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      Cellular Functions and Gene and Protein Expression Profiles in Endothelial Cells Derived from Moyamoya Disease-Specific iPS Cells

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          Abstract

          Background and purpose

          Moyamoya disease (MMD) is a slow, progressive steno-occlusive disease, arising in the terminal portions of the cerebral internal carotid artery. However, the functions and characteristics of the endothelial cells (ECs) in MMD are unknown. We analyzed these features using induced pluripotent stem cell (iPSC)-derived ECs.

          Methods

          iPSC lines were established from the peripheral blood of three patients with MMD carrying the variant RNF213 R4810K, and three healthy persons used as controls. After the endothelial differentiation of iPSCs, CD31 +CD144 + cells were purified as ECs using a cell sorter. We analyzed their proliferation, angiogenesis, and responses to some angiogenic factors, namely VEGF, bFGF, TGF-β, and BMP4. The ECs were also analyzed using DNA microarray and proteomics to perform comprehensive gene and protein expression analysis.

          Results

          Angiogenesis was significantly impaired in MMD regardless of the presence of any angiogenic factor. On the contrary, endothelial proliferation was not significant between control- and MMD-derived cells. Regarding DNA microarray, pathway analysis illustrated that extracellular matrix (ECM) receptor-related genes, including integrin β3, were significantly downregulated in MMD. Proteomic analysis revealed that cytoskeleton-related proteins were downregulated and splicing regulation-related proteins were upregulated in MMD.

          Conclusions

          Downregulation of ECM receptor-related genes may be associated with impaired angiogenic activity in ECs derived from iPSCs from patients with MMD. Upregulation of splicing regulation-related proteins implied differences in splicing patterns between control and MMD ECs.

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          Most cited references16

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          Transmembrane crosstalk between the extracellular matrix--cytoskeleton crosstalk.

          B. Geiger, A Bershadsky, R Pankov … (2001)
          Integrin-mediated cell adhesions provide dynamic, bidirectional links between the extracellular matrix and the cytoskeleton. Besides having central roles in cell migration and morphogenesis, focal adhesions and related structures convey information across the cell membrane, to regulate extracellular-matrix assembly, cell proliferation, differentiation, and death. This review describes integrin functions, mechanosensors, molecular switches and signal-transduction pathways activated and integrated by adhesion, with a unifying theme being the importance of local physical forces.
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            A genome-wide association study identifies RNF213 as the first Moyamoya disease gene.

            Fumiaki Kamada, Yoko Aoki, Ayumi Narisawa … (2011)
            Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although ∼ 15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P = 5.3 × 10(-10)). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P = 1.2 × 10(-43), odds ratio = 190.8, 95% confidence interval = 71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.
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              Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease.

              Tian-da Wang, Seung-Baik Kang, T. J. Kim … (2010)
              To document the expression patterns of various matrixins, cytokines and angiogenic factors in plasma to assess their involvement in the pathogenesis of moyamoya disease (MMD). This study included plasma samples from 20 MMD patients and nine healthy individuals. The plasma concentration of five matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, MMP-12), monocyte chemoattractant protein-1 (MCP-1), resistin, three interleukins (IL-1beta, IL-6, IL-8), tumour necrosis factor-alpha, vascular endothelial growth factor (VEGF), platelet-derived growth factor BB (PDGF-BB) and basic fibroblast growth factor was determined using multianalyte profiling systems. The concentration of the tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) was measured using ELISA. Gelatin zymography for MMP-2 and MMP-9 was also performed. MMD patients exhibited significantly higher plasma concentrations of MMP-9, MCP-1, IL-1beta, VEGF and PDGF-BB, and lower plasma concentrations of MMP-3, TIMP-1 and TIMP-2 compared with healthy controls. Significant correlations were found among MMP-9, MCP-1, VEGF, PDGF-BB and TIMP-2 in MMD patients. There were distinctive expression patterns of matrixins, cytokines and angiogenic factors in MMD patients, which seemed to correlate with disease pathogenesis. The balance between MMPs and TIMPs was disrupted in MMD and correlated with disease pathogenesis. Increased plasma levels of MCP-1 and VEGF in MMD patients may play a role in the recruitment of vascular progenitor cells and in the formation of collateral vessels.
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                Author and article information

                Contributors
                Johnson Rajasingh: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 23 September 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 9
                Electronic Location Identifier: e0163561
                Affiliations
                [1 ]Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
                [2 ]Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
                University of Kansas Medical Center, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: KH HS.

                • Data curation: SH HS TE.

                • Formal analysis: HS TA.

                • Funding acquisition: KH HS.

                • Investigation: SH HS TE.

                • Methodology: SH TE.

                • Project administration: KH HS TE.

                • Resources: KH HS TE.

                • Software: HU SY KK.

                • Supervision: TE HS.

                • Validation: NN TO.

                • Visualization: SY HS.

                • Writing – original draft: SH HS.

                • Writing – review & editing: SH HS TE.

                Article
                Publisher ID: PONE-D-15-53935
                DOI: 10.1371/journal.pone.0163561
                PMC ID: 5035048
                PubMed ID: 27662211
                SO-VID: 4d830a50-06f9-4d84-b5fd-81895520540f
                Copyright © © 2016 Hamauchi et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 31 January 2016
                Date accepted : 11 September 2016
                Page count
                Figures: 6, Tables: 0, Pages: 14
                Funding
                Funded by: Mihara Cerebrovascular Disorder Research Promotion FUnd
                Award Recipient :
                Funded by: SENSHIN Medical Research Fundation
                Award Recipient :
                This work was supported by The 32th Mihara Award (2012) (URLs: http://www.mihara.umin.jp/index.html) and the 2014 SENSHIN Medical Research Foundation (URLs: https://www.smrf.or.jp/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Stem Cells
                Subject: Induced Pluripotent Stem Cells
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Brain Diseases
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Molecular Biology Assays and Analysis Techniques
                Subject: Gene Expression and Vector Techniques
                Subject: Protein Expression
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Molecular Biology Assays and Analysis Techniques
                Subject: Gene Expression and Vector Techniques
                Subject: Protein Expression
                Subject: Research and Analysis Methods
                Subject: Bioassays and Physiological Analysis
                Subject: Microarrays
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Artificial Gene Amplification and Extension
                Subject: Polymerase Chain Reaction
                Subject: Reverse Transcriptase-Polymerase Chain Reaction
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Artificial Gene Amplification and Extension
                Subject: Polymerase Chain Reaction
                Subject: Reverse Transcriptase-Polymerase Chain Reaction
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Cell Differentiation
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Cardiovascular Physiology
                Subject: Angiogenesis
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Cardiovascular Physiology
                Subject: Angiogenesis
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Angiogenesis
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteomics
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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