Endothelial Plasticity in Human Disease

血管瘤是由不受控制的血管生成形成的血管肿瘤。这些肿瘤病变 出生后大约2周出现，在第二年增殖，然后经历缓慢的 退化期(回归)。尽管在理解分子机制方面取得了一些突破 导致血管瘤进展的增殖期的因素已经取得了进展，但对其原因知之甚少。 这些肿瘤会自然消退。脂肪生成是退化期的一种普遍机制，如 血管组织被脂肪组织取代。然而，对这一过程的分子基础的重大见解 都不存在。我们的长期目标是了解引起血管瘤的机制。 回归。这一知识可能会导致开发治疗血管肿瘤和 其他疾病。我们假设巨噬细胞渗入血管瘤诱导内皮细胞 间充质转化(EndMT)，这些内皮来源的间充质细胞具有多潜能 干细胞样表型，分化为脂肪细胞，介导血管瘤消退。具体目标 包括： 1.确定巨噬细胞是否促进内皮细胞向间充质转化的机制 血管瘤消退。我们怀疑单核细胞趋化蛋白-1的高表达导致了 巨噬细胞转化为消退的血管瘤。我们假设这些巨噬细胞分泌转化生长因子-2，它 会诱导血管瘤内皮细胞经历内皮细胞向间充质细胞的转化。 2.确定由内皮细胞向间充质转化形成的细胞是否具有干细胞表型 在血管瘤消退过程中分化为脂肪细胞。我们假设血管内皮细胞 间充质转化在血管瘤中形成多能干细胞样细胞。我们预测像这样的细胞因子 巨噬细胞分泌IGF-1，诱导这些干细胞分化为脂肪细胞 血管瘤复旧。 3.建立小鼠内皮细胞向间充质细胞转化模型。我们计划生产 多西环素可诱导野生型和突变(成分活性)的ALK2-RFP转基因小鼠 与VE-Caherin-Cre；rosa26-RTTA-EGFP小鼠杂交，选择性诱导和示踪EndMT和 体内随后的细胞分化。这将使我们能够进一步研究EndMT在血管中的作用 体内的退化和其他生理或病理过程。

Hemangiomas are vascular tumors formed by uncontrolled angiogenesis. These neoplastic lesions appear approximately 2 weeks after birth, proliferate over the following year, then subsequently undergo a slow period of involution (regression). Although some breakthroughs in understanding the molecular mechanisms that induce the proliferative phase of hemangioma progression have been made, little is known about why these tumors naturally regress. Adipogenesis is a prevalent mechanism during the involuting phase, as vascular tissue is replaced by fat tissue. However, significant insights into the molecular basis of this process do not exist. Our long-term goal is to gain an understanding of the mechanisms that cause hemangioma regression. This knowledge may lead to development of novel therapies for treatment of vascular tumors and other diseases. We hypothesize that macrophage infiltration into hemangiomas induces endothelial to mesenchymal transition (EndMT), and that these endothelial-derived mesenchymal cells take on a multipotent stem cell-like phenotype and differentiate into adipocytes to mediate hemangioma involution. The specific aims are: 1. To determine whether macrophages promote endothelial to mesenchymal transition as a mechanism of hemangioma regression. We suspect that elevated expression of MCP-1 causes recruitment of macrophages into involuting hemangiomas. We hypothesize that these macrophages secrete TGF-ß2, which will induce hemangioma endothelial cells to undergo endothelial to mesenchymal transition. 2. To determine if cells formed by endothelial to mesenchymal transition acquire a stem cell phenotype and differentiate into adipocytes during hemangioma regression. We hypothesize that endothelial to mesenchymal transition forms multipotent stem-like cells in hemangiomas. We predict that cytokines such as IGF-1 are secreted from macrophages to induce differentiation of these stem-like cells into adipocytes during hemangioma involution. 3. To generate a mouse model of endothelial to mesenchymal transition. We propose to produce doxycycline inducible wild-type and mutant (constitutively active) ALK2-RFP transgenic mice that will be crossed with VE-Cadherin-Cre;Rosa26-rtTA-EGFP mice in order to selectively induce and track EndMT and subsequent cell differentiation in vivo. This will allow us to further investigate the role of EndMT in vascular regression and other physiological or pathological processes in vivo.