Weinstein Nathan, Mendoza Luis, Álvarez-Buylla Elena R
Instituto de Ecología, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Front Genet. 2020 Mar 12;11:40. doi: 10.3389/fgene.2020.00040. eCollection 2020.
Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.
内皮细胞（ECs）构成淋巴管和血管的内壁。组织需求的变化或伤口可能导致ECs表现为尖端细胞或茎细胞。或者，它们可能分化为间充质细胞（MCs）。这些过程分别被称为EC激活和内皮-间充质转化（EndMT）。EndMT、尖端和茎EC行为都需要SNAI1、SNAI2和基质金属蛋白酶（MMP）的功能。然而，只有EndMT会抑制VE-钙黏蛋白、PECAM1和VEGFR2的表达，还会导致EC脱离。在生理上，EndMT参与心脏瓣膜发育，而EndMT调节缺陷则参与心血管畸形、先天性心脏病、系统性和器官纤维化、肺动脉高压以及动脉粥样硬化的病理生理过程。因此，EndMT的控制在再生医学中有许多有前景的潜在应用。尽管已经鉴定出许多参与EC激活和EndMT的分子成分，但该过程所涉及的系统水平分子机制尚未阐明。为此，我们在此提出参与EC激活和EndMT调节的分子的布尔网络模型。我们模型的模拟动态行为达到了固定和循环的激活模式，这与预期的EC和MC细胞类型及行为相对应，恢复了简单功能获得和功能丧失突变的大部分特定效应以及与几种疾病进展相关的条件。因此，我们的模型构成了一个理论框架，可用于生成假设并指导实验探究，以理解EndMT背后的调节机制。我们的主要发现包括细胞外微环境和细胞内分子活性模式都调节EndMT。EndMT需要细胞外微环境中缺乏VEGFA且有足够的氧气，以及细胞内没有FLI1和GATA2活性。此外，尖端细胞不能直接经历EndMT。此外，足以触发EndMT的特定条件取决于细胞内分子激活的特定模式。
