Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115.
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5399-5404. doi: 10.1073/pnas.1815208116. Epub 2019 Mar 4.
Three-dimensional renal tissues that emulate the cellular composition, geometry, and function of native kidney tissue would enable fundamental studies of filtration and reabsorption. Here, we have created 3D vascularized proximal tubule models composed of adjacent conduits that are lined with confluent epithelium and endothelium, embedded in a permeable ECM, and independently addressed using a closed-loop perfusion system to investigate renal reabsorption. Our 3D kidney tissue allows for coculture of proximal tubule epithelium and vascular endothelium that exhibits active reabsorption via tubular-vascular exchange of solutes akin to native kidney tissue. Using this model, both albumin uptake and glucose reabsorption are quantified as a function of time. Epithelium-endothelium cross-talk is further studied by exposing proximal tubule cells to hyperglycemic conditions and monitoring endothelial cell dysfunction. This diseased state can be rescued by administering a glucose transport inhibitor. Our 3D kidney tissue provides a platform for in vitro studies of kidney function, disease modeling, and pharmacology.
三维肾组织模拟了天然肾组织的细胞组成、几何形状和功能，将能够实现对过滤和重吸收的基础研究。在这里，我们构建了由相邻导管组成的三维血管化近端小管模型，这些导管内衬着连续的上皮细胞和内皮细胞，嵌入在可渗透的细胞外基质中，并使用闭环灌注系统独立处理，以研究肾脏重吸收。我们的 3D 肾组织允许近端小管上皮细胞和血管内皮细胞共培养，通过类似于天然肾组织的管状 - 血管溶质交换实现主动重吸收。使用该模型，可以定量测量白蛋白摄取和葡萄糖重吸收随时间的变化。通过将近端小管细胞暴露于高血糖条件并监测内皮细胞功能障碍，进一步研究了上皮细胞 - 内皮细胞的串扰。通过给予葡萄糖转运抑制剂可以挽救这种疾病状态。我们的 3D 肾组织为体外研究肾脏功能、疾病建模和药理学提供了一个平台。
