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: 7789467
• 负责人: Joyce E. Bischoff
• 金额: $ 42.88万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789467
• 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; Hemangioma; Human; Immune; Immunodeficient Mouse; In Vitro; Infant; Knowledge; Lead; Lesion; Life; Life Cycle Stages; Measures; Mesenchymal Stem Cells; Modeling; Molecular; Mus; Natural regeneration; Neoplasms in Vascular Tissue; Newborn Infant; Normal Cell; 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; Tissues; Translating; Tumor Angiogenesis; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factors; Wound Healing; base; cell growth; cell type; clinical application; early childhood; in vivo; infancy; insight; novel; prevent; public health relevance; self-renewal; small hairpin RNA; stem cell differentiation; tissue regeneration; 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 By five to eight years of age, most hemangiomas have reached the "involuted phase" at which point the tumor mass has been replaced by a fibrofatty residuum.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，由混乱的血管和未成熟的内皮细胞组成。血管瘤遵循独特的生命周期，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“涉及阶段”，该阶段是在一岁以后开始的。到五到八岁的时候，大多数血管瘤已达到“相关阶段”，这时肿瘤质量已被纤维曲霉残留物取代。因此，婴儿血管瘤是一种人类血管异常，我们可以从中可以从中获得重要的见解，以了解血管的形成方式以及它们如何回归。我们的目标是找到启动IH生长和扩展的细胞，并建立一种密切反映人类血管肿瘤的动物模型。实际上，我们现在已经从30种不同的增殖血管瘤的血管瘤样本中分离出多功能血管瘤干细胞（HEMSC），这些血管瘤从患有危险的血管疾病的婴儿中移除，并证明了它们强大的自我更新能力，多领域的自我更新能力，多光谱差异差异潜力和形成血管瘤样血管在Vivo Invivo Invivo Invivo Invivo Invivo in Vive in In josce in josce in khan khan khan khan khan khan khan khan khan e eT），End n e eT）。总而言之，本文将HEMSC鉴定为婴儿血管瘤的细胞起源，并提供了真正反映这种血管病变的第一个动物模型。我们先前曾分离并研究了血管瘤来源的内皮细胞（HEMEC）和血管瘤衍生的内皮祖细胞（HEMEPC），但是当注射到免疫缺陷型小鼠中时，这些细胞不会形成血管，这表明细胞可能过于区分以至于无法重新调节婴儿血管瘤。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以引起婴儿血管瘤中发生异常血管的形成。我们将为三个具体目标。第一个将集中于HEMSC分化为周细胞，以及EPC对血管瘤血管发育的潜在影响。第二个目标将集中于HEMSC分化为内皮细胞的VEGF-R1。第三个目的是筛选具有抗血管生成活性的FDA批准药物，以便使用我们开发的模型在体外抑制HEMSC生长和血管形成的能力。这三个目的代表了细胞（目标1），分子（目标2）和转化（目标3）方法，以提高我们对血管瘤的理解，并鉴定潜在的药物，以阻止在血甘西马发生的生长和血管形成。此外，这项研究可能与其他血管异常，血管肿瘤和肿瘤血管生成有关。最后，由于这项研究的重点是导致血管形成的机制，因此它可以揭示有关如何使用人血管祖细胞来重建血管网络以进行组织再生的见解。公共卫生相关性：该提案将研究从称为婴儿血管瘤的常见儿童肿瘤中分离出来的干细胞。我们希望了解这些干细胞如何被破坏，因此血管瘤衍生的干细胞并没有遵循正常的健康途径成为正常细胞和组织，而是形成了一系列混乱的血管，这些血管在婴儿期生长巨大。这项研究的结果可能会导致危害血管瘤儿童的新，快速效果和安全的治疗。此外，研究可能会提供对人血管祖细胞行为的基本见解，然后将其应用于使用此类祖细胞进行组织修复和再生的策略，特别是用于建立健康的血管网络。