Distinguishing Specific CXCL12 Isoforms on Their Angiogenesis and Vascular Permeability Promoting Properties
Distinguishing Specific CXCL12 Isoforms on Their Angiogenesis and Vascular Permeability Promoting Properties
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DOI：
10.1002/adhm.201901399
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发表时间：
2020-01-15
影响因子：
10
通讯作者：
Song, Jonathan W.
中科院分区：
文献类型：
--
作者：
Chang, Chia-Wen;Seibel, Alex J.;Song, Jonathan W.
血管生成与血管发芽和渗透性增加有关。这些血管生成反应的重要介质包括信号分子和支持细胞外基质（ECM）的局部环境。然而，解剖这些指导性信号在体内与多种细胞和细胞外分子的相互作用仍然是一个核心挑战。在这里，微流体仿生学与3D ECM水凝胶相结合，这些水凝胶具有良好的分子结合和机械特性，可以在体外重建血管样类似物。这项研究的重点是促转移趋化因子CXCL 12的三种不同亚型。在仅含胶原的水凝胶中，CXCL 12-α是促进发芽和渗透性的最有效同种型，其次是CXCL 12-β和CXCL 12-γ。引人注目的是，加入透明质酸（HA），一种大的带负电荷的糖胺聚糖，与胶原蛋白基质选择性地增加血管发芽和CXCL 12-γ赋予的渗透性。测量的与胶原蛋白/HA ECM的结合亲和力支持该结果，表明带负电荷的HA增加了CXCL 12-γ的结合以增强其血管生成效力。此外，它表明，除了HA的胶原蛋白基质本身降低血管发芽和渗透性，这些反应是无效的，通过阻断HA受体CD 44。总的来说，这些结果表明，在结合细胞外HA的差异有助于基础CXCL 12亚型特异性反应，以指导血管生成。
Angiogenesis is associated with increased vessel sprouting and permeability. Important mediators of these angiogenic responses include local environment of signaling molecules and supporting extracellular matrix (ECM). However, dissecting the interplay of these instructive signals in vivo with multiple cells and extracellular molecules remains a central challenge. Here, microfluidic biomimicry is integrated with 3D ECM hydrogels that are well-characterized for molecular-binding and mechanical properties to reconstitute vessel-like analogues in vitro. This study focuses on three distinct isoforms of the pro-metastatic chemokine CXCL12. In collagen-only hydrogel, CXCL12-alpha is the most potent isoform in promoting sprouting and permeability, followed by CXCL12-beta and CXCL12-gamma. Strikingly, addition of hyaluronan (HA), a large and negatively charged glycosaminoglycan, with collagen matrices selectively increases vessel sprouting and permeability conferred by CXCL12-gamma. This outcome is supported by the measured binding affinities to collagen/HA ECM, suggesting that negatively charged HA increases the binding of CXCL12-gamma to augment its angiogenic potency. Moreover, it is shown that addition of HA to collagen matrices on its own decreases vessel sprouting and permeability, and these responses are nullified by blocking the HA receptor CD44. Collectively, these results demonstrate that differences in binding to extracellular HA help underlie CXCL12 isoform-specific responses toward directing angiogenesis.