Semi-autonomous wound invasion via matrix-deposited, haptotactic cues

Abstract

Proper wound healing relies on invasion of fibroblasts via directed migration. While the related experimental and mathematical modeling literature has mainly focused on cell migration directed by soluble cues (chemotaxis), there is ample evidence that fibroblast migration is also directed by insoluble, matrix-bound cues (haptotaxis). Furthermore, numerous studies indicate that fibronectin (FN), a haptotactic ligand for fibroblasts, is present and dynamic in the provisional matrix throughout the proliferative phase of wound healing. In the present work, we show the plausibility of a hypothesis that fibroblasts themselves form and maintain haptotactic gradients in a semi-autonomous fashion. As a precursor to this, we examine the positive control scenario where FN is pre-deposited in the wound matrix, and fibroblasts maintain haptotaxis by removing FN at an appropriate rate. After developing conceptual and quantitative understanding of this scenario, we consider two cases in which fibroblasts activate the latent form of a matrix-loaded cytokine, TGFβ, which upregulates the fibroblasts’ own secretion of FN. In the first of these, the latent cytokine is pre-patterned and released by the fibroblasts. In the second, fibroblasts in the wound produce the latent TGFβ, with the presence of the wound providing the only instruction. In all cases, wound invasion is more effective than a negative control model with haptotaxis disabled; however, there is a trade-off between the degree of fibroblast autonomy and the rate of invasion.