Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis.
复制标题
DOI：
10.1371/journal.pcbi.1000549
复制
发表时间：
2009-10
影响因子：
4.3
通讯作者：
Bates PA
中科院分区：
文献类型：
--
作者：
Bentley K;Mariggi G;Gerhardt H;Bates PA
血管异常导致许多疾病，如癌症和糖尿病视网膜病变。在血管生成中，由迁移的尖端细胞领导的新血管响应于信号从预先存在的血管中发芽，例如，血管内皮生长因子（VEGF）。尖端细胞相遇并融合（吻合）形成血流支持环。顶端细胞选择通过Dll 4-Notch介导的侧向抑制实现，在正常条件下，导致顶端和非迁移柄细胞的交错排列。以前，我们发现，在许多疾病中发现的VEGF水平的增加可以导致侧抑制的延迟负反馈，产生异常振荡的尖/柄细胞的命运。在这里，我们描述了一种新的基于物理学的分层代理模型的开发和实现，紧密耦合到体内数据，探索系统动力学永久侧抑制结合尖端细胞迁移和融合。我们探讨了正常和异常发芽之间的临界点，随着VEGF的增加。提出了一种新的丝状伪足粘附驱动的迁移机制，并对体内数据进行了验证。由于正在进行的侧抑制的独特功能，“稳定”的尖端/柄细胞模式显示融合过程中新的细胞-细胞连接的形成的敏感性：我们预测细胞的命运可以逆转。融合的尖端细胞被抑制，邻近的柄细胞翻转命运，递归地提供新的尖端细胞。结的大小出现作为一个关键因素，在建立一个稳定的尖/茎模式。细胞-细胞连接随着尖端细胞的迁移而伸长，这显示出对侧抑制提供正反馈，使其更容易受到病理性振荡的影响。重要的是，单独的迁移途径的下调被证明足以拯救发芽系统振荡和恢复稳定。因此，我们建议使用迁移抑制剂作为癌症血管正常化的治疗剂。异常的脉管系统会加重许多疾病，如癌症和糖尿病视网膜病变。在血管生成过程中，新的血管在迁移的尖端细胞的引导下，响应于化学信号从预先存在的血管中发芽。这些信号是从新缺氧的组织中释放出来的。这些信号在疾病中是不同的，被认为是导致血管生成过程异常进展的原因，尽管其原因尚不清楚。正常化的血管生成具有巨大的潜力作为一种治疗策略，它已被证明可以减少转移和改善药物输送的肿瘤。在这里，我们专注于与组织信号条件的变化相关的三个相互关联的初始血管生成途径的行为，利用在硅片和体内的方法。通过构建和实现一种新的细胞运动和信号处理的计算模型，我们提出了一个新的理论，为什么血管生成表现出这样的敏感性信号的变化，并表明，在疾病中的行为是令人惊讶的比正常功能更强大。我们将此归因于细胞迁移的正反馈增强了细胞命运选择中的异常振荡。我们做出了独特的预测，即正常化可以通过单独减少细胞迁移来实现。
Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, ‘stabilised’ tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer. Abnormal vasculature exacerbates many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to chemical signals. The signals are released from newly oxygen deficient tissue. The signals are known to be different in disease and are thought to cause the process of angiogenesis to progress abnormally, though the reasons for this remain unclear. Normalisation of angiogenesis has great potential as a therapeutic strategy; it has been shown to reduce metastasis and improve drug delivery in tumours. Here we focus on the behaviours of three inter-related initial angiogenic pathways associated with changes in tissue signal conditions, utilising both in silico and in vivo approaches. By the construction and implementation of a novel computational model for cell motility and signal processing we present a new theory on why angiogenesis exhibits such sensitivity to signal changes and show that the behaviour in disease is surprisingly more robust than normal functioning. This we attribute to the positive feedback of cell migration reinforcing abnormal oscillations in cell fate selection. We make the unique prediction that normalisation could be achieved by reducing cell migration alone.
登录
查看更多内容
影响因子：
2.7
作者：
Blum, Yannick;Belting, Heinz-Georg;Affolter, Markus
通讯作者：
Affolter, Markus
DOI：
10.1073/pnas.0702449104
发表时间：
2007-07-10
影响因子：
11.1
作者：
Kress, Holger;Stelzer, Ernst H. K.;Rohrbach, Alexander
通讯作者：
Rohrbach, Alexander
影响因子：
4.8
作者：
Chai, JY;Jones, MK;Tarnawski, AS
通讯作者：
Tarnawski, AS
影响因子：
3.1
作者：
AUSPRUNK, DH;FOLKMAN, J
通讯作者：
FOLKMAN, J
DOI：
10.1126/science.1160617
发表时间：
2008-10-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Brandman O;Meyer T
通讯作者：
Meyer T