Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218.
Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, MD 21218.
Proc Natl Acad Sci U S A. 2018 Aug 7;115(32):8167-8172. doi: 10.1073/pnas.1808021115. Epub 2018 Jul 23.
Morphogenesis during human development relies on the interplay between physiochemical cues that are mediated in part by cellular density and cytoskeletal tension. Here, we interrogated these factors on vascular lineage specification during human-induced pluripotent stem-cell (hiPSC) fate decision. We found that independent of chemical cues, spatially presented physical cues induce the self-organization of Brachyury-positive mesodermal cells, in a RhoA/Rho-associated kinase (ROCK)-dependent manner. Using unbiased support vector machine (SVM) learning, we found that density alone is sufficient to predict mesodermal fate. Furthermore, the long-withstanding presentation of spatial confinement during hiPSC differentiation led to an organized vascular tissue, reminiscent of native blood vessels, a process dependent on cell density as found by SVM analysis. Collectively, these results show how tension and density relate to vascular identity mirroring early morphogenesis. We propose that such a system can be applied to study other aspects of the stem-cell niche and its role in embryonic patterning.
人类发育过程中的形态发生依赖于生理化学线索的相互作用，这些线索部分是由细胞密度和细胞骨架张力介导的。在这里，我们在人诱导多能干细胞（hiPSC）命运决定过程中研究了这些因素对血管谱系特化的影响。我们发现，独立于化学线索，空间呈现的物理线索以 RhoA/Rho 相关激酶（ROCK）依赖性方式诱导 Brachyury 阳性中胚层细胞的自组织。使用无偏支持向量机（SVM）学习，我们发现仅密度就足以预测中胚层命运。此外，hiPSC 分化过程中空间限制的长期存在导致了组织有序的血管组织，类似于天然血管，这一过程依赖于 SVM 分析中发现的细胞密度。总之，这些结果表明张力和密度如何与血管特征相关，反映了早期形态发生。我们提出，这样的系统可以应用于研究干细胞生态位的其他方面及其在胚胎模式形成中的作用。
