Fibrin and Collagen Differentially but Synergistically Regulate Sprout Angiogenesis of Human Dermal Microvascular Endothelial Cells in 3-Dimensional Matrix

Abstract

Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors.

Enhancing the Three-Dimensional Structure of Adherent Gingival Fibroblasts and Spheroids via a Fibrous Protein-Based Hydrogel Cover

“…The cells were rearranged into thin-wall ring-shaped structures. The addition of fibrin [Wolf et al, 2009;Feng et al, 2013] was required to fill the inner opened space of the ring and increase its thickness. Supplementation of collagen1 hydrogels with fibronectin and vitronectin had no effect on ring texture or thickness.…”

Fibrin-based 3D matrices induce angiogenic behavior of adipose-derived stem cells

“…Collagen is known for greater mechanical strength, facilitating its use for mechanically loaded tissues [21]. The higher modulus of collagen is known to result in low endothelial cell sprouting compared to fibrin [19, 39]. In studies, fibrin showed a 32.4% increase in microvessel formation from ECs and a 73.5% wider vascular area than collagen [40].…”

“…Even though we have chosen to use one uniform concentration, the difference in cell behaviors and morphologies in each gel can be a result of combined characteristics such as biochemical and biomechanical cues. According to a literature, in cell-matrix interactions, αvβ3 and α5β1 integrins dominate in fibrin-based environments and α2β1 integrins dominate in collagen [19, 41]. According to Feng et al ’s study, the sprouting action of ECs was enhanced in fibrin over collagen, as determined by microbead outgrowth assay [19].…”

“…Collagen-based materials show low-level immunogenicity and have been widely researched and clinically tested in numerous tissue engineering applications, such as bone, cartilage, and vascular tissues [19–21]. Furthermore, collagen gels containing ASCs showed therapeutic potential for both rigid ( e.g ., bone and tendon) as well as soft tissues ( e.g ., blood vessels and skin) [22–24].…”

Integrative Utilization of Microenvironments, Biomaterials and Computational Techniques for Advanced Tissue Engineering

“…Stable and long sprouts were formed within moderate matrix density of 1.2 and 1.9 mg/ml [109]. Feng et al also demonstrated that the composition of proteins of the extracellular matrix has an effect on sprout angiogenesis [271]. Nguyen et al developed a novel microfluidic device to study the effect of angiogenic factors on angiogenesis sprouting in the presence of fluid flow in the parent vessel [272].…”