Perivascular extracellular matrix hydrogels mimic native matrix microarchitecture and promote angiogenesis via basic fibroblast growth factor.
Perivascular extracellular matrix hydrogels mimic native matrix microarchitecture and promote angiogenesis via basic fibroblast growth factor.
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DOI：
10.1016/j.biomaterials.2017.01.037
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发表时间：
2017-04
期刊：
影响因子：
14
通讯作者：
Phillippi JA
中科院分区：
文献类型：
--
作者：
Fercana GR;Yerneni S;Billaud M;Hill JC;VanRyzin P;Richards TD;Sicari BM;Johnson SA;Badylak SF;Campbell PG;Gleason TG;Phillippi JA
细胞外基质（ECM）衍生的生物支架已被证明通过保留生物活性信号引起组织修复。鉴于大血管的外膜是一个丰富的血管化微环境，我们假设血管周围ECM含有影响血管谱系细胞的生物活性信号。ECM生物支架衍生自脱细胞的人和猪主动脉外膜（分别为hAdv和pAdv），然后显示具有最小的DNA含量并保留弹性蛋白和胶原蛋白。hAdv和pAdv ECM生物支架的水凝胶制剂表现出与源自猪小肠粘膜下层（pSIS）的ECM水凝胶相似的凝胶化动力学。hAdv和pAdv ECM水凝胶显示出更薄、更少波动和纤维微结构，使人联想到天然外膜，与pSIS ECM水凝胶相比，超微结构可见轻微差异。胃蛋白酶消化的pAdv和pSIS ECM生物支架增加了人外膜衍生的内皮细胞的增殖，并且这种作用部分由碱性成纤维细胞生长因子（FGF 2）介导。当补充pAdv ECM生物支架时，在Matrigel基质上培养的人内皮细胞形成了更多、更长的管状结构，并且FGF 2介导了这种基质信号传导。来源于pAdv的ECM生物支架在鸡胚绒毛尿囊膜模型中促进FGF 2依赖的体内血管生成。使用血管生成聚焦蛋白阵列，我们检测了55个血管生成相关蛋白，包括hAdv，pAdv和pSIS ECM中的FGF 2。有趣的是，这些因子中的19个在来自人主动脉的血管平滑肌标本的ECM生物支架中的丰度低于非血管平滑肌（正常）标本。这项研究表明，Adv ECM水凝胶重现了天然外膜的基质纤维微结构，并保留了血管生成相关因子和生物活性特性，如能够影响血管生成重要过程的FGF 2信号传导。这项工作支持使用Adv ECM生物支架用于发现生物学和在临床应用中向微血管再生的潜在转化。
Extracellular matrix (ECM)-derived bioscaffolds have been shown to elicit tissue repair through retention of bioactive signals. Given that the adventitia of large blood vessels is a richly vascularized microenvironment, we hypothesized that perivascular ECM contains bioactive signals that influence cells of blood vessel lineages. ECM bioscaffolds were derived from decellularized human and porcine aortic adventitia (hAdv and pAdv, respectively) and then shown have minimal DNA content and retain elastin and collagen proteins. Hydrogel formulations of hAdv and pAdv ECM bioscaffolds exhibited gelation kinetics similar to ECM hydrogels derived from porcine small intestinal submucosa (pSIS). hAdv and pAdv ECM hydrogels displayed thinner, less undulated, and fibrous microarchitecture reminiscent of native adventitia, with slight differences in ultrastructure visible in comparison to pSIS ECM hydrogels. Pepsin-digested pAdv and pSIS ECM bioscaffolds increased proliferation of human adventitia-derived endothelial cells and this effect was mediated in part by basic fibroblast growth factor (FGF2). Human endothelial cells cultured on Matrigel substrates formed more numerous and longer tube-like structures when supplemented with pAdv ECM bioscaffolds, and FGF2 mediated this matrix signaling. ECM bioscaffolds derived from pAdv promoted FGF2-dependent in vivo angiogenesis in the chick chorioallantoic membrane model. Using an angiogenesis-focused protein array, we detected 55 angiogenesis-related proteins, including FGF2 in hAdv, pAdv and pSIS ECMs. Interestingly, 19 of these factors were less abundant in ECMs bioscaffolds derived from aneurysmal specimens of human aorta when compared with nonaneurysmal (normal) specimens. This study reveals that Adv ECM hydrogels recapitulate matrix fiber microarchitecture of native adventitia, and retain angiogenesis-related actors and bioactive properties such as FGF2 signaling capable of influencing processes important for angiogenesis. This work supports the use of Adv ECM bioscaffolds for both discovery biology and potential translation towards microvascular regeneration in clinical applications.