P < .001, I2 = 97 %) and 3rd trimester (12 studies, MD:31.006, 95 %CI:24.734-37.278, P < .001, I2 = 98 %). Levels were also higher during 1st trimester; however, the difference was marginally not significant (MD:1.105, 95 %CI: -0.071 to 2.282, P = .06, I2 = 64 %). Furthermore, levels were significantly higher both in early-onset and late-onset preeclamptic vs normotensive pregnancies, (4 studies, MD:51.611, 95 %CI:2.250-100.972, P = .04, I2 = 97 %), (5 studies, MD:12.426, 95 %CI:7.863-16.989, P < .001, I2 = 98 %) respectively. However, when comparing directly early and late-onset preeclamptic women, no significant difference was detected (3 studies, MD:20.725, 95 %CI: -11.601 to 53.052, P = .209, I2 = 93 %). CONCLUSIONS Soluble endoglin levels were consistently higher in preeclamptic compared to normotensive pregnant women almost throughout pregnancy. Our results firmly indicate soluble endoglin's potential use as predictor of preeclampsia. Further studies are required to support the use of soluble endoglin as a diagnostic tool for preeclampsia in clinical settings.
Collapse
Affiliation(s)
- Georgia Margioula-Siarkou
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | | | - Stamatios Petousis
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kosmas Margaritis
- 2nd Department of Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Alexandratou
- Department of Radiology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Dinas
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alexandros Sotiriadis
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios Mavromatidis
- 2nd Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| |
Collapse
|