■淋巴管(LV)通过排出多余的间质液来维持液体稳态,这通过两个不同的LV来实现:初始LV和收集LV。间质液首先通过可渗透的“纽扣状”淋巴内皮细胞(LEC)连接排入初始LV。接下来,排出的液体(“淋巴液”)通过收集的LV输送到淋巴结,其渗透性较低,“拉链状”连接可最大程度地减少淋巴液的损失。尽管LEC连接在淋巴引流和运输中具有重要意义,目前尚不清楚在血管内皮生长因子A和C(VEGF-A和VEGF-C)条件下,管腔或间质血流如何影响LEC连接.此外,目前尚不清楚这些流量和生长因子条件如何影响淋巴发芽。
■我们开发了一种3D人类淋巴管-芯片,可产生四种不同的流动条件(无流动,管腔流动,间隙流,腔和间质流动),以允许工程,基本的LV经历这些流动并在VEGF-A/C中对它们做出反应。
■我们检查了LEC结的不连续性,淋巴发芽,LEC结厚度,VEGF-A/C中四种不同流动条件下的细胞收缩性依赖性血管直径我们发现VEGF-C中的间质流产生不连续的LEC连接,该连接可能类似于纽扣状连接,而没有淋巴发芽。然而,间质流或腔和间质流均刺激VEGF-A的淋巴发芽,保持拉链状的LEC接头。这些条件不会改变LEC连接厚度和细胞收缩性依赖性血管直径。
■在这项研究中,我们提供了一个工程化的淋巴管平台,可以产生四种不同的流态,并揭示了间质流和VEGF-A/C在淋巴发芽和不连续连接形成中的作用。
■在线版本包含补充材料,可在10.1007/s12195-023-00780-0获得。
UNASSIGNED: Lymphatic vessels (LVs) maintain fluid homeostasis by draining excess interstitial fluid, which is accomplished by two distinct LVs: initial LVs and collecting LVs. The interstitial fluid is first drained into the initial LVs through permeable \"button-like\" lymphatic endothelial cell (LEC) junctions. Next, the drained fluid (\"lymph\") transports to lymph nodes through the collecting LVs with less permeable \"zipper-like\" junctions that minimize loss of lymph. Despite the significance of LEC junctions in lymphatic drainage and transport, it remains unclear how luminal or interstitial flow affects LEC junctions in vascular endothelial growth factors A and C (VEGF-A and VEGF-C) conditions. Moreover, it remains unclear how these flow and growth factor conditions impact lymphatic sprouting.
UNASSIGNED: We developed a 3D human lymphatic vessel-on-chip that can generate four different flow conditions (no flow, luminal flow, interstitial flow, both luminal and interstitial flow) to allow an engineered, rudimentary LV to experience those flows and respond to them in VEGF-A/C.
UNASSIGNED: We examined LEC junction discontinuities, lymphatic sprouting, LEC junction thicknesses, and cell contractility-dependent vessel diameters in the four different flow conditions in VEGF-A/C. We discovered that interstitial flow in VEGF-C generates discontinuous LEC junctions that may be similar to the button-like junctions with no lymphatic sprouting. However, interstitial flow or both luminal and interstitial flow stimulated lymphatic sprouting in VEGF-A, maintaining zipper-like LEC junctions. LEC junction thickness and cell contractility-dependent vessel diameters were not changed by those conditions.
UNASSIGNED: In this study, we provide an engineered lymphatic vessel platform that can generate four different flow regimes and reveal the roles of interstitial flow and VEGF-A/C for lymphatic sprouting and discontinuous junction formation.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12195-023-00780-0.