A unique Thy-1-negative immuno-fibroblast population emerges as a key determinant of fibrotic outcomes to biomaterials

Microporous annealed particle (MAP) hydrogels are an exciting new development in biomaterial design. They regulate innate and acquired immunity which has been linked to their ability to evade normal host-material fibrosis. Yet, resident stromal fibroblasts, not immune cells, are the arbiters of the extracellular matrix assembly that characterizes fibrosis. In other idiopathic fibrotic disorders, a fibroblast subpopulation defined by its loss of cell surface Thy-1 expression is strongly correlated with degree of fibrosis. We have previously shown that Thy-1 is a critical αvβ3 integrin regulator that enables normal fibroblast mechanosensing and here, leveraging non-fibrosing MAP gels, we demonstrate that Thy-1-/- mice mount a robust response to MAP gels that remarkably resembles a classical foreign body response. We further find that within the naive, Thy-1+ fibroblast population exists a distinct and cryptic αSMA+ Thy-1- population that emerges in response to IL-1β and TNFα. Employing single-cell RNA sequencing, we find that IL-1β/TNFα-induced Thy-1- fibroblasts actually consist of two distinct subpopulations, both of which are strongly pro-inflammatory. These findings illustrate the emergence of a unique pro-inflammatory, pro-fibrotic fibroblast subpopulation that is central to material-associated fibrosis likely through amplifying local inflammatory signaling.

Trigonelline hydrochloride conjugated onto PEGylated nanodiamond for a selective encapsulation efficiency and controlled release for inhibition of collagen fibrillation

Recently, researchers are involved in finding a cure for fibrotic disorders, which is an acute disease. Along with an ideal drug, a superlative carrier is required for developing a sustainable...

Lysophospholipid Mediators in Health and Disease

Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes. Both molecules are established extracellular lipid mediators that signal via specific G protein–coupled receptors in vertebrates. This widespread signaling axis regulates the development, physiological functions, and pathological processes of all organ systems. Indeed, recent research into LPA and S1P has revealed their important roles in cellular stress signaling, inflammation, resolution, and host defense responses. In this review, we focus on how LPA regulates fibrosis, neuropathic pain, abnormal angiogenesis, endometriosis, and disorders of neuroectodermal development such as hydrocephalus and alopecia. In addition, we discuss how S1P controls collective behavior, apoptotic cell clearance, and immunosurveillance of cancers. Advances in lysophospholipid research have led to new therapeutics in autoimmune diseases, with many more in earlier stages of development for a wide variety of diseases, such as fibrotic disorders, vascular diseases, and cancer. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Naringenin: A Promising Therapeutic Agent against Organ Fibrosis

Fibrosis is the final common pathology of most chronic diseases as seen in the heart, liver, lung, kidney, and skin and contributes to nearly half of death in the developed countries. Fibrosis, or scarring, is mainly characterized by the transdifferentiation of fibroblasts into myofibroblasts and the excessive accumulation of extracellular matrix (ECM) secreted by myofibroblasts. Despite immense efforts made in the field of organ fibrosis over the past decades and considerable understanding of the occurrence and development of fibrosis gained, there is still lack of an effective treatment for fibrotic diseases. Therefore, identifying a new therapeutic strategy against organ fibrosis is an unmet clinical need. Naringenin, a flavonoid that occurs naturally in citrus fruits, has been found to confer a wide range of pharmacological effects including antioxidant, anti-inflammatory, and anticancer benefits and thus potentially exerting preventive and curative effects on numerous diseases. In addition, emerging evidence has revealed that naringenin can prevent the pathogenesis of fibrosis in vivo and in vitro via the regulation of various pathways that involved signaling molecules such as transforming growth factor-β1/small mother against decapentaplegic protein 3 (TGF-β1/Smad3), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), sirtuin1 (SIRT1), nuclear factor-kappa B (NF-κB), or reactive oxygen species (ROS). Targeting these profibrotic pathways by naringenin could potentially become a novel therapeutic approach for the management of fibrotic disorders. In this review, we present a comprehensive summary of the antifibrotic roles of naringenin in vivo and in vitro and their underlying mechanisms of action. As a food derived compound, naringenin may serve as a promising drug candidate for the treatment of fibrotic disorders.

Understanding Drivers of Ocular Fibrosis: Current and Future Therapeutic Perspectives

Ocular fibrosis leads to severe visual impairment and blindness worldwide, being a major area of unmet need in ophthalmology and medicine. To date, the only available treatments are antimetabolite drugs that have significant potentially blinding side effects, such as tissue damage and infection. There is thus an urgent need to identify novel targets to prevent/treat scarring and postsurgical fibrosis in the eye. In this review, the latest progress in biological mechanisms underlying ocular fibrosis are discussed. We also summarize the current knowledge on preclinical studies based on viral and non-viral gene therapy, as well as chemical inhibitors, for targeting TGFβ or downstream effectors in fibrotic disorders of the eye. Moreover, the role of angiogenetic and biomechanical factors in ocular fibrosis is discussed, focusing on related preclinical treatment approaches. Moreover, we describe available evidence on clinical studies investigating the use of therapies targeting TGFβ-dependent pathways, angiogenetic factors, and biomechanical factors, alone or in combination with other strategies, in ocular tissue fibrosis. Finally, the recent progress in cell-based therapies for treating fibrotic eye disorders is discussed. The increasing knowledge of these disorders in the eye and the promising results from testing of novel targeted therapies could offer viable perspectives for translation into clinical use.

Reidel’s Thyroiditis, a Diagnostic and Management Challenge: A Case Report and Review of the Literature

Riedel's thyroiditis is a very rare inflammatory condition. It affects not only the thyroid gland but also the adjacent vital structures. It may also be associated with different forms of systemic fibrotic disorders. The exact etiology is unknown, but currently, the most favorable opinion is that it is a localized form of the systemic fibrotic process. We report the case of a 38-year-old woman, presented with a 10-month history of progressive hypothyroidism, dysphonia, and dysphagia. A Doppler ultrasound study revealed massive thyroid enlargement with multiple Eu TIRADS 3 and 4 nodules. Fine needle aspiration was noncontributive on two occasions. A hard subtotal thyroidectomy was performed. Pathological study confirmed Riedel's thyroiditis with the presence of IgG4 antibodies in immunohistochemistry. The patient was successfully treated with levothyroxine replacement and corticosteroid therapy with rapid resolution of obstructive symptoms. The case descriptions highlight the diagnostic challenge of this disease, describe the response to surgical management and corticosteroid therapy, and give a short review of the subject.

Perspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies

Tissue fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components that result from the disruption of regulatory processes responsible for ECM synthesis, deposition, and remodeling. Fibrosis develops in response to a trigger or injury and can occur in nearly all organs of the body. Thus, fibrosis leads to severe pathological conditions that disrupt organ architecture and cause loss of function. It has been estimated that severe fibrotic disorders are responsible for up to one-third of deaths worldwide. Although intensive research on the development of new strategies for fibrosis treatment has been carried out, therapeutic approaches remain limited. Since stem cells, especially mesenchymal stem cells (MSCs), show remarkable self-renewal, differentiation, and immunomodulatory capacity, they have been intensively tested in preclinical studies and clinical trials as a potential tool to slow down the progression of fibrosis and improve the quality of life of patients with fibrotic disorders. In this review, we summarize in vitro studies, preclinical studies performed on animal models of human fibrotic diseases, and recent clinical trials on the efficacy of allogeneic and autologous stem cell applications in severe types of fibrosis that develop in lungs, liver, heart, kidney, uterus, and skin. Although the results of the studies seem to be encouraging, there are many aspects of cell-based therapy, including the cell source, dose, administration route and frequency, timing of delivery, and long-term safety, that remain open areas for future investigation. We also discuss the contemporary status, challenges, and future perspectives of stem cell transplantation for therapeutic options in fibrotic diseases as well as we present recent patents for stem cell-based therapies in organ fibrosis.

Epithelial-to-Mesenchymal Transition in Fibrosis: Concepts and Targeting Strategies

The epithelial-to-mesenchymal transition (EMT), an embryonic program relaunched during wound healing and in pathological conditions such as fibrosis and cancer, continues to gain the attention of the research community, as testified by the exponential trend of publications since its discovery in the seventies. From the first description as a mesenchymal transformation, the concept of EMT has been substantially refined as an in-depth comprehension of its functional role has recently emerged thanks to the implementation of novel mouse models as well as the use of sophisticated mathematical modeling and bioinformatic analysis. Nevertheless, attempts to targeting EMT in fibrotic diseases are at their infancy and continue to pose several challenges. The aim of this mini review is to recapitulate the most recent concepts in the EMT field and to summarize the different strategies which have been exploited to target EMT in fibrotic disorders.

Interpreting Immunoregulation in Lung Fibrosis: A New Branch of the Immune Model

Immunostimulation is recognized as an important contribution in lung fibrosis in some animal models and patient subsets. With this review, we illustrate an additional scenario covering the possible implication of immunoregulation during fibrogenesis. Available animal and human data indicate that pulmonary fibrosis also includes diverse and discrete immunoregulating populations comprising regulatory lymphocytes (T and B regs) and myeloid cells (immunosuppressive macrophages and myeloid-derived suppressive cells; MDSC). They are initially recruited to limit the establishment of deleterious inflammation but participate in the development of lung fibrosis by producing immunoregulatory mediators (mainly TGF-β1 and IL-10) that directly or indirectly stimulate fibroblasts and matrix protein deposition. The existence of this silent immunoregulatory environment sustains an alternative mechanism of fibrosis that explains why in some conditions neither pro-inflammatory cytokine deficiency nor steroid and immunosuppressive therapies limit lung fibrosis. Therefore, the persistent presence of immunoregulation is an important parameter to consider for refining therapeutical strategies in lung fibrotic disorders under non-immunostimulatory conditions.