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: 8248244
• 负责人: Joyce E. Bischoff
• 金额: $ 43.07万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248244
• 关键词: Address; Age; Age-Years; Angiogenesis Inhibitors; Animal Model; Basic Science; Behavior; Benign; Birth; Blood Vessels; Cell Proliferation; Cells; Child; Common Neoplasm; Data; Development; Differentiation and Growth; Drug Delivery Systems; Endothelial Cells; European; Exhibits; FDA approved; Family; Goals; Growth; Health; Hemangioma; Human; Immune; Immunodeficient Mouse; In Vitro; Infant; Knowledge; Lead; Lesion; Life; Life Cycle Stages; Measures; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Neoplasms in Vascular Tissue; Newborn Infant; Normal Cell; Normal tissue morphology; Paper; Pathway interactions; Pediatric Neoplasm; Pericytes; Pharmaceutical Preparations; Phase; Process; Proliferating; Property; Research; Role; Signal Transduction; Smooth Muscle Myocytes; Specimen; Stem cells; Strawberry nevus; Testing; Translating; Tumor Angiogenesis; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factors; base; cell growth; cell type; clinical application; early childhood; in vivo; infancy; insight; novel; prevent; self-renewal; small hairpin RNA; stem cell differentiation; tissue regeneration; tissue repair; transcription factor; tumor

DESCRIPTION (provided by applicant): Infantile hemangioma is a common childhood tumor composed of disorganized blood vessels and immature endothelial cells. Hemangioma follows a unique life-cycle in which the tumor appears soon after birth and grows dramatically during infancy. This "proliferating phase" is followed by a spontaneous but slow "involuting phase" that begins after age one. By five to eight years of age, most hemangiomas have reached the "involuted phase" at which point the tumor mass has been replaced by a fibrofatty residuum. Hence, infantile hemangioma is a human vascular anomaly from which we might gain important insight into how blood vessels are formed and how they regress. Our goal has been to find the cell that initiates growth and expansion of IH and to establish an animal model that closely reflects this human vascular tumor. Indeed, we have now isolated a multi-potent hemangioma stem cell (HemSC) from 30 different proliferating hemangioma specimens removed from infants with endangering hemangiomas, and demonstrated their robust self-renewal capacity, multi- lineage differentiation potential and ability to form hemangioma-like blood vessels in vivo in immunodeficient mice (Khan, Boscolo et al, J Clin Invest. 2008). In summary, this paper identifies the HemSC as the cellular origin of infantile hemangioma and provides the first animal model that truly reflects this vascular lesion. We had previously isolated and studied hemangioma-derived endothelial cells (HemECs) and hemangioma-derived endothelial progenitor cells (HemEPCs) but these cells do not form blood vessels when injected into immune-deficient mice, suggesting that the cells may be too differentiated to recapitulate infantile hemangioma. Our current goal is to further our studies on HemSC and HemEPCs/HemECs and how these cells interact to cause the aberrant vessel formation that occurs in infantile hemangioma. We will purse three specific aims. The first will focus on HemSC differentiation into pericytes and the potential influence of EPCs on hemangioma vessel development. The second aim will focus on VEGF-R1 in HemSC differentiation into endothelial cells. The third aim will be to screen FDA-approved drugs with anti-angiogenic activity for ability to inhibit HemSC growth in vitro and blood vessel formation in vivo using the models we have developed. These three aims represent cellular (Aim 1), molecular (Aim 2) and translational (Aim 3) approaches to advance our understanding of hemangioma and to identify potential drugs that will stop the growth and blood vessel formation that occurs in hemangima. Furthermore, this research may have relevance to other vascular anomalies, vascular tumors and tumor angiogenesis. Finally, because this research focuses on mechanisms leading to blood vessel formation, it may reveal insights into how human vascular progenitor cells can be used to rebuild vascular networks for tissue regeneration. PUBLIC HEALTH RELEVANCE: This proposal will study stem cells isolated from a common childhood tumor known as infantile hemangioma. We hope to understand how and why these stem cells have become disrupted, such that instead of following a normal healthy pathway to become normal cells and tissue, the hemangioma-derived stem cells form a mass of disorganized blood vessels that grows dramatically during infancy. The results from this study may lead to new, fast-acting and safe treatments for children with endangering hemangiomas. In addition, the studies may provide fundamental insights into the behavior of human vascular progenitor cells which could then be applied to strategies to use such progenitor cells for tissue repair and regeneration, and specifically to build healthy vascular networks.

描述(申请人提供)：婴儿血管瘤是一种常见的儿童肿瘤，由紊乱的血管和未成熟的内皮细胞组成。血管瘤有一个独特的生命周期，肿瘤在出生后不久就会出现，并在婴儿期急剧增长。这个“增殖期”之后是一个自发但缓慢的“退化期”，从一岁以后开始。到五到八岁时，大多数血管瘤已经到了“消退期”，此时肿块已经被纤维脂肪残留物所取代。因此，婴儿血管瘤是一种人类血管异常，我们可以从中获得关于血管是如何形成和如何退化的重要见解。我们的目标一直是找到启动IH生长和扩张的细胞，并建立一个接近反映这种人类血管肿瘤的动物模型。事实上，我们现在已经从30个不同的增殖性血管瘤标本中分离出了一种多潜能的血管瘤干细胞(HemSC)，这些标本取自患有危险血管瘤的婴儿，并展示了它们强大的自我更新能力、多系分化潜力以及在免疫缺陷小鼠体内形成血管瘤样血管的能力(Khan，Boscolo等，J Clin Invest)。2008年)。综上所述，本论文认为血管干细胞是婴幼儿血管瘤的细胞起源，并提供了第一个真实反映这一血管病变的动物模型。我们之前已经分离和研究了血管瘤来源的内皮细胞(HemECs)和血管瘤来源的内皮祖细胞(HemEPC)，但这些细胞在注射到免疫缺陷小鼠体内时不能形成血管，这表明这些细胞可能分化过高，无法重现婴儿血管瘤。我们目前的目标是进一步研究血液干细胞和血液内皮祖细胞/血管内皮细胞，以及这些细胞如何相互作用导致婴儿血管瘤中出现的异常血管形成。我们将追求三个具体目标。第一部分将着重于向周细胞分化的研究以及内皮祖细胞对血管瘤血管发育的潜在影响。第二个目标将集中在血管内皮生长因子-R1在血管内皮细胞分化中的作用。第三个目标是利用我们开发的模型筛选FDA批准的具有抗血管生成活性的药物，以了解其在体外抑制血液干细胞生长和体内血管形成的能力。这三个目标分别代表细胞(目标1)、分子(目标2)和翻译(目标3)方法，以促进我们对血管瘤的理解，并确定将阻止血管生长和血管形成的潜在药物。此外，本研究还可能与其他血管畸形、血管肿瘤和肿瘤血管生成相关。最后，由于这项研究集中在导致血管形成的机制上，它可能会揭示如何利用人类血管前体细胞来重建血管网络，以实现组织再生。与公共卫生相关：这项提案将研究从一种常见的儿童肿瘤--婴儿血管瘤中分离出的干细胞。我们希望了解这些干细胞是如何以及为什么被破坏的，以至于血管瘤来源的干细胞不是沿着正常的健康途径变成正常的细胞和组织，而是形成了一大堆在婴儿期急剧增长的无序血管。这项研究的结果可能会为患有危险血管瘤的儿童带来新的、快速有效和安全的治疗方法。此外，这些研究可能会为人类血管前体细胞的行为提供基本的见解，然后可以应用于利用这些前体细胞进行组织修复和再生的策略，特别是建立健康的血管网络。