Special Issue "Tissue Regeneration and Fibrosis"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 February 2019)

Special Issue Editor

Guest Editor
Dr. Dimitrios Karamichos

Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Ophthalmology/Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
Website | E-Mail
Interests: corneal wound healing; cornea trauma; keratoconus; bioengineering; bioprinting; diabetic keratopathy

Special Issue Information

Dear Colleagues,

The tissue/organ fibrosis is the formation of excess fibrous connective tissue that can be reactive, benign, or pathological. More often than not, fibrosis leads to devastating results altering the architecture and function of the underlying tissue/organ. The renewal and regeneration of the damaged tissue/organ has been a focal point for many in the basic sciences and translational researches alike for the past 30–40 years. To date, several strategies have been deployed to tackle this biological problem often focusing on cellular or extracellular matrix control/alterations. Powerful developments in this multidisciplinary field have yielded novel technologies and models; however, there are still major challenges ahead including the need for more complex functionality and biochemical stability.  

In this Special Issue, we invite you to contribute original research articles, reviews, or shorter “Perspective” articles on all aspects related to the theme of “Tissue Regeneration and Fibrosis”. We hope to highlight current trends and novel models with functional insights from a cellular and molecular perspective.

Dr. Dimitrios Karamichos
Guest Editor

Manuscript Submission Information

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Keywords

  • scarring
  • fibrosis
  • regeneration
  • tissue engineering
  • biomaterials

Published Papers (7 papers)

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Research

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Open AccessCommunication
YAP, ΔNp63, and β-Catenin Signaling Pathways Are Involved in the Modulation of Corneal Epithelial Stem Cell Phenotype Induced by Substrate Stiffness
Received: 15 February 2019 / Revised: 5 April 2019 / Accepted: 10 April 2019 / Published: 12 April 2019
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Abstract
Recent studies have established that the phenotype of epithelial stem cells residing in the corneal periphery (the limbus) depends on this niche’s distinct biomechanical properties. However, the signaling pathways underlying this dependency are still poorly understood. To address this issue, we investigated the [...] Read more.
Recent studies have established that the phenotype of epithelial stem cells residing in the corneal periphery (the limbus) depends on this niche’s distinct biomechanical properties. However, the signaling pathways underlying this dependency are still poorly understood. To address this issue, we investigated the effect of substrate stiffness on the migration, proliferation, and molecular phenotype of human limbal epithelial stem cells (LESCs). Specifically, we demonstrated that cells grown on collagen-based substrates with limbus-like compliance showed higher proliferation and stratification and lower migration capabilities, as well as higher levels of pro-proliferative markers Ki67 and β-Catenin, and LESC markers ΔNp63, ABCG2, and CK15. In contrast, cells on stiffer substrates lost these stem/progenitor cell markers, but instead expressed the key mechanotransduction factor YAP, as well as elevated levels of BMP4, a promotor of cell differentiation known to be negatively regulated by Wnt/β-Catenin signaling. This data allowed us to propose a new model that integrates the various molecular pathways involved in LESC response to substrate stiffness. This model will potentially be a useful guide to future research on the mechanisms underlying LESC loss following fibrosis-causing injuries. Full article
(This article belongs to the Special Issue Tissue Regeneration and Fibrosis)
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Open AccessFeature PaperArticle
Thymosin Beta-4 and Ciprofloxacin Adjunctive Therapy Improves Pseudomonas aeruginosa-Induced Keratitis
Cells 2018, 7(10), 145; https://doi.org/10.3390/cells7100145
Received: 6 August 2018 / Revised: 12 September 2018 / Accepted: 18 September 2018 / Published: 20 September 2018
Cited by 1 | PDF Full-text (4758 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
With increasing multidrug resistance and contraindication for corticosteroid use, the goal of this study was to develop thymosin beta-4 (Tβ4) as an adjunctive therapy to antibiotics for the treatment of bacterial keratitis that effectively promotes enhanced wound healing, host defense, and inflammation resolution. [...] Read more.
With increasing multidrug resistance and contraindication for corticosteroid use, the goal of this study was to develop thymosin beta-4 (Tβ4) as an adjunctive therapy to antibiotics for the treatment of bacterial keratitis that effectively promotes enhanced wound healing, host defense, and inflammation resolution. Disease outcome was assessed by clinical score, slit lamp photography, and histopathology. Cytokine profile, bacterial load, PMN infiltration, and Griess and reactive oxygen species (ROS) levels were determined. Adjunct Tβ4 treatment resulted in a significant improvement compared to PBS, Tβ4, and most remarkably, ciprofloxacin, correlating with changes in mediators of inflammation and wound healing. Collectively, these data provide evidence that wound healing is an essential aspect in the development of new therapies to treat corneal infection. Use of adjunctive Tβ4 provides a more efficacious approach for bacterial keratitis by addressing both the infectious pathogen and deleterious host response. Full article
(This article belongs to the Special Issue Tissue Regeneration and Fibrosis)
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Open AccessArticle
Platelet-Rich Plasma Prevents In Vitro Transforming Growth Factor-β1-Induced Fibroblast to Myofibroblast Transition: Involvement of Vascular Endothelial Growth Factor (VEGF)-A/VEGF Receptor-1-Mediated Signaling
Received: 31 July 2018 / Revised: 14 September 2018 / Accepted: 16 September 2018 / Published: 19 September 2018
Cited by 3 | PDF Full-text (3091 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The antifibrotic potential of platelet-rich plasma (PRP) is controversial. This study examined the effects of PRP on in vitro transforming growth factor (TGF)-β1-induced differentiation of fibroblasts into myofibroblasts, the main drivers of fibrosis, and the involvement of vascular endothelial growth factor (VEGF)-A in [...] Read more.
The antifibrotic potential of platelet-rich plasma (PRP) is controversial. This study examined the effects of PRP on in vitro transforming growth factor (TGF)-β1-induced differentiation of fibroblasts into myofibroblasts, the main drivers of fibrosis, and the involvement of vascular endothelial growth factor (VEGF)-A in mediating PRP-induced responses. The impact of PRP alone on fibroblast differentiation was also assessed. Myofibroblastic phenotype was evaluated by confocal fluorescence microscopy and western blotting analyses of α-smooth muscle actin (sma) and type-1 collagen expression, vinculin-rich focal adhesion clustering, and stress fiber assembly. Notch-1, connexin 43, and VEGF-A expression were also analyzed by RT-PCR. PRP negatively regulated fibroblast-myofibroblast transition via VEGF-A/VEGF receptor (VEGFR)-1-mediated inhibition of TGF-β1/Smad3 signaling. Indeed TGF-β1/PRP co-treated fibroblasts showed a robust attenuation of the myofibroblastic phenotype concomitant with a decrease of Smad3 expression levels. The VEGFR-1 inhibition by KRN633 or blocking antibodies, or VEGF-A neutralization in these cells prevented the PRP-promoted effects. Moreover PRP abrogated the TGF-β1-induced reduction of VEGF-A and VEGFR-1 cell expression. The role of VEGF-A signaling in counteracting myofibroblast generation was confirmed by cell treatment with soluble VEGF-A. PRP as single treatment did not induce fibroblast myodifferentiation. This study provides new insights into cellular and molecular mechanisms underpinning PRP antifibrotic action. Full article
(This article belongs to the Special Issue Tissue Regeneration and Fibrosis)
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Review

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Open AccessReview
Hyaluronan-Based Hydrogel Scaffolds for Limbal Stem Cell Transplantation: A Review
Received: 9 February 2019 / Revised: 8 March 2019 / Accepted: 11 March 2019 / Published: 14 March 2019
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Abstract
Hyaluronan (HA), also termed hyaluronic acid or hyaluronate, is a major component of the extracellular matrix. This non-sulfated glycosaminoglycan plays a key role in cell proliferation, growth, survival, polarization, and differentiation. The diverse biological roles of HA are linked to the combination of [...] Read more.
Hyaluronan (HA), also termed hyaluronic acid or hyaluronate, is a major component of the extracellular matrix. This non-sulfated glycosaminoglycan plays a key role in cell proliferation, growth, survival, polarization, and differentiation. The diverse biological roles of HA are linked to the combination of HA’s physicochemical properties and HA-binding proteins. These unique characteristics have encouraged the application of HA-based hydrogel scaffolds for stem cell-based therapy, a successful method in the treatment of limbal stem cell deficiency (LSCD). This condition occurs following direct damage to limbal stem cells and/or changes in the limbal stem cell niche microenvironment due to intrinsic and extrinsic insults. This paper reviews the physical properties, synthesis, and degradation of HA. In addition, the interaction of HA with other extracellular matrix (ECM) components and receptor proteins are discussed. Finally, studies employing HA-based hydrogel scaffolds in the treatment of LSCD are reviewed. Full article
(This article belongs to the Special Issue Tissue Regeneration and Fibrosis)
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Open AccessReview
Signals from the Niche: Insights into the Role of IGF-1 and IL-6 in Modulating Skeletal Muscle Fibrosis
Received: 11 February 2019 / Revised: 6 March 2019 / Accepted: 6 March 2019 / Published: 11 March 2019
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Abstract
Muscle regeneration, characterized by the activation and proliferation of satellite cells and other precursors, is accompanied by an inflammatory response and the remodeling of the extracellular matrix (ECM), necessary to remove cellular debris and to mechanically support newly generated myofibers and activated satellite [...] Read more.
Muscle regeneration, characterized by the activation and proliferation of satellite cells and other precursors, is accompanied by an inflammatory response and the remodeling of the extracellular matrix (ECM), necessary to remove cellular debris and to mechanically support newly generated myofibers and activated satellite cells. Muscle repair can be considered concluded when the tissue architecture, vascularization, and innervation have been restored. Alterations in these connected mechanisms can impair muscle regeneration, leading to the replacement of functional muscle tissue with a fibrotic scar. In the present review, we will discuss the cellular mediators of fibrosis and how the altered expression and secretion of soluble mediators, such as IL-6 and IGF-1, can modulate regulatory networks involved in the altered regeneration and fibrosis during aging and diseases. Full article
(This article belongs to the Special Issue Tissue Regeneration and Fibrosis)
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Graphical abstract

Open AccessReview
Impact of Biomaterials on Differentiation and Reprogramming Approaches for the Generation of Functional Cardiomyocytes
Received: 21 July 2018 / Revised: 17 August 2018 / Accepted: 18 August 2018 / Published: 21 August 2018
Cited by 1 | PDF Full-text (2177 KB) | HTML Full-text | XML Full-text
Abstract
The irreversible loss of functional cardiomyocytes (CMs) after myocardial infarction (MI) represents one major barrier to heart regeneration and functional recovery. The combination of different cell sources and different biomaterials have been investigated to generate CMs by differentiation or reprogramming approaches although at [...] Read more.
The irreversible loss of functional cardiomyocytes (CMs) after myocardial infarction (MI) represents one major barrier to heart regeneration and functional recovery. The combination of different cell sources and different biomaterials have been investigated to generate CMs by differentiation or reprogramming approaches although at low efficiency. This critical review article discusses the role of biomaterial platforms integrating biochemical instructive cues as a tool for the effective generation of functional CMs. The report firstly introduces MI and the main cardiac regenerative medicine strategies under investigation. Then, it describes the main stem cell populations and indirect and direct reprogramming approaches for cardiac regenerative medicine. A third section discusses the main techniques for the characterization of stem cell differentiation and fibroblast reprogramming into CMs. Another section describes the main biomaterials investigated for stem cell differentiation and fibroblast reprogramming into CMs. Finally, a critical analysis of the scientific literature is presented for an efficient generation of functional CMs. The authors underline the need for biomimetic, reproducible and scalable biomaterial platforms and their integration with external physical stimuli in controlled culture microenvironments for the generation of functional CMs. Full article
(This article belongs to the Special Issue Tissue Regeneration and Fibrosis)
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Open AccessFeature PaperReview
Vascular Mechanobiology: Towards Control of In Situ Regeneration
Received: 20 May 2017 / Revised: 16 June 2017 / Accepted: 23 June 2017 / Published: 3 July 2017
Cited by 6 | PDF Full-text (4132 KB) | HTML Full-text | XML Full-text
Abstract
The paradigm of regenerative medicine has recently shifted from in vitro to in situ tissue engineering: implanting a cell-free, biodegradable, off-the-shelf available scaffold and inducing the development of functional tissue by utilizing the regenerative potential of the body itself. This approach offers a [...] Read more.
The paradigm of regenerative medicine has recently shifted from in vitro to in situ tissue engineering: implanting a cell-free, biodegradable, off-the-shelf available scaffold and inducing the development of functional tissue by utilizing the regenerative potential of the body itself. This approach offers a prospect of not only alleviating the clinical demand for autologous vessels but also circumventing the current challenges with synthetic grafts. In order to move towards a hypothesis-driven engineering approach, we review three crucial aspects that need to be taken into account when regenerating vessels: (1) the structure-function relation for attaining mechanical homeostasis of vascular tissues, (2) the environmental cues governing cell function, and (3) the available experimental platforms to test instructive scaffolds for in situ tissue engineering. The understanding of cellular responses to environmental cues leads to the development of computational models to predict tissue formation and maturation, which are validated using experimental platforms recapitulating the (patho)physiological micro-environment. With the current advances, a progressive shift is anticipated towards a rational and effective approach of building instructive scaffolds for in situ vascular tissue regeneration. Full article
(This article belongs to the Special Issue Tissue Regeneration and Fibrosis)
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