European Molecular Biology Laboratory (EMBL), Barcelona, Spain.
Proteomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
Sci Adv. 2023 Dec 22;9(51):eadj8540. doi: 10.1126/sciadv.adj8540.
Proper placental vascularization is vital for pregnancy outcomes, but assessing it with animal models and human explants has limitations. We introduce a 3D in vitro model of human placenta terminal villi including fetal mesenchyme and vascular endothelium. By coculturing HUVEC, placental fibroblasts, and pericytes in a macrofluidic chip with a flow reservoir, we generate fully perfusable fetal microvessels. Pressure-driven flow facilitates microvessel growth and remodeling, resulting in early formation of interconnected and lasting placental-like vascular networks. Computational fluid dynamics simulations predict shear forces, which increase microtissue stiffness, decrease diffusivity, and enhance barrier function as shear stress rises. Mass spectrometry analysis reveals enhanced protein expression with flow, including matrix stability regulators, proteins associated with actin dynamics, and cytoskeleton organization. Our model provides a powerful tool for deducing complex in vivo parameters, such as shear stress on developing vascularized placental tissue, and holds promise for unraveling gestational disorders related to the vasculature.
适当的胎盘血管生成对于妊娠结局至关重要，但使用动物模型和人体外植体进行评估存在局限性。我们引入了一种包含胎儿间质和血管内皮的人胎盘终末绒毛的 3D 体外模型。通过在具有流储器的宏观芯片中共同培养 HUVEC、胎盘成纤维细胞和周细胞，我们生成了完全可灌注的胎儿微血管。压力驱动的流动促进微血管生长和重塑，导致早期形成相互连接和持久的胎盘样血管网络。计算流体动力学模拟预测剪切力，随着剪切应力的增加，剪切力会增加微组织的刚度、降低扩散率并增强屏障功能。质谱分析显示，随着流动的进行，蛋白质表达增强，包括基质稳定性调节剂、与肌动蛋白动力学相关的蛋白质和细胞骨架组织。我们的模型为推断复杂的体内参数提供了有力工具，例如发育中的血管化胎盘组织上的剪切力，并且有望揭示与血管有关的妊娠障碍。
