Bone marrow stromal cells stimulate an angiogenic program that requires endothelial MT1‐MMP

Abstract

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.

Stromal Cell Identity Influences the In Vivo Functionality of Engineered Capillary Networks Formed by Co-delivery of Endothelial Cells and Stromal Cells

“…47 A final possibility relates to the influence of stromal cell identity on the proteolytic remodeling of the ECM during the neovascularization process. 24,48 Our published data suggest that capillary formation induced by fibroblasts is very fast (perhaps tumor-like), resulting from a plasmin-mediated proteolysis that rapidly degrades the matrix and disrupts its mechanical properties in a global fashion. By contrast, BMSCs and AdSCs induce a much more focal, strategic matrix remodeling that is MT1-MMP dependent and results in capillaries that form more slowly, but also in a more stable manner.…”

Role of microRNA-mediated MMP regulation in the treatment and diagnosis of malignant tumors

“…Clinical studies have revealed that MMP-14 overexpression is associated with poor prognoses in patients with various malignant tumors. [75][76][77][78] However, the mechanisms underlying MMP-14 expression in tumors remain largely uncharacterized. Of note, MMP-14 expression has been reported to be associated with microRNAs in pancreatic cancer, neuroblastoma, and glioma.…”

Evaluation of gold nanotracers to track adipose-derived stem cells in a PEGylated fibrin gel for dermal tissue engineering applications

“…21,22 It is also known to induce ASC activity in vitro and in vivo. 23,24 In addition, it is commonly used in vascular tissue engineering due to its inherent angiogenic activity.…”