The Transformation of Corneal Stromal Cells to Fibroblasts in Corneal Wound Healing*

Weimar, Virginia

doi:10.1016/0002-9394(57)90445-2

Cited by 50 publications

(13 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Keratocytes are the quiescent cells in the normal corneal stroma that, upon wounding, are activated to become fibroblasts and myofibroblasts (Weimar, 1957;Nakayasu, 1988). They have no relationship to keratinocytes of the skin, which are epithelial.…”

Section: Preparation Of Corneal Keratocytes Fibroblasts and Myofibrmentioning

confidence: 99%

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Bernstein¹,

Twining

Warejcka

et al. 2007

MBoC

View full text Add to dashboard Cite

Fibroblasts migrate into and repopulate connective tissue wounds. At the wound edge, fibroblasts differentiate into myofibroblasts, and they promote wound closure. Regulated fibroblast-to-myofibroblast differentiation is critical for regenerative healing. Previous studies have focused on the role in fibroblasts of urokinase plasmingen activator/urokinase plasmingen activator receptor (uPA/uPAR), an extracellular protease system that promotes matrix remodeling, growth factor activation, and cell migration. Whereas fibroblasts have substantial uPA activity and uPAR expression, we discovered that cultured myofibroblasts eventually lost cell surface uPA/uPAR. This led us to investigate the relevance of uPA/uPAR activity to myofibroblast differentiation. We found that fibroblasts expressed increased amounts of full-length cell surface uPAR (D1D2D3) compared with myofibroblasts, which had reduced expression of D1D2D3 but increased expression of the truncated form of uPAR (D2D3) on their cell surface. Retaining full-length uPAR was found to be essential for regulating myofibroblast differentiation, because 1) protease inhibitors that prevented uPAR cleavage also prevented myofibroblast differentiation, and 2) overexpression of cDNA for a noncleavable form of uPAR inhibited myofibroblast differentiation. These data support a novel hypothesis that maintaining full-length uPAR on the cell surface regulates the fibroblast to myofibroblast transition and that down-regulation of uPAR is necessary for myofibroblast differentiation. INTRODUCTIONMyofibroblast differentiation from fibroblasts is a critical component of the healing process. Regenerative healing (without scarring) results from the successful execution of what have been characterized as three distinct phases of wound healing. In the first phase, fibroblasts that migrate into the wound secrete proteases, extracellular matrix (ECM) molecules, and growth factors. In the second phase, fibroblasts differentiate into nonmotile, wound-contracting myofibroblasts that also secrete ECM proteins and remodel the ECM (Jester et al., 1995;Mohan et al., 2003;Netto et al., 2005). In the third phase, after wound closure, myofibroblasts usually disappear by apoptosis (Desmouliere et al., 1995). Pathological states such as hypertrophic scars, liver cirrhosis, idiopathic lung fibrosis, and glomerulosclerosis are characterized by the persistence of myofibroblasts, which contribute to disease progression by overproduction of ECM and by excessive contraction (Desmouliere et al., 2003;Gabbiani, 2003).To better understand the molecular basis for the fibroblast to myofibroblast transition, we have focused on the role of the urokinase plasmingen activator (uPA) pathway during wound healing. uPA is an extracellular serine protease that binds to its receptor, uPAR, and generates plasmin from plasminogen at the cell-matrix interface. Plasmin is a broadspectrum protease that not only cleaves fibrin and other ECM proteins but also promotes cell migration by activating matrix-sequestered metallopr...

show abstract

Section: Preparation Of Corneal Keratocytes Fibroblasts and Myofibrmentioning

confidence: 99%

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Bernstein¹,

Twining

Warejcka

et al. 2007

MBoC

View full text Add to dashboard Cite

show abstract

“…Weimar (68) has reported the apparent transformation of stromal ceils to fibroblasts in corneal wound healing. She has further described (69) the activation of corneal stromal cells to take up neutral red after wounding of the epithelium.…”

Section: Figure 15mentioning

confidence: 99%

Studies on the Cornea

Kaye

Pappas

1962

The Journal of Cell Biology

165

View full text Add to dashboard Cite

Physiological studies have demonstrated that ions, as well as large molecules such as hemoglobin or fluorescein, can diffuse across and within the cornea. Most of the substrates for corneal metabolism are obtained from aqueous humor filling the anterior chamber. In order to receive its nutrients and in order to maintain its normal conditions of hydration, the avascular cornea must transport relatively large amounts of solute and solvent across the cellular layers which cover this structure. It has been suggested in the past that there may be a morphological basis for the transport of large amounts of solvents and solutes by cells by the mechanism of pinocytosis. The use of electron-opaque markers to study fluid movements at the electron microscope magnification level was described by Wissig (29). The present study describes the fine structure of the normal rabbit cornea and the pathways of transport of colloidal particles by the cornea in vivo. Rabbit corneas were exposed in vivo to suspensions of saccharated iron oxide, thorium dioxide, or ferritin by injection of the material into the anterior chamber. In other experiments thorium dioxide or saccharated iron oxide was injected into the corneal stroma, producing a small bleb. Particles presented at the aqueous humor surface of the rabbit corneal endothelium are first attached to the cell surface and then pinocytosed. It appears that the particles are carried around the terminal bar by an intracellular pathway involving the pinocytosis of the particles and their subsequent transport in vesicles to the lateral cell margin basal to the terminal bar. Particles introduced at the basal surface of the endothelium (via blebs in the corneal stroma) are apparently carried through the endothelial cells in membrane-bounded vesicles without appearing in the intercellular space. There appears to be free diffusion of these particles through Descemet's membrane and the corneal stroma. The stromal cells take up large quantities of the particles when blebs are injected into the stroma.

show abstract

“…Immediately after wounding, fibroblasts become activated, exhibit protein synthesis, and lose cell-cell contact (10,11 §To whom reprint requests should be addressed.…”

Section: Introductionmentioning

confidence: 99%

“…Immediately after wounding, fibroblasts become activated, exhibit protein synthesis, and lose cell-cell contact (10,11). Cell-cell connections are also disrupted when quiescent corneal fibroblasts are placed in culture and become activated.…”

mentioning

confidence: 99%

Myofibroblasts differentiate from fibroblasts when plated at low density.

Masur

Dewal

Dinh

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

433

317

View full text Add to dashboard Cite

Myofibroblasts, defined by their expression of smooth muscle a-actin, appear at corneal and dermal incisions and promote wound contraction. We TGF-,. Myofibroblasts are essential to wound contraction and healing (1). They differentiate from fibroblasts and are characterized by the presence of stress fibers containing the a-actin isoform that is expressed in smooth muscle (SM) cells (2-5). In the cornea, fibroblasts adjacent to an incision quickly become myofibroblasts (6). Myofibroblasts disappear with the completion of healing; the continuous presence of myofibroblasts is characteristic of abnormal healing as in fibrotic lesions (7).In the normal cornea, quiescent fibroblasts are connected to one another via gap junctions (8, 9). Immediately after wounding, fibroblasts become activated, exhibit protein synthesis, and lose cell-cell contact (10,11 §To whom reprint requests should be addressed.

show abstract

The Transformation of Corneal Stromal Cells to Fibroblasts in Corneal Wound Healing*

Cited by 50 publications

References 5 publications

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

Studies on the Cornea

Myofibroblasts differentiate from fibroblasts when plated at low density.

Contact Info

Product

Resources

About