Systems Biology of Aorta Growth_ProcessedData

After birth, tissues grow continuously until reaching adult size, with each organ exhibiting unique cellular dynamics, growth patterns, and (stem or non-stem) cell sources. Using a suite of experimental and computational multiscale approaches, we found that aortic expansion is guided by specific biological principles and scales with the vertebral column rather than animal body weight. Expansion proceeds via two distinct waves of arterial cell proliferation along blood flow that are spatially stochastic, yet temporally coordinated. Each wave exhibits unique cell cycle kinetics and properties, with the first wave exhibiting cell cycle durations as fast as 6 hours. Single-cell RNA sequencing showed changes in fatty acid metabolism concomitant with an increase in cell size. Mathematical modeling and experiments indicated endothelial cell extrusion is essential for homeostatic aortic growth and balancing excess proliferation. In a genetic model of achondroplasia, the aorta achieves proper scaling through enhanced cell extrusion while maintaining normal proliferation dynamics. Collectively, these results provide a blueprint of the principles that orchestrate aortic growth which depends entirely on differentiated cell proliferation rather than resident stem cells.

生物体出生后，组织会持续生长直至达到成体体型，且各器官均具备独特的细胞动态特征、生长模式以及（干细胞（stem cell）或非干细胞）细胞来源。本研究借助一系列实验与计算多尺度方法（multiscale approach），发现主动脉生长扩张遵循特定的生物学原则，且其生长尺度与脊柱（vertebral column）而非动物体重相匹配。主动脉的生长扩张通过沿血流方向的两波截然不同的动脉细胞增殖过程完成，这些增殖波在空间上呈随机分布，但在时间上相互协调。每一波增殖过程均具备独特的细胞周期动力学（cell cycle kinetics）特征与属性，其中第一波增殖的细胞周期时长最快仅为6小时。单细胞RNA测序（single-cell RNA sequencing）结果显示，脂肪酸代谢发生改变的同时，细胞体积也随之增大。数学建模与实验结果表明，内皮细胞挤出（endothelial cell extrusion）对于维持主动脉的稳态生长以及平衡过度增殖至关重要。在软骨发育不全（achondroplasia）的遗传模型中，主动脉通过增强细胞挤出过程并维持正常的增殖动态，实现了适宜的尺度匹配。综上，本研究结果为调控主动脉生长的核心原则提供了一套完整框架：主动脉生长完全依赖于分化细胞（differentiated cell）的增殖，而非驻留干细胞（resident stem cell）。