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 By five to eight years of age, most hemangiomas have reached the "involuted phase" at which point the tumor mass has been replaced by a fibrofatty residuum.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（申请人提供）：婴儿血管瘤是一种常见的儿童肿瘤，由紊乱的血管和不成熟的内皮细胞组成。血管瘤遵循独特的生命周期，肿瘤在出生后不久出现，并在婴儿期急剧生长。这个“增殖期”之后是一岁后开始的自发但缓慢的“退化期”。到五到八岁时，大多数血管瘤已达到“消退期”，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，从中我们可以深入了解血管如何形成以及如何消退。我们的目标是找到启动 IH 生长和扩张的细胞，并建立密切反映这种人类血管肿瘤的动物模型。事实上，我们现在已经从患有危及血管瘤的婴儿身上取出的30个不同的增殖性血管瘤样本中分离出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等人，J Clin Invest.2008）。综上所述，本文将 HemSC 确定为婴儿血管瘤的细胞起源，并提供了第一个真正反映这种血管病变的动物模型。我们之前分离并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（HemEPCs），但这些细胞在注射到免疫缺陷小鼠体内时不会形成血管，这表明这些细胞可能过于分化而无法重现婴儿血管瘤。我们当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。第一个重点是 HemSC 分化为周细胞以及 EPC 对血管瘤血管发育的潜在影响。第二个目标将重点关注 VEGF-R1 在 HemSC 分化为内皮细胞中的作用。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的能力。这三个目标代表细胞（目标 1）、分子（目标 2）和转化（目标 3）方法，以增进我们对血管瘤的了解，并确定阻止血管瘤生长和血管形成的潜在药物。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，因此它可能揭示如何利用人类血管祖细胞重建血管网络以实现组织再生的见解。公共健康相关性：该提案将研究从一种常见的儿童肿瘤（称为婴儿血管瘤）中分离出来的干细胞。我们希望了解这些干细胞如何以及为何被破坏，这样，血管瘤来源的干细胞就不会遵循正常的健康途径成为正常细胞和组织，而是形成大量杂乱的血管，并在婴儿期急剧生长。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、快速起效且安全的治疗方法。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，特别是构建健康的血管网络。