Corneal myofibroblast biology and pathobiology: Generation, persistence, and transparency

Abstract

Important advances have led to a better understanding of the biology and pathobiology of corneal myofibroblasts and their generation after surgery, injury, infection and disease. Transforming growth factor (TGF) beta, along with platelet-derived growth factor (PDGF) and interleukin (IL)-1, has been shown to regulate myofibroblast development and death in in-vitro and in-situ animal models. The myofibroblast precursor cells regulated by these cytokines include both keratocyte-derived and bone marrow-derived cells. Cytokines that promote and maintain myofibroblasts associated with late haze after photorefractive keratectomy are modulated in part by the epithelial basement membrane functioning as barrier between the epithelium and stroma. Structural and functional defects in the basement membrane likely lead to prolonged elevation of TGFβ, and perhaps other cytokine, levels in the stroma necessary to promote differentiation of myofibroblasts. Conversely, repair of the epithelial basement membrane likely leads to a decrease in stromal TGFβ levels and apoptosis of myofibroblasts. Repopulating keratocytes subsequently reorganize the associated fibrotic extracellular matrix deposited in the anterior stroma by the myofibroblasts. Investigations of myofibroblast biology are likely to lead to safer pharmacological modulators of corneal wound healing and transparency.

Introduction

Injury to the cornea, and resultant loss of vision, threatens the survival of animals dependent on sight. The myofibroblast is a cell particularly suited to restore the integrity of the cornea after a penetrating injury, for example, because of its ability to contract wounds, secrete extracellular matrix, and generate adhesion structures with the surrounding substrate. Myofibroblast generation, and contraction produced by these cells, is, therefore, likely to be a beneficial contributor to the processes that restore the integrity of the eye after traumatic corneal laceration, even iatrogenic ones such as radial keratotomy incisions (Garana et al., 1992), although unpredictability in their generation is likely a contributor to variability of the surgical result between different patients. Similarly, these cells tend to be beneficial contributors to wound strength at the donor-recipient interface after penetrating keratoplasty and the flap edge in laser in situ keratomileusis (LASIK) (Netto et al., 2007), especially in eyes that don’t require flap lift for retreatment. The development of corneal myofibroblasts after other surgeries, however, is considered a pathological response to injury. For example, the development of clinically significant superficial stromal opacity one to three months after photorefractive keratectomy (PRK), termed “late haze” as seen in the slit lamp images in Fig. 1A and B, leads to persistent corneal opacity, regression of the intended effect of surgery and development of irregular astigmatism (Lipshitz et al., 1997, Mohan et al., 2003). It is important to distinguish pathological late haze associated with myofibroblasts from the mild haze that occurs in the first few weeks to months in nearly all corneas that have PRK, including those with perfect clinical outcomes. The more common, clinically insignificant haze is not attributable to myofibroblasts, and the excessive extracellular matrix they produce, but likely to corneal fibroblasts that are opaque due to decreased corneal crystallin production (Jester et al., 1999b) and alterations to extracellular matrix materials. This common haze increases proportionally with increasing stromal keratectomy depth (Møller-Pedersen et al., 1998a).

Myofibroblasts also may contribute to interface opacity and graft failure following modern corneal endothelial replacement surgeries such as Descemet’s stripping automated endothelial keratoplasty (DSAEK) and Descemet’s membrane endothelial keratoplasty (DMEK), although limited studies have been performed to characterize their role in the wound healing response to these surgeries (Heindl et al., 2011). They are also likely contributors to persistent scars that occur following corneal alkali burns and infections caused by bacteria, fungi and viruses, such as herpes simplex virus.

Ideally, the development and persistence of myofibroblasts in the cornea could be regulated pharmacologically to optimize the wound healing response—augmenting their development when their functions are beneficial and inhibiting their development when their functions are detrimental to the goals of treatment or surgery. In order to approach this ideal, a detailed understanding of the biology of corneal myofibroblasts is needed. The purpose of this review article is to highlight what is currently known about myofibroblast development, disappearance and function in the cornea.