Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA.
J Cell Physiol. 2012 Nov;227(11):3546-55. doi: 10.1002/jcp.24056.
Bone marrow-derived stromal/stem cells (BMSCs) have recently been characterized as mediators of tissue regeneration after injury. In addition to preventing fibrosis at the wound site, BMSCs elicit an angiogenic response within the fibrin matrix. The mechanistic interactions between BMSCs and invading endothelial cells (ECs) during this process are not fully understood. Using a three-dimensional, fibrin-based angiogenesis model, we sought to investigate the proteolytic mechanisms by which BMSCs promote vessel morphogenesis. We find that BMSC-mediated vessel formation depends on the proteolytic ability of membrane type 1-matrix metalloproteinase (MT1-MMP). Knockdown of the protease results in a small network of vessels with enlarged lumens. Contrastingly, vessel morphogenesis is unaffected by the knockdown of MMP-2 and MMP-9. Furthermore, we find that BMSC-mediated vessel morphogenesis in vivo follows mechanisms similar to what we observe in vitro. Subcutaneous, cellular fibrin implants in C.B-17/SCID mice form aberrant vasculature when MMPs are inhibited with a broad-spectrum chemical inhibitor, and a very minimal amount of vessels when MT1-MMP proteolytic activity is interrupted in ECs. Other studies have debated the necessity of MT1-MMP in the context of vessel invasion in fibrin, but this study clearly demonstrates its requirement in BMSC-mediated angiogenesis.
骨髓基质/干细胞 (BMSCs) 最近被描述为损伤后组织再生的介质。BMSCs 除了在创伤部位防止纤维化外，还在纤维蛋白基质中引发血管生成反应。在这个过程中，BMSCs 和浸润的内皮细胞 (ECs) 之间的机械相互作用还不完全清楚。我们使用基于纤维蛋白的三维血管生成模型，试图研究 BMSCs 促进血管生成的蛋白水解机制。我们发现 BMSC 介导的血管形成取决于膜型 1 基质金属蛋白酶 (MT1-MMP) 的蛋白水解能力。蛋白酶的敲低导致血管腔扩大的小血管网络。相比之下，MMP-2 和 MMP-9 的敲低对血管形态发生没有影响。此外，我们发现体内 BMSC 介导的血管形态发生遵循与我们在体外观察到的类似的机制。当用广谱化学抑制剂抑制 MMP 时，C.B-17/SCID 小鼠皮下细胞纤维蛋白植入物形成异常血管，而当 EC 中 MT1-MMP 蛋白水解活性被阻断时，只有非常少量的血管形成。其他研究曾就纤维蛋白中血管浸润是否需要 MT1-MMP 进行了争论，但这项研究清楚地表明其在 BMSC 介导的血管生成中的必要性。
