Blood vessel assembly from multipotent hemangioma-derived stem cells

来自多能血管瘤干细胞的血管组装

• 批准号: 10609870
• 负责人: Joyce E. Bischoff
• 金额: $ 49.42万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609870
• 关键词: 6 year old; Adipocytes; Adrenergic Antagonists; Benign; Binding; Blood Vessels; Breathing; Cell Separation; Cells; Child; Chromatin; Chromosomal translocation; Copy Number Polymorphism; Corneal Neovascularization; Data; Deformity; Didelphidae; Dimerization; Dominant-Negative Mutation; Endothelial Cells; Endothelium; Face; Funding; Gene Fusion; Genes; Genetic; Genetic Transcription; Goals; Growth; Hemangioendothelioma; Hemangioma; Home; Homo; Human; Hypotrichosis; Immune; Implant; In Vitro; Infant; Kidney; Learning; Life Cycle Stages; Location; Lymphedema; Medical; Methods; Modeling; Molecular; Mus; Mutation; Neoplasms in Vascular Tissue; Nuclear Extract; Nude Mice; Operative Surgical Procedures; Organ; Pathogenesis; Pathologic; Pathway interactions; Patients; Pericytes; Pharmaceutical Preparations; Prevalence; Progress Reports; Propranolol; Publications; Reagent; Role; SOX18 gene; Sampling; Somatic Mutation; Specimen; Strawberry nevus; Structure; Syndrome; Telangiectasis; Testing; Time; Tissues; Transcript; Variant; Vascular Diseases; Vascular Proliferation; Visual impairment; Work; Xenograft Model; beta-adrenergic receptor; bioinformatics tool; blood vessel development; dimer; effective therapy; enantiomer; endothelial stem cell; exome; experimental study; feeding; genome sequencing; human stem cells; improved; in vivo Model; infancy; insight; knock-down; neovascular; neovascularization; next generation sequencing; novel; pharmacologic; prevent; small hairpin RNA; small molecule inhibitor; stem cells; transcription factor; transcriptome sequencing; whole genome

Project Abstract Infantile hemangioma (IH) is a common vascular tumor with a unique lifecycle of rapid blood vessel formation over the first 6-9 months of infancy, followed by a slow spontaneous involution of blood vessels over several years. For most children, IH does not pose a serious threat and therapy is unnecessary; however, in about 10% of cases, IH can enlarge dramatically, threaten organs and cause permanent disfigurement. Over the last 10 years, propranolol, a well-known non-selective β-adrenergic receptor antagonist, has emerged as first-line therapy for endangering IH, yet how and why it works so well in reducing the vascular overgrowth in IH has remained a mystery. There is a significant need to improve propranolol therapy because up to 18% of IHs fail to respond, up to 25% resume growth when the drug is stopped, and 37% of propranolol-treated infants require surgery at 5-6 years of age to minimize deformity caused by remaining fibrofatty residua. To improve on propranolol, it is essential to elucidate it’s mechanism of action against vascular overgrowth, which will then provide a path forward to advance IH medical therapy, and potentially other neovascular diseases as well. In previous funding cycles, we identified a hemangioma stem cell (HemSC) from human IH surgical specimens that can differentiate into endothelial cells, pericytes and adipocytes and form hemangioma-like vessels within 7 days when implanted into immune-deficient mice. Subsequent studies from our lab and others validate HemSCs as the IH-initiating cell. Our recent results show that a small molecule inhibitor of the transcription factor SOX18 and propranolol both effectively block HemSC-to-endothelial differentiation. Furthermore, the R(+) enantiomer of propranolol, which lacks β-adrenergic receptor antagonistic activity, is equally effective. This novel discovery identifies a β-adrenergic receptor-independent, SOX18-dependent mechanism by which propranolol reduces vascular overgrowth in IH. To investigate deeply, we propose three specific aims. Aim 1 will directly and rigorously test the requirement for SOX18 in IH vessel formation using our in vivo model in which IH-derived HemSC form IH-like blood vessels in nude mice. Aim 2 will investigate dimerization status of SOX18 in IH (sub-aim 2a), how propranolol and the R(+) enantiomer disrupt SOX18 dimerization and sub- cellular localization (sub-aim 2b), and how this alters transcription to prevent HemSC-blood vessel formation (sub-aim 2c). Aim 3, conducted in parallel, will analyze our existing next generation sequencing data using new bioinformatic tools to identify potential chromosomal translocations or small copy number variants that could produce fusion transcripts with new activities (sub-aim 3a) and will perform deep coverage RNA-Seq on IH tissue and freshly isolated IH cells as an alternative method to identify fusion transcripts (sub-aim 3b); once identified, the connection to SOX18 and IH vessel formation will tested in in vitro and in vivo models.

项目摘要

项目成果

Endoglin regulates mural cell adhesion in the circulatory system.

• DOI: 10.1007/s00018-015-2099-4
• 发表时间: 2016-04
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Rossi E;Smadja DM;Boscolo E;Langa C;Arevalo MA;Pericacho M;Gamella-Pozuelo L;Kauskot A;Botella LM;Gaussem P;Bischoff J;Lopez-Novoa JM;Bernabeu C
• 通讯作者: Bernabeu C

IGF-2 and FLT-1/VEGF-R1 mRNA levels reveal distinctions and similarities between congenital and common infantile hemangioma.

IGF-2 和 FLT-1/VEGF-R1 mRNA 水平揭示了先天性血管瘤和普通婴儿血管瘤之间的区别和相似之处。

• DOI: 10.1203/pdr.0b013e318163a243
• 发表时间: 2008
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Picard,Arnaud;Boscolo,Elisa;Khan,ZiaA;Bartch,TatiannaC;Mulliken,JohnB;Vazquez,MariePaule;Bischoff,Joyce
• 通讯作者: Bischoff,Joyce

Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells.

• DOI: 10.1002/stem.1841
• 发表时间: 2015-01
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Huang, Lan;Nakayama, Hironao;Klagsbrun, Michael;Mulliken, John B.;Bischoff, Joyce
• 通讯作者: Bischoff, Joyce

Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma.

• DOI: 10.1038/jid.2011.300
• 发表时间: 2011-12
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Greenberger, Shoshana;Yuan, Siming;Walsh, Logan A.;Boscolo, Elisa;Kang, Kyu-Tae;Matthews, Benjamin;Mulliken, John B.;Bischoff, Joyce
• 通讯作者: Bischoff, Joyce

α6-Integrin is required for the adhesion and vasculogenic potential of hemangioma stem cells.

血管瘤干细胞的粘附和血管生成潜力需要α6-整合素。

• DOI: 10.1002/stem.1539
• 发表时间: 2014-03
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Smadja, David M.;Guerin, Coralie L.;Boscolo, Elisa;Bieche, Ivan;Mulliken, John B.;Bischoff, Joyce
• 通讯作者: Bischoff, Joyce