Brigid M. Bleaken

A central role for vimentin in regulating repair function during healing of the lens epithelium

A unique ex vivo mock cataract surgery model is used to study the role of vimentin in repair cell function during wound healing within a clinically relevant setting. Vimentin is found to be critical for the function of repair cells in directing the collective migration of the epithelium during wound healing.

Unique precursors for the mesenchymal cells involved in injury response and fibrosis.

We investigated an alternative pathway for emergence of the mesenchymal cells involved in epithelial sheet wound healing and a source of myofibroblasts that cause fibrosis. Using a mock cataract surgery model, we discovered a unique subpopulation of polyploid mesenchymal progenitors nestled in small niches among lens epithelial cells that expressed the surface antigen G8 and mRNA for the myogenic transcription factor MyoD. These cells rapidly responded to wounding of the lens epithelium with population expansion, acquisition of a mesenchymal phenotype, and migration to the wound edges where they regulate the wound response of the epithelium. These mesenchymal cells also were a principal source of myofibroblasts that emerged following lens injury and were responsible for fibrotic disease of the lens that occurs following cataract surgery. These studies provide insight into the mechanisms of wound-healing and fibrosis.

Distinct roles for N-Cadherin linked c-Src and fyn kinases in lens development

Background: Src family tyrosine kinases (SFKs) are often coincidently expressed but few studies have dissected their individual functions in the same cell during development. Using the classical embryonic lens as our model, we investigated SFK signaling in the regulation of both differentiation initiation and morphogenesis, and the distinct functions of c‐Src and Fyn in these processes. Results: Blocking SFK activity with the highly specific inhibitor PP1 induced initiation of the lens differentiation program but blocked lens fiber cell elongation and organization into mini lens‐like structures called lentoids. These dichotomous roles for SFK signaling were discovered to reflect distinct functions of c‐Src and Fyn and their differentiation‐state‐specific recruitment to and action at N‐cadherin junctions. c‐Src was highly associated with the nascent N‐cadherin junctions of undifferentiated lens epithelial cells. Its siRNA knockdown promoted N‐cadherin junctional maturation, blocked proliferation, and induced lens cell differentiation. In contrast, Fyn was recruited to mature N‐cadherin junctions of differentiating lens cells and siRNA knockdown suppressed differentiation‐specific gene expression and blocked morphogenesis. Conclusions: Through inhibition of N‐cadherin junction maturation, c‐Src promotes lens epithelial cell proliferation and the maintenance of the lens epithelial cell undifferentiated state, while Fyn, signaling downstream of mature N‐cadherin junctions, promotes lens fiber cell morphogenesis. Developmental Dynamics 242:469–474, 2013.

Cells activated for wound repair have the potential to direct collective invasion of an epithelium

Studies using a clinically relevant injury invasion model reveal that cells critical to wound repair are inherently invasive, acting as leaders to direct the collective invasion of a wounded epithelium. This model is a valuable tool with which to study leader cell–directed invasion and help understand how mechanisms of wound healing are hijacked to cause disease.