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17 pages, 12332 KiB

Open AccessArticle

Understanding the Role of Yes-Associated Protein (YAP) Signaling in the Transformation of Lens Epithelial Cells (EMT) and Fibrosis

by Aftab Taiyab, Yasmine Belahlou, Vanessa Wong, Saranya Pandi, Madhu Shekhar, Gowri Priya Chidambaranathan and Judith West-Mays

Biomolecules 2023, 13(12), 1767; https://doi.org/10.3390/biom13121767 - 9 Dec 2023

Cited by 1 | Viewed by 1176

Abstract

Fibrotic cataracts, posterior capsular opacification (PCO), and anterior subcapsular cataracts (ASC) are mainly attributed to the transforming growth factor-β (TGFβ)-induced epithelial-to-mesenchymal transition (EMT) of lens epithelial cells (LECs). Previous investigations from our laboratory have shown the novel role of non-canonical TGFβ signaling in [...] Read more.

Fibrotic cataracts, posterior capsular opacification (PCO), and anterior subcapsular cataracts (ASC) are mainly attributed to the transforming growth factor-β (TGFβ)-induced epithelial-to-mesenchymal transition (EMT) of lens epithelial cells (LECs). Previous investigations from our laboratory have shown the novel role of non-canonical TGFβ signaling in the progression of EMT in LECs. In this study, we have identified YAP as a critical signaling molecule involved in lens fibrosis. The observed increase in nuclear YAP in capsules of human ASC patients points toward the involvement of YAP in lens fibrosis. In addition, the immunohistochemical (IHC) analyses on ocular sections from mice that overexpress TGFβ in the lens (TGFβ^tg) showed a co-expression of YAP and α-SMA in the fibrotic plaques when compared to wild-type littermate lenses, which do not. The incubation of rat lens explants with verteporfin, a YAP inhibitor, prevented a TGFβ-induced fiber-like phenotype, α-SMA, and fibronectin expression, as well as delocalization of E-cadherin and β-catenin. Finally, LECs co-incubated with TGFβ and YAP inhibitor did not exhibit an induction in matrix metalloproteinase 2 compared to those LECs treated with TGFβ alone. In conclusion, these data demonstrate that YAP is required for TGFβ-mediated lens EMT and fibrosis. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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19 pages, 4973 KiB

Open AccessArticle

Immune Responses Induced at One Hour Post Cataract Surgery Wounding of the Chick Lens

by JodiRae DeDreu, Morgan D. Basta, Janice L. Walker and A. Sue Menko

Biomolecules 2023, 13(11), 1615; https://doi.org/10.3390/biom13111615 - 4 Nov 2023

Viewed by 1185

Abstract

While the lens is an avascular tissue with an immune-privileged status, studies have now revealed that there are immune responses specifically linked to the lens. The response to lens injury, such as following cataract surgery, has been shown to involve the activation of [...] Read more.

While the lens is an avascular tissue with an immune-privileged status, studies have now revealed that there are immune responses specifically linked to the lens. The response to lens injury, such as following cataract surgery, has been shown to involve the activation of the resident immune cell population of the lens and the induction of immunomodulatory factors by the wounded epithelium. However, there has been limited investigation into the immediate response of the lens to wounding, particularly those induced factors that are intrinsic to the lens and its associated resident immune cells. Using an established chick embryo ex vivo cataract surgery model has made it possible to determine the early immune responses of this tissue to injury, including its resident immune cells, through a transcriptome analysis. RNA-seq studies were performed to determine the gene expression profile at 1 h post wounding compared to time 0. The results provided evidence that, as occurs in other tissues, the resident immune cells of the lens rapidly acquired a molecular signature consistent with their activation. These studies also identified the expression of many inflammatory factors by the injured lens that are associated with both the induction and regulation of the immune response. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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20 pages, 4233 KiB

Open AccessArticle

Immune Cells Localize to Sites of Corneal Erosions in C57BL/6 Mice

by Phuong M. Le, Sonali Pal-Ghosh, A. Sue Menko and Mary Ann Stepp

Biomolecules 2023, 13(7), 1059; https://doi.org/10.3390/biom13071059 - 29 Jun 2023

Viewed by 1111

Abstract

Recurrent epithelial erosions develop in the cornea due to prior injury or genetic predisposition. Studies of recurrent erosions in animal models allow us to gain insight into how erosions form and are resolved. While slowing corneal epithelial cell migration and reducing their proliferation [...] Read more.

Recurrent epithelial erosions develop in the cornea due to prior injury or genetic predisposition. Studies of recurrent erosions in animal models allow us to gain insight into how erosions form and are resolved. While slowing corneal epithelial cell migration and reducing their proliferation following treatment with mitomycin C reduce erosion formation in mice after sterile debridement injury, additional factors have been identified related to cytokine expression and immune cell activation. The relationship between recruitment of immune cells to the region of the cornea where erosions form and their potential roles in erosion formation and/or erosion repair remains unexplored in the C57BL/6 mouse recurrent erosion model. Here, high resolution imaging of mouse corneas was performed at D1, D7, and D28 after dulled-blade debridement injury in C57BL/6 mice. Around 50% of these mice have frank corneal erosions at D28 after wounding. A detailed assessment of corneas revealed the involvement of M2 macrophages in both frank and developing erosions at early stages of their formation. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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13 pages, 6103 KiB

Open AccessArticle

Trametinib-Induced Epidermal Thinning Accelerates a Mouse Model of Junctional Epidermolysis Bullosa

by Grace Tartaglia, Pyung Hun Park, Michael H. Alexander, Alexander Nyström, Joel Rosenbloom and Andrew P. South

Biomolecules 2023, 13(5), 740; https://doi.org/10.3390/biom13050740 - 25 Apr 2023

Cited by 1 | Viewed by 1732

Abstract

Junctional epidermolysis bullosa (JEB) patients experience skin and epithelial fragility due to a pathological deficiency in genes associated with epidermal adhesion. Disease severity ranges from post-natal lethality to localized skin involvement with persistent blistering followed by granulation tissue formation and atrophic scarring. We [...] Read more.

Junctional epidermolysis bullosa (JEB) patients experience skin and epithelial fragility due to a pathological deficiency in genes associated with epidermal adhesion. Disease severity ranges from post-natal lethality to localized skin involvement with persistent blistering followed by granulation tissue formation and atrophic scarring. We evaluated the potential of utilizing Trametinib, an MEK inhibitor previously shown to target fibrosis, with and without the documented EB-anti-fibrotic Losartan for reducing disease severity in a mouse model of JEB; Lamc2^jeb mice. We found that Trametinib treatment accelerated disease onset and decreased epidermal thickness, which was in large part ameliorated by Losartan treatment. Interestingly, a range of disease severity was observed in Trametinib-treated animals that tracked with epidermal thickness; those animals grouped with higher disease severity had thinner epidermis. To examine if the difference in severity was related to inflammation, we conducted immunohistochemistry for the immune cell markers CD3, CD4, CD8, and CD45 as well as the fibrotic marker αSMA in mouse ears. We used a positive pixel algorithm to analyze the resulting images and demonstrated that Trametinib caused a non-significant reduction in CD4 expression that inversely tracked with increased fibrotic severity. With the addition of Losartan to Trametinib, CD4 expression was similar to control. Together, these data suggest that Trametinib causes a reduction in both epidermal proliferation and immune cell infiltration/proliferation, with concurrent acceleration of skin fragility, while Losartan counteracts Trametinib’s adverse effects in a mouse model of JEB. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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Review

Jump to: Research

17 pages, 1566 KiB

Open AccessReview

Gap Junctions or Hemichannel-Dependent and Independent Roles of Connexins in Fibrosis, Epithelial–Mesenchymal Transitions, and Wound Healing

by Yuting Li, Francisca M. Acosta and Jean X. Jiang

Biomolecules 2023, 13(12), 1796; https://doi.org/10.3390/biom13121796 - 14 Dec 2023

Viewed by 1426

Abstract

Fibrosis initially appears as a normal response to damage, where activated fibroblasts produce large amounts of the extracellular matrix (ECM) during the wound healing process to assist in the repair of injured tissue. However, the excessive accumulation of the ECM, unresolved by remodeling [...] Read more.

Fibrosis initially appears as a normal response to damage, where activated fibroblasts produce large amounts of the extracellular matrix (ECM) during the wound healing process to assist in the repair of injured tissue. However, the excessive accumulation of the ECM, unresolved by remodeling mechanisms, leads to organ dysfunction. Connexins, a family of transmembrane channel proteins, are widely recognized for their major roles in fibrosis, the epithelial–mesenchymal transition (EMT), and wound healing. Efforts have been made in recent years to identify novel mediators and targets for this regulation. Connexins form gap junctions and hemichannels, mediating communications between neighboring cells and inside and outside of cells, respectively. Recent evidence suggests that connexins, beyond forming channels, possess channel-independent functions in fibrosis, the EMT, and wound healing. One crucial channel-independent function is their role as the primary functional component for cell adhesion. Other channel-independent functions of connexins involve their roles in mitochondria and exosomes. This review summarizes the latest advances in the channel-dependent and independent roles of connexins in fibrosis, the EMT, and wound healing, with a particular focus on eye diseases, emphasizing their potential as novel, promising therapeutic targets. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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19 pages, 8488 KiB

Open AccessReview

Fibroblasts—Warriors at the Intersection of Wound Healing and Disrepair

by Jesse Roman

Biomolecules 2023, 13(6), 945; https://doi.org/10.3390/biom13060945 - 6 Jun 2023

Cited by 4 | Viewed by 2082

Abstract

Wound healing is triggered by inflammation elicited after tissue injury. Mesenchymal cells, specifically fibroblasts, accumulate in the injured tissues, where they engage in tissue repair through the expression and assembly of extracellular matrices that provide a scaffold for cell adhesion, the re-epithelialization of [...] Read more.

Wound healing is triggered by inflammation elicited after tissue injury. Mesenchymal cells, specifically fibroblasts, accumulate in the injured tissues, where they engage in tissue repair through the expression and assembly of extracellular matrices that provide a scaffold for cell adhesion, the re-epithelialization of tissues, the production of soluble bioactive mediators that promote cellular recruitment and differentiation, and the regulation of immune responses. If appropriately deployed, these processes promote adaptive repair, resulting in the preservation of the tissue structure and function. Conversely, the dysregulation of these processes leads to maladaptive repair or disrepair, which causes tissue destruction and a loss of organ function. Thus, fibroblasts not only serve as structural cells that maintain tissue integrity, but are key effector cells in the process of wound healing. The review will discuss the general concepts about the origins and heterogeneity of this cell population and highlight the specific fibroblast functions disrupted in human disease. Finally, the review will explore the role of fibroblasts in tissue disrepair, with special attention to the lung, the role of aging, and how alterations in the fibroblast phenotype underpin disorders characterized by pulmonary fibrosis. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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25 pages, 2290 KiB

Open AccessReview

Extracellular Targets to Reduce Excessive Scarring in Response to Tissue Injury

by Jolanta Fertala, Mark L. Wang, Michael Rivlin, Pedro K. Beredjiklian, Joseph Abboud, William V. Arnold and Andrzej Fertala

Biomolecules 2023, 13(5), 758; https://doi.org/10.3390/biom13050758 - 27 Apr 2023

Cited by 4 | Viewed by 2769

Abstract

Excessive scar formation is a hallmark of localized and systemic fibrotic disorders. Despite extensive studies to define valid anti-fibrotic targets and develop effective therapeutics, progressive fibrosis remains a significant medical problem. Regardless of the injury type or location of wounded tissue, excessive production [...] Read more.

Excessive scar formation is a hallmark of localized and systemic fibrotic disorders. Despite extensive studies to define valid anti-fibrotic targets and develop effective therapeutics, progressive fibrosis remains a significant medical problem. Regardless of the injury type or location of wounded tissue, excessive production and accumulation of collagen-rich extracellular matrix is the common denominator of all fibrotic disorders. A long-standing dogma was that anti-fibrotic approaches should focus on overall intracellular processes that drive fibrotic scarring. Because of the poor outcomes of these approaches, scientific efforts now focus on regulating the extracellular components of fibrotic tissues. Crucial extracellular players include cellular receptors of matrix components, macromolecules that form the matrix architecture, auxiliary proteins that facilitate the formation of stiff scar tissue, matricellular proteins, and extracellular vesicles that modulate matrix homeostasis. This review summarizes studies targeting the extracellular aspects of fibrotic tissue synthesis, presents the rationale for these studies, and discusses the progress and limitations of current extracellular approaches to limit fibrotic healing. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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14 pages, 2624 KiB

Open AccessReview

The Yin and Yang of Mesenchymal Cells in the Corneal Stromal Fibrosis Response to Injury: The Cornea as a Model of Fibrosis in Other Organs

by Steven E. Wilson

Biomolecules 2023, 13(1), 87; https://doi.org/10.3390/biom13010087 - 31 Dec 2022

Cited by 9 | Viewed by 1930

Abstract

Mesenchymal cells (keratocytes, corneal fibroblasts, and myofibroblasts), as well as mesenchymal progenitor bone marrow-derived fibrocytes, are the major cellular contributors to stromal fibrosis after injury to the cornea. Corneal fibroblasts, in addition to being major progenitors to myofibroblasts, also have anti-fibrotic functions in [...] Read more.

Mesenchymal cells (keratocytes, corneal fibroblasts, and myofibroblasts), as well as mesenchymal progenitor bone marrow-derived fibrocytes, are the major cellular contributors to stromal fibrosis after injury to the cornea. Corneal fibroblasts, in addition to being major progenitors to myofibroblasts, also have anti-fibrotic functions in (1) the production of non-basement membrane collagen type IV that binds activated transforming growth factor (TGF) beta-1 and TGF beta-2 to downregulate TGF beta effects on cells in the injured stroma, (2) the production of chemokines that modulate the entry of bone marrow-derived cells into the stroma, (3) the production of hepatocyte growth factor and keratinocyte growth factor to regulate corneal epithelial healing, (4) the cooperation with the epithelium or corneal endothelium in the regeneration of the epithelial basement membrane and Descemet’s membrane, and other functions. Fibrocytes also serve as major progenitors to myofibroblasts in the corneal stroma. Thus, mesenchymal cells and mesenchymal cell progenitors serve Yin and Yang functions to inhibit and promote tissue fibrosis depending on the overall regulatory milieu within the injured stroma. Full article

(This article belongs to the Special Issue Role of Mesenchymal Cells in Wound Healing and Fibrosis)

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