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Sanchez V, Harel S, Sa’ub AK, Mayaki D, Hussain SNA. miR-1233-3p Inhibits Angiopoietin-1-Induced Endothelial Cell Survival, Migration, and Differentiation. Cells 2025; 14:75. [PMID: 39851503 PMCID: PMC11763389 DOI: 10.3390/cells14020075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/10/2024] [Accepted: 01/03/2025] [Indexed: 01/26/2025] Open
Abstract
Angiopoietin-1 (Ang-1) and its receptor Tie-2 promote vascular integrity and angiogenesis. MicroRNAs (miRNAs) are involved in the regulation of many cellular functions, including endothelial cell (EC) survival, proliferation, and differentiation. Several reports indicate that these effects of miRNAs on EC functions are mediated through the modulation of angiogenesis factor signaling including that of vascular endothelial growth factor (VEGF). To date, very little is known about the roles played by miRNAs in the signaling and angiogenesis promoted by the Ang-1-Tie-2 receptor axis. Our high-throughput screening of miRNAs regulated by Ang-1 exposure in human umbilical vein endothelial cells (HUVECs) has identified miR-1233-3p as a mature miRNA whose cellular levels are significantly downregulated in response to Ang-1 exposure. The expression of miR-1233-3p in these cells is also downregulated by other angiogenesis factors including VEGF, fibroblast growth factor 2 (FGF-2), transforming growth factor β (TGFβ), and angiopoietin-2 (Ang-2). The overexpression of miR-1233-3p in HUVECs using specific mimics significantly attenuated cell survival, migration, and capillary-like tube formation, and promoted apoptosis. Moreover, miR-1233-3p overexpression resulted in reversal of the anti-apoptotic, pro-migration, and pro-differentiation effects of Ang-1. Biotinylated miRNA pull-down assays showed that p53 and DNA damage-regulated 1 (PDRG1) is a direct target of miR-1233-3p in HUVECs. The exposure of HUVECs to Ang-1, angiopoietin-2 (Ang-2), fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), or transforming growth factor β (TGFβ) triggers the regulation of PDRG1 expression. This study highlights that miR-1233-3p exerts inhibitory effects on Ang-1-induced survival, migration, and the differentiation of cultured ECs.
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Affiliation(s)
- Veronica Sanchez
- Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada (A.K.S.); (D.M.)
- Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, 1001 Décarie Blvd., Montreal, QC H4A 3J1, Canada
- Department of Critical Care, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Sharon Harel
- Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada (A.K.S.); (D.M.)
- Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, 1001 Décarie Blvd., Montreal, QC H4A 3J1, Canada
- Department of Critical Care, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Anas Khalid Sa’ub
- Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada (A.K.S.); (D.M.)
- Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, 1001 Décarie Blvd., Montreal, QC H4A 3J1, Canada
- Department of Critical Care, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Dominique Mayaki
- Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada (A.K.S.); (D.M.)
- Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, 1001 Décarie Blvd., Montreal, QC H4A 3J1, Canada
- Department of Critical Care, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Sabah N. A. Hussain
- Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada (A.K.S.); (D.M.)
- Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, 1001 Décarie Blvd., Montreal, QC H4A 3J1, Canada
- Department of Critical Care, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
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Wang C, Wang X, Wang W, Chen Y, Chen H, Wang W, Ye T, Dong J, Sun C, Li X, Li C, Li J, Wang Y, Feng X, Ding H, Xu D, Shi J. Single‑cell RNA sequencing analysis of human embryos from the late Carnegie to fetal development. Cell Biosci 2024; 14:118. [PMID: 39267141 PMCID: PMC11395182 DOI: 10.1186/s13578-024-01302-9] [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: 04/27/2024] [Accepted: 09/03/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND The cell development atlas of transition stage from late Carnegie to fetal development (7-9 weeks) remain unclear. It can be seen that the early period of human embryos (7-9 weeks) is a critical research gap. Therefore, we employed single‑cell RNA sequencing to identify cell types and elucidate differentiation relationships. RESULTS The single‑cell RNA sequencing analysis determines eighteen cell clusters in human embryos during the 7-9 weeks period. We uncover two distinct pathways of cellular development and differentiation. Initially, mesenchymal progenitor cells differentiated into osteoblast progenitor cells and neural stem cells, respectively. Neural stem cells further differentiated into neurons. Alternatively, multipotential stem cells differentiated into adipocyte, hematopoietic stem cells and neutrophil, respectively. Additionally, COL1A2-(ITGA1 + ITGB1) mediated the cell communication between mesenchymal progenitor cells and osteoblast progenitor cells. NCAM1-FGFR1 facilitated the cell communication between mesenchymal progenitor cells and neural stem cells. Notably, NCAM1-NCAM1 as a major contributor mediated the cell communication between neural stem cells and neurons. Moreover, CGA-FSHR simultaneously mediated the communication between multipotential stem cells, adipocyte, hematopoietic stem cells and neutrophil. Distinct cell clusters activated specific transcription factors such as HIC1, LMX1B, TWIST1, and et al., which were responsible for their specific functions. These coregulators, such as HOXB13, VSX2, PAX5, and et al., may mediate cell development and differentiation in human embryos. CONCLUSIONS We provide the cell development atlas for human embryos (7-9 weeks). Two distinct cell development and differentiation pathways are revealed.
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Affiliation(s)
- Chengniu Wang
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Xiaorong Wang
- Center for Reproductive Medicine, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, 226018, Jiangsu, China
- Nantong Institute of Genetics and Reproductive Medicine, Affiliated Maternity and Child Healthcare Hospital of Nantong University, Nantong, 226018, Jiangsu, China
- Nantong Key Laboratory of Genetics and Reproductive Medicine, Nantong, 226018, Jiangsu, China
| | - Wenran Wang
- Blood Purification Centre, Third People's Hospital of Rugao, Nantong, 226531, Jiangsu, China
| | - Yufei Chen
- Basic Medical Research Centre, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Hanqing Chen
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Weizhen Wang
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Taowen Ye
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Jin Dong
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Chenliang Sun
- Department of Critical Care Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
| | - Xiaoran Li
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Chunhong Li
- Blood Purification Centre, Third People's Hospital of Rugao, Nantong, 226531, Jiangsu, China
| | - Jiaying Li
- Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, 226001, Jiangsu, China
| | - Yong Wang
- Department of Neurosurgery, Affiliated Hospital 2 of Nantong University, Nantong, 226006, Jiangsu, China
| | - Xingmei Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Hongping Ding
- Blood Purification Centre, Third People's Hospital of Rugao, Nantong, 226531, Jiangsu, China.
| | - Dawei Xu
- Department of Orthopedics, Affiliated Hospital 2 of Nantong University, Nantong, 226000, Jiangsu, China.
| | - Jianwu Shi
- Basic Medical Research Centre, Medical School, Nantong University, Nantong, 226001, Jiangsu, China.
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Zhou Y, Wu Q, Guo Y. Deciphering the emerging landscape of HOX genes in cardiovascular biology, atherosclerosis and beyond (Review). Int J Mol Med 2024; 53:17. [PMID: 38131178 PMCID: PMC10781420 DOI: 10.3892/ijmm.2023.5341] [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: 08/05/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023] Open
Abstract
Atherosclerosis, a dominant driving force underlying multiple cardiovascular events, is an intertwined and chronic inflammatory disease characterized by lipid deposition in the arterial wall, which leads to diverse cardiovascular problems. Despite unprecedented advances in understanding the pathogenesis of atherosclerosis and the substantial decline in cardiovascular mortality, atherosclerotic cardiovascular disease remains a global public health issue. Understanding the molecular landscape of atherosclerosis is imperative in the field of molecular cardiology. Recently, compelling evidence has shown that an important family of homeobox (HOX) genes endows causality in orchestrating the interplay between various cardiovascular biological processes and atherosclerosis. Despite seemingly scratching the surface, such insight into the realization of biology promises to yield extraordinary breakthroughs in ameliorating atherosclerosis. Primarily recapitulated herein are the contributions of HOX in atherosclerosis, including diverse cardiovascular biology, knowledge gaps, remaining challenges and future directions. A snapshot of other cardiovascular biological processes was also provided, including cardiac/vascular development, cardiomyocyte pyroptosis/apoptosis, cardiac fibroblast proliferation and cardiac hypertrophy, which are responsible for cardiovascular disorders. Further in‑depth investigation of HOX promises to provide a potential yet challenging landscape, albeit largely undetermined to date, for partially pinpointing the molecular mechanisms of atherosclerosis. A plethora of new targeted therapies may ultimately emerge against atherosclerosis, which is rapidly underway. However, translational undertakings are crucially important but increasingly challenging and remain an ongoing and monumental conundrum in the field.
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Affiliation(s)
- Yu Zhou
- Medical College, Guizhou University, Guiyang, Guizhou 550025, P.R. China
- Department of Cardiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Qiang Wu
- Department of Cardiology, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
| | - Yingchu Guo
- Department of Clinical Laboratory, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, P.R. China
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Lv J, Meng S, Gu Q, Zheng R, Gao X, Kim JD, Chen M, Xia B, Zuo Y, Zhu S, Zhao D, Li Y, Wang G, Wang X, Meng Q, Cao Q, Cooke JP, Fang L, Chen K, Zhang L. Epigenetic landscape reveals MECOM as an endothelial lineage regulator. Nat Commun 2023; 14:2390. [PMID: 37185814 PMCID: PMC10130150 DOI: 10.1038/s41467-023-38002-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
A comprehensive understanding of endothelial cell lineage specification will advance cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures preferentially regulate cell identity genes. We thus systematically investigate the epigenetic landscape of endothelial cell lineage and identify MECOM to be the leading candidate as an endothelial cell lineage regulator. Single-cell RNA-Seq analysis verifies that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide endothelial cells derived from induced pluripotent stem cells. Our experiments demonstrate that MECOM depletion impairs human endothelial cell differentiation, functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes. Further, we identify and verify the VEGF signaling pathway to be a key target of MECOM. Our work provides important insights into epigenetic regulation of cell identity and uncovered MECOM as an endothelial cell lineage regulator.
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Affiliation(s)
- Jie Lv
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - Shu Meng
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - Qilin Gu
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - Rongbin Zheng
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Xinlei Gao
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Jun-Dae Kim
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - Min Chen
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Bo Xia
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - Yihan Zuo
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Sen Zhu
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
| | - Dongyu Zhao
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Yanqiang Li
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Guangyu Wang
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Xin Wang
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Qingshu Meng
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Qi Cao
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - John P Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
| | - Longhou Fang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
| | - Kaifu Chen
- Center for Bioinformatics and Computational Biology, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
| | - Lili Zhang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
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5
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Steens J, Klein D. HOX genes in stem cells: Maintaining cellular identity and regulation of differentiation. Front Cell Dev Biol 2022; 10:1002909. [PMID: 36176275 PMCID: PMC9514042 DOI: 10.3389/fcell.2022.1002909] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Stem cells display a unique cell type within the body that has the capacity to self-renew and differentiate into specialized cell types. Compared to pluripotent stem cells, adult stem cells (ASC) such as mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) exhibit restricted differentiation capabilities that are limited to cell types typically found in the tissue of origin, which implicates that there must be a certain code or priming determined by the tissue of origin. HOX genes, a subset of homeobox genes encoding transcription factors that are generally repressed in undifferentiated pluripotent stem cells, emerged here as master regulators of cell identity and cell fate during embryogenesis, and in maintaining this positional identity throughout life as well as specifying various regional properties of respective tissues. Concurrently, intricate molecular circuits regulated by diverse stem cell-typical signaling pathways, balance stem cell maintenance, proliferation and differentiation. However, it still needs to be unraveled how stem cell-related signaling pathways establish and regulate ASC-specific HOX expression pattern with different temporal-spatial topography, known as the HOX code. This comprehensive review therefore summarizes the current knowledge of specific ASC-related HOX expression patterns and how these were integrated into stem cell-related signaling pathways. Understanding the mechanism of HOX gene regulation in stem cells may provide new ways to manipulate stem cell fate and function leading to improved and new approaches in the field of regenerative medicine.
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6
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Moon JE, Lawrence JB. Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling. Cell Rep 2022; 40:111174. [PMID: 35947952 PMCID: PMC9505374 DOI: 10.1016/j.celrep.2022.111174] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 12/24/2021] [Accepted: 07/18/2022] [Indexed: 11/28/2022] Open
Abstract
Despite the prevalence of Down syndrome (DS), little is known regarding the specific cell pathologies that underlie this multi-system disorder. To understand which cell types and pathways are more directly affected by trisomy 21 (T21), we used an inducible-XIST system to silence one chromosome 21 in vitro. T21 caused the dysregulation of Notch signaling in iPSCs, potentially affecting cell-type programming. Further analyses identified dysregulation of pathways important for two cell types: neurogenesis and angiogenesis. Angiogenesis is essential to many bodily systems, yet is understudied in DS; therefore, we focused next on whether T21 affects endothelial cells. An in vitro assay for microvasculature formation revealed a cellular pathology involving delayed tube formation in response to angiogenic signals. Parallel transcriptomic analysis of endothelia further showed deficits in angiogenesis regulators. Results indicate a direct cell-autonomous impact of T21 on endothelial function, highlighting the importance of angiogenesis, with wide-reaching implications for development and disease progression. Moon and Lawrence examine the immediate effects of trisomy 21 silencing and find angiogenesis and neurogenesis pathways, including Notch signaling, affected as early as pluripotency. In endothelial cells, functional analyses show that trisomy delays the angiogenic response for microvessel formation and transcriptomics show a parallel impact on angiogenic regulators and signal-response and cytoskeleton processes.
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Affiliation(s)
- Jennifer E Moon
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Jeanne B Lawrence
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655, USA.
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7
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Guebel DV, Torres NV, Acebes Á. Mapping the transcriptomic changes of endothelial compartment in human hippocampus across aging and mild cognitive impairment. Biol Open 2021; 10:bio057950. [PMID: 34184731 PMCID: PMC8181899 DOI: 10.1242/bio.057950] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/07/2021] [Indexed: 12/17/2022] Open
Abstract
Compromise of the vascular system has important consequences on cognitive abilities and neurodegeneration. The identification of the main molecular signatures present in the blood vessels of human hippocampus could provide the basis to understand and tackle these pathologies. As direct vascular experimentation in hippocampus is problematic, we achieved this information by computationally disaggregating publicly available whole microarrays data of human hippocampal homogenates. Three conditions were analyzed: 'Young Adults', 'Aged', and 'aged with Mild Cognitive Impairment' (MCI). The genes identified were contrasted against two independent data-sets. Here we show that the endothelial cells from the Younger Group appeared in an 'activated stage'. In turn, in the Aged Group, the endothelial cells showed a significant loss of response to shear stress, changes in cell adhesion molecules, increased inflammation, brain-insulin resistance, lipidic alterations, and changes in the extracellular matrix. Some specific changes in the MCI group were also detected. Noticeably, in this study the features arisen from the Aged Group (high tortuosity, increased bifurcations, and smooth muscle proliferation), pose the need for further experimental verification to discern between the occurrence of arteriogenesis and/or vascular remodeling by capillary arterialization. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Daniel V. Guebel
- Program Agustín de Betancourt, Universidad de La Laguna, Tenerife 38200, Spain
- Department of Biochemistry, Cellular Biology and Genetics, Institute of Biomedical Technologies, Universidad de La Laguna, Tenerife 38200, Spain
| | - Néstor V. Torres
- Department of Biochemistry, Cellular Biology and Genetics, Institute of Biomedical Technologies, Universidad de La Laguna, Tenerife 38200, Spain
| | - Ángel Acebes
- Department of Basic Medical Sciences, Institute of Biomedical Technologies, University of La Laguna, Tenerife 38200, Spain
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Wu Z, Gong H, Zhang M, Tong X, Ai H, Xiao S, Perez-Enciso M, Yang B, Huang L. A worldwide map of swine short tandem repeats and their associations with evolutionary and environmental adaptations. Genet Sel Evol 2021; 53:39. [PMID: 33892623 PMCID: PMC8063339 DOI: 10.1186/s12711-021-00631-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 04/09/2021] [Indexed: 11/10/2022] Open
Abstract
Background Short tandem repeats (STRs) are genetic markers with a greater mutation rate than single nucleotide polymorphisms (SNPs) and are widely used in genetic studies and forensics. However, most studies in pigs have focused only on SNPs or on a limited number of STRs. Results This study screened 394 deep-sequenced genomes from 22 domesticated pig breeds/populations worldwide, wild boars from both Europe and Asia, and numerous outgroup Suidaes, and identified a set of 878,967 polymorphic STRs (pSTRs), which represents the largest repository of pSTRs in pigs to date. We found multiple lines of evidence that pSTRs in coding regions were affected by purifying selection. The enrichment of trinucleotide pSTRs in coding sequences (CDS), 5′UTR and H3K4me3 regions suggests that trinucleotide STRs serve as important components in the exons and promoters of the corresponding genes. We demonstrated that, compared to SNPs, pSTRs provide comparable or even greater accuracy in determining the breed identity of individuals. We identified pSTRs that showed significant population differentiation between domestic pigs and wild boars in Asia and Europe. We also observed that some pSTRs were significantly associated with environmental variables, such as average annual temperature or altitude of the originating sites of Chinese indigenous breeds, among which we identified loss-of-function and/or expanded STRs overlapping with genes such as AHR, LAS1L and PDK1. Finally, our results revealed that several pSTRs show stronger signals in domestic pig—wild boar differentiation or association with the analysed environmental variables than the flanking SNPs within a 100-kb window. Conclusions This study provides a genome-wide high-density map of pSTRs in diverse pig populations based on genome sequencing data, enabling a more comprehensive characterization of their roles in evolutionary and environmental adaptation. Supplementary Information The online version contains supplementary material available at 10.1186/s12711-021-00631-4.
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Affiliation(s)
- Zhongzi Wu
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China
| | - Huanfa Gong
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China
| | - Mingpeng Zhang
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China
| | - Xinkai Tong
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China
| | - Huashui Ai
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China
| | - Shijun Xiao
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China
| | - Miguel Perez-Enciso
- Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB, Barcelona, Spain.,ICREA, Passeig de Lluís Companys 23, Barcelona, Spain
| | - Bin Yang
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China.
| | - Lusheng Huang
- State Key Laboratory for Pig Genetic Improvement and Production Technology, Jiangxi Agricultural University, Nanchang, China.
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Zhu Q, Hu S, He Y, Qiu C, Chen T, He Y, Wu Z, Tian L, Shang T, Xiang Y, Zhang H, Li D. Nuclear Factor Kappa-B/Homeobox A9-Mediated Modulation of Leucine-Rich Repeat Flightless-Interacting Protein 1 Is Involved in Advanced Glycation End Product-Induced Endothelial Dysfunction. J Vasc Res 2021; 58:311-320. [PMID: 33882503 DOI: 10.1159/000515177] [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] [Received: 06/16/2020] [Accepted: 02/04/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Pathogenesis of cardiovascular diseases begins with endothelial dysfunction. Our previous study has shown that advanced glycation end products (AGE) could inhibit the expression of homeobox A9 (Hoxa9), thereby inducing endothelial dysfunction. Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) has been found to participate in a variety of pathological processes, but reports of its role in endothelial dysfunction are rare. OBJECTIVES This study aims to investigate whether LRRFIP1 is involved in AGE-induced endothelial dysfunction through Hoxa9-mediated transcriptional activation. METHODS Chromatin immunoprecipitation was used to detect the transcriptional regulation of Hoxa9 on LRRFIP1 promoters. Human umbilical vein endothelial cells were treated with AGE or pyrrolidinedithiocarbamate (nuclear factor kappa-B [NF-κB] inhibitor). Moreover, changes in apoptosis, proliferation, migration, release of nitric oxide, and angiogenesis were detected. RESULTS Hoxa9 promotes LRRFIP1 expression by binding to the -LRRFIP1 promoter. Meanwhile, overexpression of LRRFIP1 inhibited phosphorylation of P65 and elevated expression of Hoxa9. Overexpression of LRRFIP1 or/and Hoxa9 reversed the effects of AGE on HUVEC. AGE-induced inhibition on the expression of LRRFIP1 and Hoxa9 could be reversed by the NF-κB inhibitor. CONCLUSION LRRFIP1 is involved in AGE-induced endothelial dysfunction via being regulated by the NF-κB/Hoxa9 axis.
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Affiliation(s)
- Qianqian Zhu
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Songjie Hu
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Yunjun He
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chenyang Qiu
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tianchi Chen
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yangyan He
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ziheng Wu
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lu Tian
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tao Shang
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yilang Xiang
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hongkun Zhang
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Donglin Li
- Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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10
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Aref-Eshghi E, Biswas S, Chen C, Sadikovic B, Chakrabarti S. Glucose-induced, duration-dependent genome-wide DNA methylation changes in human endothelial cells. Am J Physiol Cell Physiol 2020; 319:C268-C276. [PMID: 32459505 DOI: 10.1152/ajpcell.00011.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
DNA methylation, a critical epigenetic mechanism, plays an important role in governing gene expressions during biological processes such as aging, which is well known to be accelerated in hyperglycemia (diabetes). In the present study, we investigated the effects of glucose on whole genome DNA methylation in small [human retinal microvascular endothelial cells (HRECs)] and large [human umbilical vein endothelial cells (HUVECs)] vessel endothelial cell (EC) lines exposed to basal or high glucose-containing media for variable lengths of time. Using the Infinium EPIC array, we obtained 773,133 CpG sites (probes) for analysis. Unsupervised clustering of the top 5% probes identified four distinct clusters within EC groups, with significant methylation differences attributed to EC types and the duration of cell culture rather than glucose stimuli alone. When comparing the ECs incubated for 2 days versus 7 days, hierarchical clustering analyses [methylation change >10% and false discovery rate (FDR) <0.05] identified 17,354 and 128 differentially methylated CpGs for HUVECs and HRECs, respectively. Predominant DNA hypermethylation was associated with the length of culture and was enriched for gene enhancer elements and regions surrounding CpG shores and shelves. We identified 88 differentially methylated regions (DMRs) for HUVECs and 8 DMRs for HRECs (all FDR <0.05). Pathway enrichment analyses of DMRs highlighted involvement of regulators of embryonic development (i.e., HOX genes) and cellular differentiation [transforming growth factor-β (TGF-β) family members]. Collectively, our findings suggest that DNA methylation is a complex process that involves tightly coordinated, cell-specific mechanisms. Such changes in methylation overlap genes critical for cellular differentiation and embryonic development.
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Affiliation(s)
- Erfan Aref-Eshghi
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada
| | - Saumik Biswas
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Charlie Chen
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada.,Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Subrata Chakrabarti
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada.,Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
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11
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Zhao R, Wang Y, Zou L, Luo Y, Tan H, Yao J, Zhang M, Liu S. Hox genes reveal variations in the genomic DNA of allotetraploid hybrids derived from Carassius auratus red var. (female) × Cyprinus carpio L. (male). BMC Genet 2020; 21:24. [PMID: 32131722 PMCID: PMC7057633 DOI: 10.1186/s12863-020-0823-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 02/04/2020] [Indexed: 11/10/2022] Open
Abstract
Background Hox transcription factors are master regulators of animal development. Although highly conserved, they can contribute to the formation of novel biological characteristics when modified, such as during the generation of hybrid species, thus potentially serving as species-specific molecular markers. Here, we systematically studied the evolution of genomic sequences of Hox loci in an artificial allotetraploid lineage (4nAT, 4n = 200) derived from a red crucian carp (♀, RCC, 2n = 100) × common carp (♂, CC, 2n = 100) cross and its parents (RCC and CC). Results PCR amplification yielded 23 distinct Hox gene fragments from 160 clones in 4nAT, 22 fragments from 90 clones in RCC, and 19 fragments from 90 clones in CC. Sequence alignment of the HoxA3a and HoxC10a genes indicated both the inheritance and loss of paternal genomic DNA in 4nAT. The HoxA5a gene from 4nAT consisted of two subtypes from RCC and two subtypes from CC, indicating that homologous recombination occurred in the 4nAT hybrid genome. Moreover, 4nAT carried genomic pseudogenization in the HoxA10b and HoxC13a loci. Interestingly, a new type of HoxC9a gene was found in 4nAT as a hybrid sequence of CC and RCC by recombination in the intronic region. Conclusion The results revealed the influence of Hox genes during polyploidization in hybrid fish. The data provided insight into the evolution of vertebrate genomes and might be benefit for artificial breeding programs.
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Affiliation(s)
- Rurong Zhao
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China.,College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China
| | - Yude Wang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China.,College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China
| | - Li Zou
- Fisheries Research Institute of Hunan Province, Changsha, 410153, People's Republic of China
| | - Yaxin Luo
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China.,College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China
| | - Huifang Tan
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China.,College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China
| | - Jiajun Yao
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China.,College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China
| | - Minghe Zhang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China.,College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China
| | - Shaojun Liu
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China. .,College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, People's Republic of China.
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12
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Alsayegh K, Cortés-Medina LV, Ramos-Mandujano G, Badraiq H, Li M. Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators. Curr Genomics 2019; 20:438-452. [PMID: 32194342 PMCID: PMC7062042 DOI: 10.2174/1389202920666191017163837] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 09/04/2019] [Accepted: 09/27/2019] [Indexed: 02/07/2023] Open
Abstract
Numerous human disorders of the blood system would directly or indirectly benefit from therapeutic approaches that reconstitute the hematopoietic system. Hematopoietic stem cells (HSCs), either from matched donors or ex vivo manipulated autologous tissues, are the most used cellular source of cell therapy for a wide range of disorders. Due to the scarcity of matched donors and the difficulty of ex vivo expansion of HSCs, there is a growing interest in harnessing the potential of pluripotent stem cells (PSCs) as a de novo source of HSCs. PSCs make an ideal source of cells for regenerative medicine in general and for treating blood disorders in particular because they could expand indefinitely in culture and differentiate to any cell type in the body. However, advancement in deriving functional HSCs from PSCs has been slow. This is partly due to an incomplete understanding of the molecular mechanisms underlying normal hematopoiesis. In this review, we discuss the latest efforts to generate human PSC (hPSC)-derived HSCs capable of long-term engraftment. We review the regulation of the key transcription factors (TFs) in hematopoiesis and hematopoietic differentiation, the Homeobox (HOX) and GATA genes, and the interplay between them and microRNAs. We also propose that precise control of these master regulators during the course of hematopoietic differentiation is key to achieving functional hPSC-derived HSCs.
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Affiliation(s)
- Khaled Alsayegh
- King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.,Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Lorena V Cortés-Medina
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Gerardo Ramos-Mandujano
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
| | - Heba Badraiq
- King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Mo Li
- Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
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13
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Coan M, Rampioni Vinciguerra GL, Cesaratto L, Gardenal E, Bianchet R, Dassi E, Vecchione A, Baldassarre G, Spizzo R, Nicoloso MS. Exploring the Role of Fallopian Ciliated Cells in the Pathogenesis of High-Grade Serous Ovarian Cancer. Int J Mol Sci 2018; 19:ijms19092512. [PMID: 30149579 PMCID: PMC6163198 DOI: 10.3390/ijms19092512] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 08/20/2018] [Accepted: 08/20/2018] [Indexed: 12/22/2022] Open
Abstract
High-grade serous epithelial ovarian cancer (HGSOC) is the fifth leading cause of cancer death in women and the first among gynecological malignancies. Despite an initial response to standard chemotherapy, most HGSOC patients relapse. To improve treatment options, we must continue investigating tumor biology. Tumor characteristics (e.g., risk factors and epidemiology) are valuable clues to accomplish this task. The two most frequent risk factors for HGSOC are the lifetime number of ovulations, which is associated with increased oxidative stress in the pelvic area caused by ovulation fluid, and a positive family history due to genetic factors. In the attempt to identify novel genetic factors (i.e., genes) associated with HGSOC, we observed that several genes in linkage with HGSOC are expressed in the ciliated cells of the fallopian tube. This finding made us hypothesize that ciliated cells, despite not being the cell of origin for HGSOC, may take part in HGSOC tumor initiation. Specifically, malfunction of the ciliary beat impairs the laminar fluid flow above the fallopian tube epithelia, thus likely reducing the clearance of oxidative stress caused by follicular fluid. Herein, we review the up-to-date findings dealing with HGSOC predisposition with the hypothesis that fallopian ciliated cells take part in HGSOC onset. Finally, we review the up-to-date literature concerning genes that are located in genomic loci associated with epithelial ovarian cancer (EOC) predisposition that are expressed by the fallopian ciliated cells.
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Affiliation(s)
- Michela Coan
- Division of Molecular Oncology, Department of Translational Research, IRCCS CRO Aviano-National Cancer Institute, Via Franco Gallini, 2 33081 Aviano PN, Italy.
| | - Gian Luca Rampioni Vinciguerra
- Division of Molecular Oncology, Department of Translational Research, IRCCS CRO Aviano-National Cancer Institute, Via Franco Gallini, 2 33081 Aviano PN, Italy.
| | - Laura Cesaratto
- Division of Molecular Oncology, Department of Translational Research, IRCCS CRO Aviano-National Cancer Institute, Via Franco Gallini, 2 33081 Aviano PN, Italy.
| | - Emanuela Gardenal
- Azienda Ospedaliera Universitaria Integrata, University of Verona, 37129 Verona, Italy.
| | - Riccardo Bianchet
- Scientific Direction, CRO Aviano Italy, Via Franco Gallini, 2 33081 Aviano, Italy.
| | - Erik Dassi
- Centre for Integrative Biology, University of Trento, 38122 Trento, Italy.
| | - Andrea Vecchione
- Department of clinical and molecular medicine, university of Rome "Sapienza", c/o sant andrea hospital, Via di Grottarossa 1035, 00189 Rome, Italy.
| | - Gustavo Baldassarre
- Division of Molecular Oncology, Department of Translational Research, IRCCS CRO Aviano-National Cancer Institute, Via Franco Gallini, 2 33081 Aviano PN, Italy.
| | - Riccardo Spizzo
- Division of Molecular Oncology, Department of Translational Research, IRCCS CRO Aviano-National Cancer Institute, Via Franco Gallini, 2 33081 Aviano PN, Italy.
| | - Milena Sabrina Nicoloso
- Division of Molecular Oncology, Department of Translational Research, IRCCS CRO Aviano-National Cancer Institute, Via Franco Gallini, 2 33081 Aviano PN, Italy.
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14
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Sui BQ, Zhang CD, Liu JC, Wang L, Dai DQ. HOXB13 expression and promoter methylation as a candidate biomarker in gastric cancer. Oncol Lett 2018; 15:8833-8840. [PMID: 29928325 DOI: 10.3892/ol.2018.8371] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 07/03/2017] [Indexed: 12/16/2022] Open
Abstract
Homeobox b13 (HOXB13) is considered to be a tumor suppressor gene in multiple types of human cancer. The present study aimed to identify the difference in expression of HOXB13 mRNA between gastric cancer (GC) tissues and corresponding non-malignant gastric tissues. The clinical significance of HOXB13 mRNA expression was also assessed in GC and a potential association between HOXB13 mRNA expression and DNA promoter methylation was observed. The expression of HOXB13 mRNA was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and HOXB13 methylation status was assessed by methylation-specific PCR (MSP) in 5 GC cell lines and 85 paired GC and normal gastric tissues. Kaplan-Meier survival curves were used to assess the survival of patients with GC. HOXB13 mRNA expression was significantly lower in primary GC tissues than in corresponding nonmalignant gastric tissues, and decreased HOXB13 expression was associated with poorer differentiation, lymph node metastasis, invasion depth and Tumor-Node-Metastasis (TNM) stage. Kaplan-Meier survival analysis demonstrated that HOXB13 mRNA expression was a significant prognostic indicator of GC patient survival. Furthermore, MSP revealed that the proportion of GC samples with hypermethylated HOXB13 (60.0%, 51/85) was increased compared with the corresponding nonmalignant gastric tissues (11.8%, 10/85). Decreased HOXB13 mRNA expression was due to DNA hypermethylation as following treatment with the DNA methyltransferase inhibitor 5-Aza-dC, HOXB13 expression in the GC MKN-45 cell line was upregulated. The results of the present study indicate that decreased expression of HOXB13 mRNA was associated with tumor differentiation, depth of invasion, lymph node metastases and TNM stage in GC, and it was a significant poor prognostic factor for patients with GC. Aberrant DNA promoter methylation was a crucial reason for the downregulation of HOXB13 mRNA expression.
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Affiliation(s)
- Bai-Qiang Sui
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Chun-Dong Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Ji-Chao Liu
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Lei Wang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
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15
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Elçin AE, Parmaksiz M, Dogan A, Seker S, Durkut S, Dalva K, Elçin YM. Differential gene expression profiling of human adipose stem cells differentiating into smooth muscle-like cells by TGFβ1/BMP4. Exp Cell Res 2017; 352:207-217. [DOI: 10.1016/j.yexcr.2017.02.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/02/2017] [Accepted: 02/05/2017] [Indexed: 12/18/2022]
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16
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Novikova EL, Bakalenko NI, Nesterenko AY, Kulakova MA. Hox genes and animal regeneration. Russ J Dev Biol 2016. [DOI: 10.1134/s106236041604007x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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17
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Almalki SG, Agrawal DK. Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation 2016; 92:41-51. [PMID: 27012163 DOI: 10.1016/j.diff.2016.02.005] [Citation(s) in RCA: 298] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 02/15/2016] [Accepted: 02/25/2016] [Indexed: 11/15/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that represent a promising source for regenerative medicine. MSCs are capable of osteogenic, chondrogenic, adipogenic and myogenic differentiation. Efficacy of differentiated MSCs to regenerate cells in the injured tissues requires the ability to maintain the differentiation toward the desired cell fate. Since MSCs represent an attractive source for autologous transplantation, cellular and molecular signaling pathways and micro-environmental changes have been studied in order to understand the role of cytokines, chemokines, and transcription factors on the differentiation of MSCs. The differentiation of MSC into a mesenchymal lineage is genetically manipulated and promoted by specific transcription factors associated with a particular cell lineage. Recent studies have explored the integration of transcription factors, including Runx2, Sox9, PPARγ, MyoD, GATA4, and GATA6 in the differentiation of MSCs. Therefore, the overexpression of a single transcription factor in MSCs may promote trans-differentiation into specific cell lineage, which can be used for treatment of some diseases. In this review, we critically discussed and evaluated the role of transcription factors and related signaling pathways that affect the differentiation of MSCs toward adipocytes, chondrocytes, osteocytes, skeletal muscle cells, cardiomyocytes, and smooth muscle cells.
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Affiliation(s)
- Sami G Almalki
- Departments of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA
| | - Devendra K Agrawal
- Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, USA.
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18
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Seifert A, Werheid DF, Knapp SM, Tobiasch E. Role of Hox genes in stem cell differentiation. World J Stem Cells 2015; 7:583-595. [PMID: 25914765 PMCID: PMC4404393 DOI: 10.4252/wjsc.v7.i3.583] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 11/20/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Hox genes are an evolutionary highly conserved gene family. They determine the anterior-posterior body axis in bilateral organisms and influence the developmental fate of cells. Embryonic stem cells are usually devoid of any Hox gene expression, but these transcription factors are activated in varying spatial and temporal patterns defining the development of various body regions. In the adult body, Hox genes are among others responsible for driving the differentiation of tissue stem cells towards their respective lineages in order to repair and maintain the correct function of tissues and organs. Due to their involvement in the embryonic and adult body, they have been suggested to be useable for improving stem cell differentiations in vitro and in vivo. In many studies Hox genes have been found as driving factors in stem cell differentiation towards adipogenesis, in lineages involved in bone and joint formation, mainly chondrogenesis and osteogenesis, in cardiovascular lineages including endothelial and smooth muscle cell differentiations, and in neurogenesis. As life expectancy is rising, the demand for tissue reconstruction continues to increase. Stem cells have become an increasingly popular choice for creating therapies in regenerative medicine due to their self-renewal and differentiation potential. Especially mesenchymal stem cells are used more and more frequently due to their easy handling and accessibility, combined with a low tumorgenicity and little ethical concerns. This review therefore intends to summarize to date known correlations between natural Hox gene expression patterns in body tissues and during the differentiation of various stem cells towards their respective lineages with a major focus on mesenchymal stem cell differentiations. This overview shall help to understand the complex interactions of Hox genes and differentiation processes all over the body as well as in vitro for further improvement of stem cell treatments in future regenerative medicine approaches.
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19
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Yang J, McNamara LE, Gadegaard N, Alakpa EV, Burgess KV, Meek RMD, Dalby MJ. Nanotopographical induction of osteogenesis through adhesion, bone morphogenic protein cosignaling, and regulation of microRNAs. ACS NANO 2014; 8:9941-53. [PMID: 25227207 DOI: 10.1021/nn504767g] [Citation(s) in RCA: 114] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
It is emerging that nanotopographical information can be used to induce osteogenesis from mesenchymal stromal cells from the bone marrow, and it is hoped that this nanoscale bioactivity can be utilized to engineer next generation implants. However, the osteogenic mechanism of surfaces is currently poorly understood. In this report, we investigate mechanism and implicate bone morphogenic protein (BMP) in up-regulation of RUNX2 and show that RUNX2 and its regulatory miRNAs are BMP sensitive. Our data demonstrate that osteogenic nanotopography promotes colocalization of integrins and BMP2 receptors in order to enhance osteogenic activity and that vitronectin is important in this interface. This provides insight that topographical regulation of adhesion can have effects on signaling cascades outside of cytoskeletal signaling and that adhesions can have roles in augmenting BMP signaling.
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Affiliation(s)
- Jingli Yang
- Centre for Cell Engineering, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, Joseph Black Building, University of Glasgow , Glasgow, G12 8QQ, U.K
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20
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Zaina S, Heyn H, Carmona FJ, Varol N, Sayols S, Condom E, Ramírez-Ruz J, Gomez A, Gonçalves I, Moran S, Esteller M. DNA methylation map of human atherosclerosis. ACTA ACUST UNITED AC 2014; 7:692-700. [PMID: 25091541 DOI: 10.1161/circgenetics.113.000441] [Citation(s) in RCA: 182] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Epigenetic alterations may contribute to the development of atherosclerosis. In particular, DNA methylation, a reversible and highly regulated DNA modification, could influence disease onset and progression because it functions as an effector for environmental influences, including diet and lifestyle, both of which are risk factors for cardiovascular diseases. METHODS AND RESULTS To address the role of DNA methylation changes in atherosclerosis, we compared a donor-matched healthy and atherosclerotic human aorta sample using whole-genome shotgun bisulfite sequencing. We observed that the atherosclerotic portion of the aorta was hypermethylated across many genomic loci in comparison with the matched healthy counterpart. Furthermore, we defined specific loci of differential DNA methylation using a set of donor-matched aortic samples and a high-density (>450 000 CpG sites) DNA methylation microarray. The functional importance in the disease was corroborated by crossing the DNA methylation signature with the corresponding expression data of the same samples. Among the differentially methylated CpGs associated with atherosclerosis onset, we identified genes participating in endothelial and smooth muscle functions. These findings provide new clues toward a better understanding of the molecular mechanisms of atherosclerosis. CONCLUSIONS Our data identify an atherosclerosis-specific DNA methylation profile that highlights the contribution of different genes and pathways to the disorder. Interestingly, the observed gain of DNA methylation in the atherosclerotic lesions justifies efforts to develop DNA demethylating agents for therapeutic benefit.
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Affiliation(s)
- Silvio Zaina
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
| | - Holger Heyn
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - F Javier Carmona
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - Nuray Varol
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - Sergi Sayols
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - Enric Condom
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - José Ramírez-Ruz
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - Antonio Gomez
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - Isabel Gonçalves
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - Sebastian Moran
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.)
| | - Manel Esteller
- From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
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Schellenberg A, Joussen S, Moser K, Hampe N, Hersch N, Hemeda H, Schnitker J, Denecke B, Lin Q, Pallua N, Zenke M, Merkel R, Hoffmann B, Wagner W. Matrix elasticity, replicative senescence and DNA methylation patterns of mesenchymal stem cells. Biomaterials 2014; 35:6351-8. [PMID: 24824582 DOI: 10.1016/j.biomaterials.2014.04.079] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 04/22/2014] [Indexed: 12/28/2022]
Abstract
Matrix elasticity guides differentiation of mesenchymal stem cells (MSCs) but it is unclear if these effects are only transient - while the cells reside on the substrate - or if they reflect persistent lineage commitment. In this study, MSCs were continuously culture-expanded in parallel either on tissue culture plastic (TCP) or on polydimethylsiloxane (PDMS) gels of different elasticity to compare impact on replicative senescence, in vitro differentiation, gene expression, and DNA methylation (DNAm) profiles. The maximal number of cumulative population doublings was not affected by matrix elasticity. Differentiation towards adipogenic and osteogenic lineage was increased on soft and rigid biomaterials, respectively - but this propensity was no more evident if cells were transferred to TCP. Global gene expression profiles and DNAm profiles revealed relatively few differences in MSCs cultured on soft or rigid matrices. Furthermore, only moderate DNAm changes were observed upon culture on very soft hydrogels of human platelet lysate. Our results support the notion that matrix elasticity influences cellular behavior while the cells reside on the substrate, but it does not have major impact on cell-intrinsic lineage determination, replicative senescence or DNAm patterns.
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Affiliation(s)
- Anne Schellenberg
- Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 20, Aachen 52074, Germany
| | - Sylvia Joussen
- Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 20, Aachen 52074, Germany
| | - Kristin Moser
- Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 20, Aachen 52074, Germany; Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Jülich 52425, Germany
| | - Nico Hampe
- Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Jülich 52425, Germany
| | - Nils Hersch
- Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Jülich 52425, Germany
| | - Hatim Hemeda
- Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 20, Aachen 52074, Germany
| | - Jan Schnitker
- Institute of Complex Systems, ICS-8: Bioelectronics, Forschungszentrum Jülich GmbH, Jülich 52425, Germany
| | - Bernd Denecke
- Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University Medical School, 52074 Aachen, Germany
| | - Qiong Lin
- Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 20, Aachen 52074, Germany; Institute for Biomedical Technology - Cell Biology, RWTH Aachen University Medical School, Aachen, Germany
| | - Norbert Pallua
- Department of Plastic and Reconstructive Surgery, RWTH Aachen University Medical School, 52074 Aachen, Germany
| | - Martin Zenke
- Institute for Biomedical Technology - Cell Biology, RWTH Aachen University Medical School, Aachen, Germany
| | - Rudolf Merkel
- Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Jülich 52425, Germany
| | - Bernd Hoffmann
- Institute of Complex Systems, ICS-7: Biomechanics, Forschungszentrum Jülich GmbH, Jülich 52425, Germany
| | - Wolfgang Wagner
- Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Pauwelsstrasse 20, Aachen 52074, Germany.
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22
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Wang HD, Hou QF, Guo QN, Li T, Wu D, Zhang XP, Chu Y, He M, Xiao H, Guo LJ, Yang K, Liao SX, Zhu BF. DNA methylation study of fetus genome through a genome-wide analysis. BMC Med Genomics 2014; 7:18. [PMID: 24731722 PMCID: PMC3996908 DOI: 10.1186/1755-8794-7-18] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Accepted: 04/10/2014] [Indexed: 01/15/2023] Open
Abstract
Background DNA methylation is a crucial epigenetic modification of the genome which is involved in embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, DNA methylation has been demonstrated to be required for vertebrate early embryogenesis and essential for regulating temporal and spatial expression of genes controlling cell fate and differentiation. Further studies have shown that abnormal DNA methylation is associated with human diseases including the embryonic development diseases. We attempt to study the DNA methylation status of CpG islands in fetus related to fetus growth and development. Methods GeneChip® Human Tiling 2.0R Array set is used for analysis of methylated DNA in a whole-genome wide in 8 pairs amniotic fluid and maternal blood DNA samples. Results We found 1 fetus hypermethylation DNA markers and 4 fetus hypomethylation DNA markers though a Genome-wide analysis. These DNA markers all found to be associated with the critical genes for fetus growth and development (SH2D3C gene, EML3 gene, TRIM71 gene, HOXA3 gene and HOXA5 gene). Conclusions These genes can be used as a biomarker for association studying of embryonic development, pathological pregnancy and so on. The present study has provided new and fundamental insights into the roles that DNA methylation has in embryonic development and in the pathological pregnancy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Shi-Xiu Liao
- Medical Genetic Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, PR China.
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23
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Li J, Dong J, Zhang ZH, Zhang DC, You XY, Zhong Y, Chen MS, Liu SM. miR-10a restores human mesenchymal stem cell differentiation by repressing KLF4. J Cell Physiol 2014; 228:2324-36. [PMID: 23696417 PMCID: PMC4285942 DOI: 10.1002/jcp.24402] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 05/07/2013] [Indexed: 12/20/2022]
Abstract
miRNAs have recently been shown to play a significant role in human aging. However, data demonstrating the effects of aging-related miRNAs in human mesenchymal stem cells (hMSCs) are limited. We observed that hMSC differentiation decreased with aging. We also identified that miR-10a expression was significantly decreased with age by comparing the miRNA expression of hMSCs derived from young and aged individuals. Therefore, we hypothesized that the downregulation of miR-10a may be associated with the decreased differentiation capability of hMSCs from aged individuals. Lentiviral constructs were used to up- or downregulate miR-10a in young and old hMSCs. Upregulation of miR-10a resulted in increased differentiation to adipogenic, osteogenic, and chondrogenic lineages and in reduced cell senescence. Conversely, downregulation of miR-10a resulted in decreased cell differentiation and increased cell senescence. A chimeric luciferase reporter system was generated, tagged with the full-length 3′-UTR region of KLF4 harboring the seed-matched sequence with or without four nucleotide mutations. These constructs were cotransfected with the miR-10a mimic into cells. The luciferase activity was significantly repressed by the miR-10a mimic, proving the direct binding of miR-10a to the 3′-UTR of KLF4. Direct suppression of KLF4 in aged hMSCs increased cell differentiation and decreased cell senescence. In conclusion, miR-10a restores the differentiation capability of aged hMSCs through repression of KLF4. Aging-related miRNAs may have broad applications in the restoration of cell dysfunction caused by aging. J. Cell. Physiol. 228: 2324–2336, 2013. © The Authors. Published by Wiley Periodicals, Inc.
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Affiliation(s)
- Jiao Li
- Department of Cardiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China
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Bronckaers A, Hilkens P, Martens W, Gervois P, Ratajczak J, Struys T, Lambrichts I. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther 2014; 143:181-96. [PMID: 24594234 DOI: 10.1016/j.pharmthera.2014.02.013] [Citation(s) in RCA: 261] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 12/30/2013] [Indexed: 12/16/2022]
Abstract
Mesenchymal stem cells or multipotent stromal cells (MSCs) have initially captured attention in the scientific world because of their differentiation potential into osteoblasts, chondroblasts and adipocytes and possible transdifferentiation into neurons, glial cells and endothelial cells. This broad plasticity was originally hypothesized as the key mechanism of their demonstrated efficacy in numerous animal models of disease as well as in clinical settings. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly caused by the multitude of bioactive molecules secreted by these remarkable cells. Numerous angiogenic factors, growth factors and cytokines have been discovered in the MSC secretome, all have been demonstrated to alter endothelial cell behavior in vitro and induce angiogenesis in vivo. As a consequence, MSCs have been widely explored as a promising treatment strategy in disorders caused by insufficient angiogenesis such as chronic wounds, stroke and myocardial infarction. In this review, we will summarize into detail the angiogenic factors found in the MSC secretome and their therapeutic mode of action in pathologies caused by limited blood vessel formation. Also the application of MSC as a vehicle to deliver drugs and/or genes in (anti-)angiogenesis will be discussed. Furthermore, the literature describing MSC transdifferentiation into endothelial cells will be evaluated critically.
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Affiliation(s)
- Annelies Bronckaers
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
| | - Petra Hilkens
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Wendy Martens
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Pascal Gervois
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Jessica Ratajczak
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Tom Struys
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
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25
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Novikova EL, Bakalenko NI, Nesterenko AY, Kulakova MA. Expression of Hox genes during regeneration of nereid polychaete Alitta (Nereis) virens (Annelida, Lophotrochozoa). EvoDevo 2013; 4:14. [PMID: 23638687 PMCID: PMC3667000 DOI: 10.1186/2041-9139-4-14] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 02/05/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hox genes are the key determinants of different morphogenetic events in all bilaterian animals. These genes are probably responsible for the maintenance of regenerative capacities by providing positional information in the regenerating animal body. Polychaetes are well known for their ability to regenerate the posterior as well as the anterior part of the body. We have recently described the expression of 10 out of 11 Hox genes during postlarval growth of Alitta (Nereis) virens. Hox genes form gradient overlapping expression patterns, which probably do not contribute to the morphological diversity of segments along the anterior-posterior axis of the homonomously segmented worm. We suggest that this gradient expression of Hox genes establishes positional information along the body that can be used to maintain coordinated growth and regeneration. RESULTS We showed that most of the Hox gene expression patterns are reorganized in the central nervous system, segmental ectoderm and mesoderm. The reorganization takes place long before regeneration becomes apparent. The most rapid reorganization was observed for the genes with the largest differences in expression levels in the amputation site and the terminal structures (pygidium and growth zone). Moreover, we revealed the expression of two antisense Hox RNAs (Nvi-antiHox5 and Nvi-antiHox7) demonstrating unique expression patterns during regeneration. CONCLUSIONS Hox genes probably participate in the maintenance and restoration of the positional information in A. virens. During postlarval growth and regeneration, Hox genes do not alter the diversity of segments but provide the positional information along the anterior-posterior axis. The reorganization of at least some Hox gene patterns during regeneration may be regulated by their anti-sense transcripts, providing a rapid response of Hox gene transcripts to positional failure. The capacity of Hox genes to maintain the positional information in the adult body is present in different bilaterian animals (planarias, polychaetes and mammals) and might be an ancestral function inherited from the common evolutionary remote ancestor.
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Affiliation(s)
- Elena L Novikova
- Department of Embryology, Laboratory of Experimental Embryology, Saint-Petersburg State University, Oranienbaumskoe sh., 2, Petergof, Saint Petersburg, Russia
| | - Nadezhda I Bakalenko
- Department of Embryology, Laboratory of Experimental Embryology, Saint-Petersburg State University, Oranienbaumskoe sh., 2, Petergof, Saint Petersburg, Russia
| | - Alexander Y Nesterenko
- Department of Embryology, Laboratory of Experimental Embryology, Saint-Petersburg State University, Oranienbaumskoe sh., 2, Petergof, Saint Petersburg, Russia
| | - Milana A Kulakova
- Department of Embryology, Laboratory of Experimental Embryology, Saint-Petersburg State University, Oranienbaumskoe sh., 2, Petergof, Saint Petersburg, Russia
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26
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Vila OF, Bagó JR, Navarro M, Alieva M, Aguilar E, Engel E, Planell J, Rubio N, Blanco J. Calcium phosphate glass improves angiogenesis capacity of poly(lactic acid) scaffolds and stimulates differentiation of adipose tissue-derived mesenchymal stromal cells to the endothelial lineage. J Biomed Mater Res A 2012; 101:932-41. [PMID: 22962041 DOI: 10.1002/jbm.a.34391] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 07/13/2012] [Accepted: 07/30/2012] [Indexed: 12/17/2022]
Abstract
The angiogenic capacity of a new biomaterial composite of poly(lactic acid) and calcium phosphate glass (PLA/CaP) was analyzed by noninvasive bioluminescence imaging (BLI) and histological procedures. Human adipose tissue-derived mesenchymal stromal cells expressing cytomegalovirus (CMV) promoter regulated Photinus pyralis luciferase (hAMSC-PLuc) grew up to 30 times the initial cell load, in vitro, when seeded in PLA/CaP scaffolds, but suffered an initial growth crisis followed by recovery when the scaffolds were subcutaneously implanted in SCID mice. To analyze changes in gene expression, hAMSC-PLuc cells were double labeled with a CMV promoter regulated Renilla reniformis luciferase and a Photinus pyralis luciferase reporter regulated by either the PECAM promoter or a hypoxia response element (HRE) artificial promoter and seeded in PLA/CaP and PLA scaffolds implanted in SCID mice. Analysis by BLI showed that hAMSCs in scaffolds were induced to differentiate to the endothelial lineage and did this faster in PLA/CaP than in PLA scaffolds. Endothelial differentiation correlated with a decrease in the activity of HRE regulated luciferase expression, indicative of a reduction of hypoxia. Histological analysis showed that PLA/CaP scaffolds were colonized by a functional host vascular system. Moreover, colonization by isolectin B(4) positive host cells was more effective in PLA/CaP than in PLA scaffolds, corroborating BLI results.
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Affiliation(s)
- Olaia F Vila
- Cardiovascular Research Center (CSIC-ICCC-UAB), Barcelona, Spain
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27
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Abstract
The members of the HOX transcription factor family are important basic regulators of morphogenesis and development and several HOX proteins have also been identified as essential regulators of physiological and pathologic angiogenesis. HOXC9 is highly expressed in quiescent endothelial cells and keeps the vasculature in a resting state via inhibition of interleukin-8 production. HOXC9 overexpression in zebra-fish negatively regulated vascular development which can be rescued by exogenous interleukin-8. The further understanding of the HOXC9-IL-8 signaling axis and the identification of other HOXC9 targets in the vasculature will provide important insights into mechanisms promoting endothelial cell activation during physiological angiogenesis. It will also be beneficial to understand pathophysiological angiogenesis regulation and thus provide important new directions for the development of novel anti-angiogenic therapeutic strategies.
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Verret V, Namur J, Ghegediban SH, Wassef M, Moine L, Bonneau M, Pelage JP, Laurent A. Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study. Cardiovasc Intervent Radiol 2012; 36:204-12. [DOI: 10.1007/s00270-012-0369-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 02/08/2012] [Indexed: 02/08/2023]
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Stoll SJ, Bartsch S, Augustin HG, Kroll J. The Transcription Factor HOXC9 Regulates Endothelial Cell Quiescence and Vascular Morphogenesis in Zebrafish via Inhibition of Interleukin 8. Circ Res 2011; 108:1367-77. [DOI: 10.1161/circresaha.111.244095] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Sandra J. Stoll
- From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (S.J.S., S.B., H.G.A., J.K.); and Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany (S.J.S., H.G.A., J.K.)
| | - Susanne Bartsch
- From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (S.J.S., S.B., H.G.A., J.K.); and Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany (S.J.S., H.G.A., J.K.)
| | - Hellmut G. Augustin
- From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (S.J.S., S.B., H.G.A., J.K.); and Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany (S.J.S., H.G.A., J.K.)
| | - Jens Kroll
- From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (S.J.S., S.B., H.G.A., J.K.); and Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany (S.J.S., H.G.A., J.K.)
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Zhu MH, Dong WB, Dong GY, Zhang P, Chen YJ, Wu BL, Han H. Disturbed tooth germ development in the absence of MINT in the cultured mouse mandibular explants. Mol Biol Rep 2011; 38:777-84. [PMID: 20393883 DOI: 10.1007/s11033-010-0166-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2009] [Accepted: 03/30/2010] [Indexed: 10/19/2022]
Abstract
The Msx2-interacting nuclear target protein (MINT) is a nuclear matrix protein that regulates the development of many tissues. However, little is known regarding the role of MINT in tooth development. In this study, we prepared polyclonal antibodies against MINT, and found that that MINT was expressed in different cells at each stage of tooth germ development by immunohistochemistry. The role of MINT in tooth development was further illustrated by the misshapen and severely hypoplastic tooth organ in the cultured mandibular explants of MINT deficient mice. From the initiation to cap stage, the differences between mutants and wild-type molars were more and more distinguished histologically. In the MINT-deficient mandibular explants, the tooth germ was reduced in the overall size and lacked enamel knot, with abnormal dental lamina and collapsed stellate reticulum. Furthermore, the BrdU incorporation experiment showed that the proliferation activity was significantly reduced in MINT-deficient dental epithelium. Our results suggest that MINT plays an important role in tooth development, in particular, epithelial morphogenesis.
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Affiliation(s)
- Ming-Hui Zhu
- Department of General and Emergency Dentistry, College of Stomatology, Xian, China
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Mahdipour E, Mace KA. Hox transcription factor regulation of adult bone-marrow-derived cell behaviour during tissue repair and regeneration. Expert Opin Biol Ther 2011; 11:1079-90. [PMID: 21513461 DOI: 10.1517/14712598.2011.579096] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Bone marrow offers a valuable source of stem/progenitor cells that contribute to the repair of injured tissues. Failure in the function of these cells results in delayed or reduced tissue repair. Identification of factors that can correct these defects is critical to treating the underlying dysfunction. Notably, homeobox (Hox) transcription factors have been identified as having significant effects on BMDC behaviour, including differentiation, migration and adhesion in injured tissue, and may provide a basis for future therapies. AREAS COVERED Hox protein regulation of bone-marrow-derived cell (BMDC) differentiation, factors that influence BMDC behaviour in response to injury, the effects of the diabetic environment on BMDCs, methods that can be used to reprogramme BMDCs, and the use of Hox transcription factors to correct BMDC behaviour. EXPERT OPINION Hox gene therapy has been successfully employed to change cell behaviour using ex vivo 'reprogramming' strategies overexpressing selected Hox genes in BMDCs to direct the fate of these cells to the desired cell type, promoting tissue repair.
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Affiliation(s)
- Elahe Mahdipour
- University of Manchester, Healing Foundation Centre, Faculty of Life Sciences, Oxford Road, Manchester M13 9PT, UK
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Bahrami SB, Veiseh M, Dunn AA, Boudreau NJ. Temporal changes in Hox gene expression accompany endothelial cell differentiation of embryonic stem cells. Cell Adh Migr 2011; 5:133-41. [PMID: 21200152 DOI: 10.4161/cam.5.2.14373] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In pluripotent embryonic stem cells (ESCs), expression of the Hox master regulatory transcription factors that play essential roles in organogenesis, angiogenesis, and maintenance of differentiated tissues, is globally suppressed. We investigated whether differentiation of endothelial cells (ECs) from mouse ESCs was accompanied by activation of distinct Hox gene expression profiles. Differentiation was observed within 3 days, as indicated by the appearance of cells expressing specific endothelial marker genes (Flk-1+ /VE-Cadherin+ ). Expression of HoxA3 and HoxD3, which drive adult endothelial cell invasion and angiogenesis, peaked at day 3 and declined thereafter, whereas expression of HoxA5 and HoxD10, which maintain a mature quiescent EC phenotype, was low at day 3, but increased over time. The temporal and reciprocal changes in HoxD3 and HoxA5 expression were accompanied by corresponding changes in expression of established downstream target genes including integrin β3 and Thrombospondin-2. Our results indicate that differentiation and maturation of ECs derived from cultured ESCs mimic changes in Hox gene expression that accompany maturation of immature angiogenic endothelium into differentiated quiescent endothelium in vivo.
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Affiliation(s)
- S Bahram Bahrami
- Department of Surgery; University of California-San Francisco, CA, USA
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Whyte JL, Ball SG, Shuttleworth CA, Brennan K, Kielty CM. Density of human bone marrow stromal cells regulates commitment to vascular lineages. Stem Cell Res 2011; 6:238-50. [PMID: 21420373 PMCID: PMC3223522 DOI: 10.1016/j.scr.2011.02.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 02/04/2011] [Accepted: 02/09/2011] [Indexed: 02/06/2023] Open
Abstract
Mechanisms underlying the vascular differentiation of human bone marrow stromal cells (HBMSCs) and their contribution to neovascularisation are poorly understood. We report the essential role of cell density-induced signals in directing HBMSCs along endothelial or smooth muscle lineages. Plating HBMSCs at high density rapidly induced Notch signaling, which initiated HBMSC commitment to a vascular progenitor cell population expressing markers for both vascular lineages. Notch also induced VEGF-A, which inhibited vascular smooth muscle commitment while consolidating differentiation to endothelial cells with cobblestone morphology and characteristic endothelial markers and functions. These mechanisms can be exploited therapeutically to regulate HBMSCs during neovascularisation.
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Affiliation(s)
| | | | | | | | - Cay M. Kielty
- Corresponding author at: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK. Fax: +44 161 275 5082.
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Hou NY, Yang K, Chen T, Chen XZ, Zhang B, Mo XM, Hu JK. CD133+ CD44+ subgroups may be human small intestinal stem cells. Mol Biol Rep 2011; 38:997-1004. [PMID: 20526812 DOI: 10.1007/s11033-010-0195-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 05/22/2010] [Indexed: 02/05/2023]
Abstract
The identification and separation of small intestinal epithelial stem cells are still on the preliminary stage. In this study, we planned to utilize immunohistochemistry, fluorescence-activated cell sorting (FACS) and RT-PCR to investigate the possibility of CD133 and CD44 as markers of human small intestinal epithelial stem cells. The expressions of CD133, CD44 and Lgr5 were studied by immunohistochemistry. Four subgroups of CD133(+)CD44(+), CD133(+)CD44(-), CD133(-)CD44(+), CD133(-)CD44(-) were sorted out through FACS and the expression level of Lgr5 gene was measured by RT-PCR and polyacrylamide gel electrophoresis (PAGE) with silver stained. Ten cases of samples were available for analyzing. By immunohistochemical staining, few cells with positive expressions of CD133, CD44 and Lgr5 were distributed in the bottom of crypts with the expression locations somewhat overlapped. The average percentage of CD133(+)CD44(+) cells was 0.0580 ± 0.0403%, while the corresponding contents of CD133(+)CD44(-) cells, CD133(-)CD44(+) cells and CD133(-)CD44(-) cells were 0.4000 ± 0.1225%, 0.7000 ± 0.2646% and 76.5600 ± 3.5529% respectively. Ten times of positive expressions of Lgr5 were detected in the CD133(+)CD44(+) groups, while 9/10, 8/10 and 4/10 times for CD133(+)CD44(-), CD133(-)CD44(+) and CD133(-)CD44(-) subgroups respectively. With the help of Quantityone 4.62 software, the densities of corresponding place to Lgr5 and reference gene were obtained. The density ratios of corresponding place to Lgr5 to reference gene were significant difference between subgroups (P < 0.001). By means of LSD method, the density ratios in CD133(+)CD44(+) subgroups had statistical differences from the other subgroups (P < 0.05). We concluded CD133(+)CD44(+) cells may be human small intestinal epithelial stem cells, which need further researches to confirm.
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Affiliation(s)
- Neng-Yi Hou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan Province, People's Republic of China
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Hoxa3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic Gr-1+CD11b+ myeloid cells. Blood 2010; 117:815-26. [PMID: 20974673 DOI: 10.1182/blood-2009-12-259549] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Injury induces the recruitment of bone marrow-derived cells (BMDCs) that contribute to the repair and regeneration process. The behavior of BMDCs in injured tissue has a profound effect on repair, but the regulation of BMDC behavior is poorly understood. Aberrant recruitment/retention of these cells in wounds of diabetic patients and animal models is associated with chronic inflammation and impaired healing. BMD Gr-1(+)CD11b(+) cells function as immune suppressor cells and contribute significantly to tumor-induced neovascularization. Here we report that Gr-1(+)CD11b(+) cells also contribute to injury-induced neovascularization, but show altered recruitment/retention kinetics in the diabetic environment. Moreover, diabetic-derived Gr-1(+)CD11b(+) cells fail to stimulate neovascularization in vivo and have aberrant proliferative, chemotaxis, adhesion, and differentiation potential. Previously we demonstrated that gene transfer of HOXA3 to wounds of diabetic mice is taken up by and expressed by recruited BMDCs. This is associated with a suppressed inflammatory response, enhanced neovascularization, and accelerated wound healing. Here we show that sustained expression of Hoxa3 in diabetic-derived BMD Gr-1(+)CD11b(+) cells reverses their diabetic phenotype. These findings demonstrate that manipulation of adult stem/progenitor cells ex vivo could be used as a potential therapy in patients with impaired wound healing.
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Vascular endothelial growth factor stimulates osteoblastic differentiation of cultured human periosteal-derived cells expressing vascular endothelial growth factor receptors. Mol Biol Rep 2010; 38:1443-50. [DOI: 10.1007/s11033-010-0249-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2009] [Accepted: 09/02/2010] [Indexed: 10/19/2022]
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Discovery of a pyrazole derivative promoting angiogenesis through modulating reactive oxygen species and interferon-inducible protein 10 levels. Mol Biol Rep 2010; 38:1491-7. [DOI: 10.1007/s11033-010-0256-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2010] [Accepted: 09/02/2010] [Indexed: 01/01/2023]
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Recombinant expression of human nerve growth factor beta in rabbit bone marrow mesenchymal stem cells. Mol Biol Rep 2010; 37:4083-90. [DOI: 10.1007/s11033-010-0068-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Accepted: 03/05/2010] [Indexed: 10/19/2022]
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Ciura J, Jagodziński PP. Butyrate increases the formation of anti-angiogenic vascular endothelial growth factor variants in human lung microvascular endothelial cells. Mol Biol Rep 2010; 37:3729-34. [PMID: 20213511 DOI: 10.1007/s11033-010-0026-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Accepted: 02/24/2010] [Indexed: 11/30/2022]
Abstract
The primary transcript of vascular endothelial growth factor (VEGF) can be alternatively spliced and translated to pro-angiogenic and anti-angiogenic VEGF variants. We investigated the effect of sodium butyrate (NaB) on pro-angiogenic and anti-angiogenic VEGF variants production in immortalized human lung microvascular endothelial cells (HLMEC). These cells were cultured in the absence or in the presence of NaB, followed by total RNA and protein isolation. The transcript and protein levels of pro-angiogenic and anti-angiogenic VEGF variants were evaluated by reverse transcription, real-time quantitative PCR and western blot analysis. We found that NaB significantly increased the anti-angiogenic transcript and protein levels of the VEGF 121b, VEGF165b and VEGF189b variants in HLMEC cells. We did not find the pro-angiogenic VEGF189a transcript variant either in control or NaB treated cells. By contrast, the pro-angiogenic VEGF121a and VEGF165a transcript variants were present in HLMEC cells, but their levels were slightly modulated in the cells treated with NaB compared to controls. Since anti-angiogenic VEGF variants inhibit angiogenesis and tumour progression, and NaB is considered an anticancer drug, our findings may have clinical significance.
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Affiliation(s)
- J Ciura
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781, Poznan, Poland
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Todoerti K, Lisignoli G, Storti P, Agnelli L, Novara F, Manferdini C, Codeluppi K, Colla S, Crugnola M, Abeltino M, Bolzoni M, Sgobba V, Facchini A, Lambertenghi-Deliliers G, Zuffardi O, Rizzoli V, Neri A, Giuliani N. Distinct transcriptional profiles characterize bone microenvironment mesenchymal cells rather than osteoblasts in relationship with multiple myeloma bone disease. Exp Hematol 2009; 38:141-53. [PMID: 19963035 DOI: 10.1016/j.exphem.2009.11.009] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Revised: 11/05/2009] [Accepted: 11/24/2009] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Multiple myeloma (MM) is characterized by a high incidence of osteolytic bone lesions, which have been previously correlated with the gene expression profiles of MM cells. The aim of this study was to investigate the transcriptional patterns of cells in the bone microenvironment and their relationships with the presence of osteolysis in MM patients. MATERIALS AND METHODS Both mesenchymal (MSC) and osteoblastic (OB) cells were isolated directly from bone biopsies of MM patients and controls to perform gene expression profiling by microarrays and real-time polymerase chain reaction on selected bone-related genes. RESULTS We identified a series of upregulated and downregulated genes that were differentially expressed in the MSC cells of osteolytic and nonosteolytic patients. Comparison of the osteolytic and nonosteolytic samples also showed that the MSC cells and OB had distinct transcriptional patterns. No significantly modulated genes were found in the OBs of the osteolytic and nonosteolytic patients. CONCLUSIONS Our data suggest that the gene expression profiles of cells of the bone microenvironment are different in MM patients and controls, and that MSC cells, but not OBs, have a distinct transcriptional pattern associated with the occurrence of bone lesions in MM patients. These data support the idea that alterations in MSC cells may be involved in MM bone disease.
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Affiliation(s)
- Katia Todoerti
- Dipartimento di Scienze Mediche, Università di Milano e U.O. Ematologia 1, Fondazione IRCCS Policlinico, Milan, Italy
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