The local wound environment is a key determinant of the outcome of TGFß signaling on the fibrotic response of CD44+ leader cells in an ex vivo post-cataract-surgery model.

ABSTRACT

The cytokine transforming growth factor beta (TGFß) has a role in regulating the normal and pathological response to wound healing, yet how it shifts from a pro-repair to a pro-fibrotic function within the wound environment is still unclear. Using a clinically relevant ex vivo post-cataract surgery model that mimics the lens fibrotic disease posterior capsule opacification (PCO), we investigated the influence of two distinct wound environments on shaping the TGFß-mediated injury response of CD44+ vimentin-rich leader cells. The substantial fibrotic response of this cell population occurred within a rigid wound environment under the control of endogenous TGFß. However, TGFß was dispensable for the role of leader cells in wound healing on the endogenous basement membrane wound environment, where repair occurs in the absence of a major fibrotic outcome. A difference between leader cell function in these distinct environments was their cell surface expression of the latent TGFß activator, αvß3 integrin. This receptor is exclusively found on this CD44+ cell population when they localize to the leading edge of the rigid wound environment. Providing exogenous TGFß to bypass any differences in the ability of the leader cells to sustain activation of TGFß in different environments revealed their inherent ability to induce pro-fibrotic reactions on the basement membrane wound environment. Furthermore, exposure of the leader cells in the rigid wound environment to TGFß led to an accelerated fibrotic response including the earlier appearance of pro-collagen + cells, alpha smooth muscle actin (αSMA)+ myofibroblasts, and increased fibrotic matrix production. Collectively, these findings show the influence of the local wound environment on the extent and severity of TGFß-induced fibrotic responses. These findings have important implications for understanding the development of the lens fibrotic disease PCO in response to cataract surgery wounding.