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 By five to eight years of age, most hemangiomas have reached the "involuted phase" at which point the tumor mass has been replaced by a fibrofatty residuum.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（由申请人提供）：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。血管瘤遵循一个独特的生命周期，其中肿瘤在出生后不久出现，并在婴儿期急剧生长。这个“增殖阶段”之后是一个自发但缓慢的“退化阶段”，从一岁开始。到5 - 8岁时，大多数血管瘤已经达到“退化期”，此时肿瘤块已被纤维脂肪残留物取代。因此，婴儿血管瘤是一种人类血管异常，我们可能从中获得重要的洞察力，了解血管是如何形成的，以及它们是如何消退的。我们的目标是找到启动IH生长和扩张的细胞，并建立一种密切反映这种人类血管肿瘤的动物模型。事实上，我们现在已经从从患有危险血管瘤的婴儿中取出的30个不同增殖血管瘤样本中分离了多能血管瘤干细胞（HemSC），并证明了它们强大的自我更新能力、多谱系分化潜力和在免疫缺陷小鼠中体内形成血管瘤样血管的能力（Khan，Bocelo等人，J Clin Invest. 2008年）。总之，本文确定了血管干细胞作为婴幼儿血管瘤的细胞来源，并提供了第一个动物模型，真正反映了这种血管病变。我们先前分离并研究了血管瘤衍生的内皮细胞（HemECs）和血管瘤衍生的内皮祖细胞（HemEPCs），但这些细胞在注射到免疫缺陷小鼠中时不形成血管，这表明这些细胞可能过于分化而无法重现婴儿血管瘤。我们目前的目标是进一步研究HemSC和HemEPCs/HemECs以及这些细胞如何相互作用导致婴儿血管瘤中发生的异常血管形成。我们将追求三个具体目标。第一个将集中在HemSC分化成周细胞和EPCs对血管瘤血管发展的潜在影响。第二个目标将集中在VEGF-R1在HemSC分化为内皮细胞。第三个目标是使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，以抑制体外HemSC生长和体内血管形成。这三个目标代表了细胞（目标1），分子（目标2）和翻译（目标3）的方法，以促进我们对血管瘤的理解，并确定潜在的药物，将停止生长和血管形成发生在血管瘤。此外，该研究可能与其他血管异常、血管性肿瘤和肿瘤血管生成相关。最后，由于这项研究的重点是导致血管形成的机制，它可能揭示人类血管祖细胞如何用于重建组织再生的血管网络。公共卫生相关性：这项提案将研究从一种常见的儿童肿瘤（婴儿血管瘤）中分离出来的干细胞。我们希望了解这些干细胞是如何以及为什么被破坏的，这样血管瘤衍生的干细胞就不会遵循正常的健康途径成为正常的细胞和组织，而是形成了大量杂乱无章的血管，在婴儿期急剧生长。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，快速有效的和安全的治疗方法。此外，这些研究可能为人类血管祖细胞的行为提供基本见解，然后可以应用于使用此类祖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。