The TGF beta-1, -2 and -3 isoforms are transcribed from different genes but bind to the same receptors and signal through the same canonical and non-canonical signal transduction pathways. There are ...numerous regulatory mechanisms controlling the action of each isoform that include the organ-specific cells producing latent TGF beta growth factors, multiple effectors that activate the isoforms, ECM-associated SLRPs and basement membrane components that modulate the activity and localization of the isoforms, other interactive cytokine-growth factor receptor systems, such as PDGF and CTGF, TGF beta receptor expression on target cells, including myofibroblast precursors, receptor binding competition, positive and negative signal transduction effectors, and transcription and translational regulatory mechanisms. While there has long been the view that TGF beta-1and TGF beta-2 are pro-fibrotic, while TGF beta-3 is anti-fibrotic, this review suggests that view is too simplistic, at least in adult tissues, since TGF beta-3 shares far more similarities in its modulation of fibrotic gene expression with TGF beta-1 and TGF beta-2, than it does differences, and often the differences are subtle. Rather, TGF beta-3 should be seen as a fibro-modulatory partner to the other two isoforms that modulates a nuanced and better controlled response to injury. The complex interplay between the three isoforms and numerous interactive proteins, in the context of the cellular milieu, controls regenerative non-fibrotic vs. fibrotic healing in a response to injury in a particular organ, as well as the resolution of fibrosis, when that occurs.
•TGF beta-1, -2 and -3 isoforms are transcribed from different genes.•TGF beta isoforms bind to the same receptors and signal through the same signal transduction pathways.•Numerous regulatory mechanisms control the action of each TGF beta isoform.•The long standing view that TGF beta-3 is anti-fibrotic, is too simplistic.•Rather, TGF beta-3 produces subtle fibro-modulatory differences.
Corneal wound healing Wilson, Steven E.
Experimental eye research,
08/2020, Letnik:
197
Journal Article
Recenzirano
Odprti dostop
The corneal wound healing response is typically initiated by injuries to the epithelium and/or endothelium that may also involve the stroma. However, it can also be triggered by immune or infectious ...processes that enter the stroma via the limbal blood vessels. For mild injuries or infections, such as epithelial abrasions or mild controlled microbial infections, limited keratocyte apoptosis occurs and the epithelium or endothelium regenerates, the epithelial basement membrane (EBM) and/or Descemet's basement membrane (DBM) is repaired, and keratocyte- or fibrocyte-derived myofibroblast precursors either undergo apoptosis or revert to the parent cell types. For more severe injuries with extensive damage to EBM and/or DBM, delayed regeneration of the basement membranes leads to ongoing penetration of the pro-fibrotic cytokines transforming growth factor (TGF) β1, TGFβ2 and platelet-derived growth factor (PDGF) that drive the development of mature alpha-smooth muscle actin (SMA)+ myofibroblasts that secrete large amounts of disordered extracellular matrix (ECM) components to produce scarring stromal fibrosis. Fibrosis is dynamic with ongoing mitosis and development of SMA + myofibroblasts and continued autocrine-or paracrine interleukin (IL)-1-mediated apoptosis of myofibroblasts and their precursors. Eventual repair of the EBM and/or DBM can lead to at least partial resolution of scarring fibrosis.
•Keratocyte apoptosis is the first observable stromal event after anterior corneal injury.•Normal or defective regeneration of the EBM controls regenerative vs. fibrotic healing.•Descemet's membrane modulates regenerative vs. fibrotic healing for posterior injuries.•Fibrosis is dynamic with ongoing mitosis, development and apoptosis of myofibroblasts.
Myofibroblasts are alpha-smooth muscle actin (SMA)+ cells that have a critical role in the corneal stromal response to infections, injuries, and surgeries, and which produce corneal scarring fibrosis ...when they develop in excess. These contractile and opaque cells—produce large amounts of disordered extracellular matrix (ECM)—and develop from keratocyte-derived corneal fibroblasts or bone marrow-derived fibrocytes, and possibly other cell types, in response to TGFβ1, TGFβ2 and PDGF from the epithelium, tears, endothelium, and other stromal cells. Recent proteomic analyses have revealed that the myofibroblasts that develop from different progenitors aren't interchangeable, but have major differences in protein expression and functions. Absence or defective regeneration of the epithelial basement membrane (EBM) and/or Descemet's basement membrane (DBM) results in development and persistence of myofibroblasts in the corneal stroma. The functions of myofibroblasts in the cornea include production of volume-additive ECM, tissue contraction, production of various growth factors, cytokines and chemokines that regulate stromal cells, including other myofibroblasts, production of collagenases and metalloproteinases involved in tissue remodeling, and the expression of toll-like receptors that likely have critical roles in the clearance of bacteria and viruses causing corneal infections.
•Myofibroblasts are the major contributor to corneal fibrosis after injury or infection.•Myofibroblasts are dependent on TGF beta-1 or-2 for development and survival.•Corneal myofibroblasts are derived from keratocyte- and fibrocyte-derived precursors.•Myofibroblasts derived from different precursors have differential gene expression.
Interleukin (IL)-1α/IL-1β and transforming growth factor (TGF)β1/TGFβ2 have both been promoted as "master regulators" of the corneal wound healing response due to the large number of processes each ...regulates after injury or infection. The purpose of this review is to highlight the interactions between these systems in regulating corneal wound healing.
We conducted a systematic review of the literature.
Both regulator pairs bind to receptors expressed on keratocytes, corneal fibroblasts, and myofibroblasts, as well as bone marrow-derived cells that include fibrocytes. IL-1α and IL-1β modulate healing functions, such as keratocyte apoptosis, chemokine production by corneal fibroblasts, hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) production by keratocytes and corneal fibroblasts, expression of metalloproteinases and collagenases by corneal fibroblasts, and myofibroblast apoptosis. TGFβ1 and TGFβ2 stimulate the development of myofibroblasts from keratocyte and fibrocyte progenitor cells, and adequate stromal levels are requisite for the persistence of myofibroblasts. Conversely, TGFβ3, although it functions via the same TGF beta I and II receptors, may, at least in some circumstances, play a more antifibrotic role-although it also upregulates the expression of many profibrotic genes.
The overall effects of these two growth factor-cytokine-receptor systems in controlling the corneal wound healing response must be coordinated during the wound healing response to injury or infection. The activities of both systems must be downregulated in coordinated fashion to terminate the response to injury and eliminate fibrosis.
A better standing of the IL-1 and TGFβ systems will likely lead to better approaches to control the excessive healing response to infections and injuries leading to scarring corneal fibrosis.
Bowman's layer lies immediately posterior to the epithelial basement membrane (EBM) and anterior to the stroma proper in humans, chickens, quail, zebra fish, deer, giraffe, antelope, California sea ...lions, guinea pig and several other species. It is not found in dog, wolf, cat, tiger, lions, rabbit, pigs, cows, goats, or horses. Developmental anomalies of Bowman's layer are rare, but acquired damage to Bowman's layer, or even complete destruction, is frequently seen in advanced bullous keratopathy or Fuchs' endothelial dystrophy. No detrimental effects of removal of Bowman's layer over the central 6–7 mm of central cornea have been noted in millions of patients who've had photorefractive keratectomy (PRK). Recent studies have suggested the randomly-oriented collagen fibrils that make up Bowman's layer do not have a significant barrier function in modulating the passage of moderate- to large-sized proteins. It is hypothesized that Bowman's layer develops in the corneas of those species that have one because of cytokine-mediated interactions occurring between corneal epithelial cells and underlying keratocytes, including negative chemotactic and apoptotic effects on the keratocytes by low levels of cytokines such as interleukin-1α that are gradually released as epithelial cells die and slough during their normal development. A “Bowman's like layer” can generate around stromal epithelial plugs after radial keratotomy, and possibly beneath the central corneal epithelial basement membrane many years after PRK.
•Bowman's layer is present in some species and absent in others.•Bowman's layer is not a barrier to passage of large molecules.•A Bowman's-like layer may regenerate after corneal surgery.•Bowman's layer likely maintained by ongoing epithelial-stromal interactions.
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.
► Corneal myofibroblasts and the matrix they produce causes corneal opacity. ► The corneal epithelium and basement membrane have key roles in generation of myofibroblasts. ► Corneal myofibroblasts can be generated from either keratocyte-derived or bone marrow-derived precursors.
Fibrocytes, Wound Healing, and Corneal Fibrosis de Oliveira, Rodrigo Carlos; Wilson, Steven E
Investigative ophthalmology & visual science,
02/2020, Letnik:
61, Številka:
2
Journal Article
Recenzirano
Odprti dostop
This review highlights the roles of fibrocytes-their origin, markers, regulation and functions-including contributions to corneal wound healing and fibrosis.
Literature review.
Peripheral blood ...fibroblast-like cells, called fibrocytes, are primarily generated as mature collagen-producing cells in the bone marrow. They are likely derived from the myeloid lineage, although the exact precursor remains unknown. Fibrocytes are identified by a combination of expressed markers, such as simultaneous expression of CD34 or CD45 or CD11b and collagen type I or collagen type III. Fibrocytes migrate into the wound from the blood where they participate in pathogen clearance, tissue regeneration, wound closure and angiogenesis. Transforming growth factor beta 1 (TGF-β1) and adiponectin induce expression of α-smooth muscle actin and extracellular matrix proteins through activation of Smad3 and adenosine monophosphate-activated protein kinase pathways, respectively. Fibrocytes are important contributors to the cornea wound healing response and there are several mechanisms through which fibrocytes contribute to fibrosis in the cornea and other organs, such as their differentiation into myofibroblasts, production of matrix metalloproteinase, secretion of tissue inhibitor of metalloproteinase, and release of TGF-β1. In some tissues, fibrocytes may also contribute to the basement membrane regeneration and to the resolution of fibrosis.
New methods that block fibrocyte generation, fibrocyte migration, and their differentiation into myofibroblasts, as well as their production of matrix metalloproteinases, tissue inhibitor of metalloproteinase, and TGF-β1, have therapeutic potential to reduce the accumulation of collagens, maintain tissue integrity and retard or prevent the development of fibrosis.
In the cornea, the epithelial basement membrane (EBM) and corneal endothelial Descemet’s basement membrane (DBM) critically regulate the localization, availability and, therefore, the functions of ...transforming growth factor (TGF)β1, TGFβ2, and platelet-derived growth factors (PDGF) that modulate myofibroblast development. Defective regeneration of the EBM, and notably diminished perlecan incorporation, occurs via several mechanisms and results in excessive and prolonged penetration of pro-fibrotic growth factors into the stroma. These growth factors drive mature myofibroblast development from both corneal fibroblasts and bone marrow-derived fibrocytes, and then the persistence of these myofibroblasts and the disordered collagens and other matrix materials they produce to generate stromal scarring fibrosis. Corneal stromal fibrosis often resolves completely if the inciting factor is removed and the BM regenerates. Similar defects in BM regeneration are likely associated with the development of fibrosis in other organs where perlecan has a critical role in the modulation of signaling by TGFβ1 and TGFβ2. Other BM components, such as collagen type IV and collagen type XIII, are also critical regulators of TGF beta (and other growth factors) in the cornea and other organs. After injury, BM components are dynamically secreted and assembled through the cooperation of neighboring cells—for example, the epithelial cells and keratocytes for the corneal EBM and corneal endothelial cells and keratocytes for the corneal DBM. One of the most critical functions of these reassembled BMs in all organs is to modulate the pro-fibrotic effects of TGFβs, PDGFs and other growth factors between tissues that comprise the organ.
Basement membranes are layers of extracellular matrix which anchor the epithelium or endothelium to connective tissues in most organs. Descemet's membrane— which is the basement membrane for the ...corneal endothelium— is a dense, thick, relatively transparent and cell-free matrix that separates the posterior corneal stroma from the underlying endothelium. It was historically named Descemet's membrane after Jean Descemet, a French physician, but it is also known as the posterior limiting elastic lamina, lamina elastica posterior, and membrane of Demours. Normal Descemet's membrane ultrastructure in humans has been shown to consist of an interfacial matrix that attaches to the overlying corneal stroma, an anterior banded layer and a posterior non-banded layer—upon which corneal endothelial cells attach. These layers have been shown to have unique composition and morphology, and to contribute to corneal homeostasis and clarity, participate in the control of corneal hydration and to modulate TGF-β-induced posterior corneal fibrosis. Pathophysiological alterations of Descemet's membrane are noted in ocular diseases such as Fuchs' dystrophy, bullous keratopathy, keratoconus, primary congenital glaucoma (Haab's striae), as well as in systemic conditions. Unrepaired extensive damage to Descemet's membrane results in severe corneal opacity and vision loss due to stromal fibrosis, which may require penetrating keratoplasty to restore corneal transparency. The purpose of this article is to highlight the current understanding of Descemet's membrane structure, function and potential for regeneration.
•Descemet's membrane is the basement membrane of the corneal endothelium.•Descemet's membrane modulates aqueous humor TGF beta and stromal fibrosis.•Descemet's membrane has poor potential to regenerate.
Recent studies in rabbits and case reports in humans have demonstrated the efficacy of topical losartan in the treatment of corneal scarring fibrosis after a wide range of injuries, including ...chemical burns, infections, surgical complications, and some diseases. It is hypothesized that the effect of losartan on the fibrotic corneal stroma occurs through a two-phase process in which losartan first triggers the elimination of myofibroblasts by directing their apoptosis via inhibition of extracellular signal-regulated kinase (ERK)-mediated signal transduction, and possibly through signaling effects on the viability and development of corneal fibroblast and fibrocyte myofibroblast precursor cells. This first step likely occurs within a week or two in most corneas with fibrosis treated with topical losartan, but the medication must be continued for much longer until the epithelial basement membrane (EBM) is fully regenerated or new myofibroblasts will develop from precursor cells. Once the myofibroblasts are eliminated from the fibrotic stroma, corneal fibroblasts can migrate into the fibrotic tissue and reabsorb/reorganize the disordered extracellular matrix (ECM) previously produced by the myofibroblasts. This second stage is longer and more variable in different eyes of rabbits and humans, and accounts for most of the variability in the time it takes for the stromal opacity to be markedly reduced by topical losartan treatment.
Eventually, keratocytes reemerge in the previously fibrotic stromal tissue to fine-tune the collagens and other ECM components and maintain the normal structure of the corneal stroma. The efficacy of losartan in the prevention and treatment of corneal fibrosis suggests that it acts as a surrogate for the EBM, by suppressing TGF beta-directed scarring of the wounded corneal stroma, until control over TGF beta action is re-established by a healed EBM, while also supporting regeneration of the EBM by allowing corneal fibroblasts to occupy the subepithelial stroma in the place of myofibroblasts.
•Topical losartan triggers myofibroblast apoptosis and may inhibit development.•Losartan inhibits erk activation by phosphorylation.•In the second phase, the disordered extracellular matrix is remodeled by corneal fibroblasts.•This two-phase losartan mechanism requires months to a year to clear the corneal opacity.
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