A 3D Human Lymphatic Vessel-on-Chip Reveals the Roles of Interstitial Flow and VEGF-A/C for Lymphatic Sprouting and Discontinuous Junction Formation.

IF 2.3 4区医学 Q3 BIOPHYSICS

Cellular and molecular bioengineering Pub Date : 2023-08-24 eCollection Date: 2023-08-01 DOI:10.1007/s12195-023-00780-0

Isabelle S Ilan, Aria R Yslas, Yansong Peng, Renhao Lu, Esak Lee

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引用次数: 0

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-023-00780-0.

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芯片上的3D人体淋巴管揭示了间质流和VEGF-A/C在淋巴萌芽和不连续连接形成中的作用。

引言：淋巴管（LV）通过排出多余的间质液来维持液体稳态，这是由两个不同的LV完成的：初始LV和收集LV。间质液首先通过可渗透的“按钮状”淋巴内皮细胞（LEC）连接排入初始LV。接下来，排出的液体（“淋巴”）通过收集LV输送到淋巴结，LV具有渗透性较低的“拉链状”连接，可最大限度地减少淋巴损失。尽管LEC连接在淋巴引流和运输中具有重要意义，但在血管内皮生长因子A和C（VEGF-A和VEGF-C）条件下，管腔或间质流如何影响LEC连接仍不清楚。此外，目前尚不清楚这些流动和生长因子条件如何影响淋巴发芽。方法：我们在芯片上开发了一种3D人体淋巴管，它可以产生四种不同的流动条件（无流动、管腔流动、间质流动、管腔和间质流动），使工程化的初级左心室能够体验这些流动，并在VEGF-a/C中对其做出反应，以及VEGF-A/C中四种不同流动条件下细胞收缩性依赖性血管直径。我们发现VEGF-C中的间质流动产生了不连续的LEC连接，这种连接可能类似于没有淋巴发芽的纽扣状连接。然而，间质流或管腔和间质流刺激VEGF-A中的淋巴发芽，维持拉链状LEC连接。LEC连接厚度和细胞收缩性依赖性血管直径没有因这些条件而改变。结论：在本研究中，我们提供了一个工程化的淋巴管平台，该平台可以产生四种不同的流动状态，并揭示间质流和VEGF-A/C在淋巴发芽和不连续连接形成中的作用。补充信息：在线版本包含补充材料，请访问10.1007/s12195-023-00780-0。

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.

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