Abstract
The formation of healthy vascularized granulation tissue is essential for rapid wound closure and the prevention of chronic wounds in humans, yet how endothelial cells and fibroblasts coordinate during this process has been difficult to study. Here, we have developed an in vitro system that reveals how human endothelial and stromal cells in a 3D matrix respond during wound healing and granulation tissue formation. By creating incisions in engineered cultures composed of human umbilical vein endothelial cells and human lung fibroblasts embedded within a 3D matrix, we observed that these tissues are able to close the wound within approximately 4 days. Live tracking of cells during wound closure revealed that the process is mediated primarily by fibroblasts. The fibroblasts migrate circumferentially around the wound edge during early phases of healing, while contracting the wound. The fibroblast-derived matrix is, then, deposited into the void, facilitating fibroblast migration toward the wound center and filling of the void. Interestingly, the endothelial cells remain at the periphery of the wound rather than actively sprouting into the healing region to restore the vascular network. This study captures the dynamics of endothelial and fibroblast-mediated closure of three-dimensional wounds, which results in the repopulation of the wound with the cell-derived extracellular matrix representative of early granulation tissue, thus presenting a model for future studies to investigate factors regulating vascularized granulation tissue formation.
Highlights
Wound healing is a critical process which progresses through tightly regulated phases and leads to repopulation of the wound with cells and extracellular matrix.[1]
By creating incisions in engineered cultures composed of human umbilical vein endothelial cells and human lung fibroblasts embedded within a 3D matrix, we observed that these tissues are able to close the wound within approximately 4 days
A platform to investigate the cooperation of endothelial cells and fibroblasts in wound healing and early granulation tissue formation
Summary
Wound healing is a critical process which progresses through tightly regulated phases and leads to repopulation of the wound with cells and extracellular matrix.[1] A key aspect to this process involves the production of granulation tissue, a densely vascularized provisional tissue composed of endothelial cells, fibroblasts, and cell-derived matrix, which fills the wound area. Given the ability of fibroblasts to support vascular network formation in 3D gels in vitro, we sought to investigate whether fibroblasts contribute to the process of endothelial cell ingrowth and repopulation of the newly formed granulation tissue
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