Serine protease 35 regulates the fibroblast matrisome in response to hyperosmotic stress.

Hyperosmotic stress occurs in several diseases, but its long-term effects are largely unknown. We used sorbitol-treated human fibroblasts in 3D culture to study the consequences of hyperosmotic stress in the skin. Sorbitol regulated many genes, which help cells cope with the stress condition.

Phase-specific signatures of wound fibroblasts and matrix patterns define cancer-associated fibroblast subtypes.

Healing wounds and cancers present remarkable cellular and molecular parallels, but the specific roles of the healing phases are largely unknown. We developed a bioinformatics pipeline to identify genes and pathways that define distinct phases across the time-course of healing. Their comparison to cancer transcriptomes revealed that a resolution phase wound signature is associated with increased severity in skin cancer and enriches for extracellular matrix-related pathways.

Long-Term Imaging of Wound Angiogenesis with Large Scale Optoacoustic Microscopy.

Wound healing is a well-coordinated process, necessitating efficient formation of new blood vessels. Vascularization defects are therefore a major risk factor for chronic, non-healing wounds. The dynamics of mammalian tissue revascularization, vessel maturation, and remodeling remain poorly understood due to lack of suitable in vivo imaging tools.

Wound Repair, Scar Formation, and Cancer: Converging on Activin.

Wound repair is a highly regulated process that requires the interaction of various cell types. It has been shown that cancers use the mechanisms of wound healing to promote their own growth. Therefore, it is of importance to identify common regulators of wound repair and tumor formation and to unravel their functions and mechanisms of action.

Antagonism of interferon signaling by fibroblast growth factors promotes viral replication.

Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross-talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FGF receptor signaling in keratinocytes promoted the expression of interferon-stimulated genes (ISG) and proteins in vitro and in vivo.

Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds.

Matrix deposition is essential for wound repair, but when excessive, leads to hypertrophic scars and fibrosis. The factors that control matrix deposition in skin wounds have only partially been identified and the consequences of matrix alterations for the mechanical properties of wounds are largely unknown. Here, we report how a single diffusible factor, activin A, affects the healing process across scales.

A paracrine activin A-mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming.

Cancer-associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next-generation therapies. We discovered that cancer cell-derived activin A reprograms fibroblasts into pro-tumorigenic CAFs. Mechanistically, this occurs via Smad2-mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration.

Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome.

Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program.

The mechanical fingerprint of murine excisional wounds.

Unlabelled: A multiscale mechanics approach to the characterization of murine excisional wounds subjected to uniaxial tensile loading is presented. Local strain analysis at a physiological level of tension uncovers the presence of two distinct regions within the wound: i) a very compliant peripheral cushion and ii) a core area undergoing modest deformation. Microstructural visualizations of stretched wound specimens show negligible engagement of the collagen located in the center of a 7-day old wound; fibers remain coiled despite the applied tension, confirming the existence of a mechanically isolated wound core.

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages.

Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes.

Pigment epithelium-derived factor as a multifunctional regulator of wound healing.

During dermal wound repair, hypoxia-driven proliferation results in dense but highly permeable, disorganized microvascular networks, similar to those in solid tumors. Concurrently, activated dermal fibroblasts generate an angiopermissive, provisional extracellular matrix (ECM). Unlike cancers, wounds naturally resolve via blood vessel regression and ECM maturation, which are essential for reestablishing tissue homeostasis.

U.S. dental students' attitudes toward research and science: impact of research experience.

This study aimed to provide a first nationwide assessment of dental students' attitudes toward the importance of research and its integration into the dental curriculum. For this purpose, the American Association for Dental Research National Student Research Group developed an online survey that was distributed to 89 percent of U.S.

Therapeutic Approaches to the Regulation of Wound Angiogenesis.

Significance: Re-establishment of a functional vascular network is a critical component of successful wound repair. One of the most potent pro-angiogenic agents is vascular endothelial growth factor (VEGF), which, from a basic science and pre-clinical perspective, seems ideal for the therapeutic stimulation of blood vessel growth in non-healing wounds.

Critical Issues: Current strategies to improve the dysfunctional angiogenesis that occurs in non-healing wounds are inadequate with regard to the nature and magnitude of the clinical problem.

Mechanisms of vessel regression: toward an understanding of the resolution of angiogenesis.

Physiological angiogenesis refers to a naturally occurring process of blood vessel growth and regression, and it occurs as an integral component of tissue repair and regeneration. During wound healing, sprouting and branching results in an extensive yet immature and leaky neovascular network that ultimately resolves by systematic pruning of extraneous vessels to yield a stable, well-perfused vascular network ideally suited to maintain tissue homeostasis. While the molecular mechanisms of blood vessel growth have been explored in numerous cell and animal models in remarkable detail, the endogenous factors that prevent further angiogenesis and control vessel regression have not received much attention and are largely unknown.

Sprouty2 downregulates angiogenesis during mouse skin wound healing.

Angiogenesis is regulated by signals received by receptor tyrosine kinases such as vascular endothelial growth factor receptors. Mammalian Sprouty (Spry) proteins are known to function by specifically antagonizing the activation of the mitogen-activated protein kinase signaling pathway by receptor tyrosine kinases, a pathway known to promote angiogenesis. To examine the role of Spry2 in the regulation of angiogenesis during wound repair, we used a model of murine dermal wound healing.