Abstract
Background: Increasing the complexity of in vitro systems to mimic three-dimensional tissues and the cellular interactions within them will increase the reliability of data that were previously collected with in vitro systems. In vivo vascularization is based on complex and clearly defined cell–matrix and cell–cell interactions, where the extracellular matrix (ECM) seems to play a very important role. The aim of this study was to monitor and visualize the subcellular and molecular interactions between endothelial cells (ECs), fibroblasts, and their surrounding microenvironment during vascular morphogenesis in a three-dimensional coculture model. Methods: Quantitative and qualitative analyses during the generation of a coculture tissue construct consisting of endothelial cells and fibroblasts were done using transmission electron microscopy and immunohistochemistry. Results: Dynamic interactions were found in cocultures between ECs, between fibroblasts (FBs), between ECs and FBs, and between the cells and the ECM. Microvesicles were involved in intercellular information transfer. FBs took an active and physical part in the angiogenesis process. The ECM deposited by the cells triggered endothelial angiogenic activity. Capillary-like tubular structures developed and matured. Moreover, some ECM assembled into a basement membrane (BM) having three different layers equivalent to those seen in vivo. Finally, the three-dimensional in vitro construct mirrored the topography of histological tissue sections. Conclusion: Our results visualize the importance of the physical contact between all cellular and acellular components of the cocultures.
Highlights
Increasing the complexity of in vitro systems to mimic three-dimensional tissues and the cellular interactions within them will increase the reliability of data that were previously collected with in vitro systems
To optimize the existing in vitro models of angiogenesis [26,27], it is essential to take into account the interaction of the endothelial cells (ECs) with the cells and molecules present in their physiologic environment, and to include further cell types, especially stromal FB [13,24,25,28]
FBs were seen frequently adjacent to the endothelial tubular structures, and physically contacted endothelial tubes at specific sites thereby initiating the degradation of the basement membrane (BM) and the sprouting of a new vessel
Summary
Increasing the complexity of in vitro systems to mimic three-dimensional tissues and the cellular interactions within them will increase the reliability of data that were previously collected with in vitro systems The development of these in vitro systems requires models that display maximum resemblance to the situations found in tissues in vivo. Capillaries are embedded in a microenvironment that consists of the extracellular matrix (ECM) and of cellular components including fibroblasts (FBs) as well as immune cells. In vivo vascularization is based on complex cell–matrix and cell–cell interactions, in which the ECM and the FBs seem to play a very important role [6,7]. The aim of this study was to monitor and visualize the subcellular and molecular interactions between endothelial cells (ECs), fibroblasts, and their surrounding microenvironment during vascular morphogenesis in a three-dimensional coculture model. Conclusion: Our results visualize the importance of the physical contact between all cellular and acellular components of the cocultures
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