Autophagy is the highly conserved catabolic process, which enables the survival of a cell under unfavorable environmental conditions. In a constantly changing environment, cells must be capable of dynamically oscillating between anabolism and catabolism in order to maintain cellular homeostasis. In this context, the activity of the mechanistic Target Of Rapamycin Complex 1 (mTORC1) is of major importance

TANK-binding kinase 1 (TBK1) is a druggable multifunctional kinase that exerts a broad spectrum of functions in cells. These range from innate immunity, inflammation and interferon (IFN) signaling, through selective autophagy, specifically mitophagy and xenophagy, to energy homeostasis. Thus, it is not surprising that TBK1 is involved in many cellular signaling pathways that contribute to diverse pathologies

Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1+ hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcanhdf lacks yolk sac vasculature, with attenuated yolk sac hematopoiesis. CRISPR/Cas9-mediated

Tissue repair and fibrosis, an abnormal form of repair, occur in most human organs in response to injury or inflammation. Fibroblasts play a major role in the normal repair process by differentiating into myofibroblasts that synthesize extracellular matrix (ECM) components and favor tissue remodeling to reestablish normal function and integrity. However, their persistent accumulation at the site of

Wound healing is a complex sequence of tissue protection, replacement, and reorganization leading to regenerated tissue. Disruption of any of these steps results in the process being incomplete as an ulcer or over-exuberant as a hypertrophic scar. Over the past decade, it has become evident that the extracellular matrix and associated components orchestrate this process. However, the cellular events

The lens, suspended in the middle of the eye by tendon-like ciliary zonule fibers and facing three different compartments of the eye, is enclosed in what has been described as the thickest basement membrane in the body. While the protein components of the capsule have been a subject of study for many years, the dynamics of capsule formation, and the region-specific relationship of its basement membrane

Autophagy is a very versatile process through which the cell degrades damaged long-lived proteins, entire organelles, or pathogens, by engulfing them in characteristic double-membrane vesicles and conveying the cargo to lysosomes. It is a dynamic pathway tunable at multiple levels and responsive to nutrient and stress stimuli, also coming from the extracellular microenvironment and its remodeling.

The conserved catabolic process of autophagy is an important control mechanism that degrades cellular organelles, debris and pathogens in autolysosomes. Although autophagy primarily protects against cellular insults, nutrient starvation or oxidative stress, hyper-activation of autophagy is also believed to cause autophagy-dependent cell death (ADCD). ADCD is a caspase-independent form of programmed

The intervertebral disc and cartilage are specialized, extracellular matrix-rich tissues critical for absorbing mechanical loads, providing flexibility to the joints, and longitudinal growth in the case of growth plate cartilage. Specialized niche conditions in these tissues, such as hypoxia, are critical in regulating cellular activities including autophagy, a lysosomal degradation pathway that promotes

A coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferation in vitro and in vivo. These

Autophagy is one of the major cellular degradation pathways, which prevents accumulation of cellular wastes including "hazardous" material such as oxidized proteins and lipids and allows removal of aggregates and dysfunctional organelles. Hence, autophagy is meant to preserve cell survival, and is mostly protective. However, autophagy may trigger a feedforward, exaggerated cycle in which cells continue

Recent in vitro evidence shows that glycosaminoglycans (GAGs) and proteoglycans (PGs) in bone matrix may functionally be involved in the tissue-level toughness of bone. In this study, we showed the effect of biglycan (Bgn), a small leucine-rich proteoglycan enriched in extracellular matrix of bone and the associated GAG subtype, chondroitin sulfate (CS), on the toughness of bone in vivo, using wild-type

SOX9 plays an important role in chondrocyte differentiation and, in the developing axial skeleton, maintains the notochord and the demarcation of intervertebral disc compartments. Diminished expression is linked to campomelic dysplasia, resulting in severe scoliosis and progressive disc degeneration. However, the specific functions of SOX9 in the adult spinal column and disc are largely unknown. Accordingly

The ubiquitin-proteasomal system and the autophagy-lysosome system are two major degradation systems in mammalian cells. Ubiquitin not only regulates proteasomal degradation of substrates but also regulates the autophagy pathway. In one type of macroautophagy, called selective autophagy targeting cargos selectively, cargos are recruited to phagophore in a ubiquitin-dependent manner. Ubiquitin can target

Degradation of dysfunctional, damaged, or misfolded proteins is a crucial component of the protein quality control network to maintain cellular proteostasis. Dysfunction in proteostasis regulation due to imbalances in protein synthesis, folding, and degradation challenges the integrity of the cellular proteome and favors the accumulation of aggregated proteins that can damage cells by a loss of their

Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, ‎poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular

In cartilage tissue engineering, one key challenge is for regenerative tissue to recapitulate the biomechanical functions of native cartilage while maintaining normal mechanosensitive activities of chondrocytes. Thus, it is imperative to discern the micromechanobiological functions of the pericellular matrix, the ∼ 2-4 µm-thick tissue domain in immediate contact with chondrocytes. In this study, we

Matrix metalloproteinases (MMPs) are enzymes with critical roles in biology and pathology. Glycosylation, nitrosylation and proteolysis are known posttranslational modifications (PTMs) regulating intrinsically the activities of MMPs. We discovered MMP citrullination by peptidyl arginine deiminases (PADs) as a new PTM. Upon hypercitrullination, MMP-9 acquired a higher affinity for gelatin than control

Tendons have a uniaxially aligned structure with a hierarchical organization of collagen fibrils crucial for tendon function. Collagen XII is expressed in tendons and has been implicated in the regulation of fibrillogenesis. It is a non-fibrillar collagen belonging to the Fibril-Associated Collagens with Interrupted Triple Helices (FACIT) family. Mutations in COL12A1 cause myopathic Ehlers Danlos Syndrome

Disturbed flow leads to increased inflammatory responses of endothelial cells (ECs) prone to atherogenic state. Currently, little is known about the physiological mechanisms protecting vasculature against disturbed flow-activated ECs leading to atherosclerosis. Understanding the protective mediators involved in EC activation could provide novel therapeutic strategies for atherosclerosis. The extracellular

The tumor microenvironment encompasses a complex cellular network that includes cancer-associated fibroblasts, inflammatory cells, neo-vessels, and an extracellular matrix enriched in angiogenic growth factors. Decorin is one of the main components of the tumor stroma, but it is not expressed by cancer cells. Lack of this proteoglycan correlates with down-regulation of E-cadherin and induction of β-catenin

Latent-transforming growth factor beta-binding protein 2 (LTBP-2) is a major component of arterial and lung tissue and of the ciliary zonule, the system of extracellular fibers that centers and suspends the lens in the eye. LTBP-2 has been implicated previously in the development of extracellular microfibrils, although its exact role remains unclear. Here, we analyzed the three-dimensional structure

Collagen XI is a fibril-forming collagen that regulates collagen fibrillogenesis. Collagen XI is normally associated with collagen II-containing tissues such as cartilage, but it also is expressed broadly during development in collagen I-containing tissues, including tendons. The goals of this study are to define the roles of collagen XI in regulation of tendon fibrillar structure and the relationship

Skin integrity and function depends to a large extent on the composition of the extracellular matrix, which regulates tissue organization. Collagen XII is a homotrimer with short collagenous domains that confer binding to the surface of collagen I-containing fibrils and extended flexible arms, which bind to non-collagenous matrix components. Thereby, collagen XII helps to maintain collagen suprastructure

Although the matricellular protein periostin is prominently upregulated in skin and gingival healing, it plays contrasting roles in myofibroblast differentiation and matrix synthesis respectively. Palatal healing is associated with scarring that can alter or restrict maxilla growth, but the expression pattern and contribution of periostin in palatal healing is unknown. Using periostin-knockout (Postn−/−)

Type V collagen (ColV) is a component of the endothelial basement membrane zone. During angiogenesis, extracellular matrix remodelling results in the release of active protein fragments that display pro- or anti-angiogenic properties. The latter often exert their activity through their heparin-binding site. We previously characterized a ColVα1-derived fragment called HEPV that contains a high affinity-binding

Re-epithelialization describes the resurfacing of a skin wound with new epithelium. In response to various stimuli including that of growth factors, cytokines and extracellular matrix (ECM), wound edge epidermal keratinocytes undergo cytoskeleton rearrangements compatible with their motile behavior and develop protrusive adhesion contacts. Matrix metalloproteinases (MMP) expression is crucial for proper

The identification of barely more than 20,000 human genes was amongst the most surprising outcomes of the human genome project. Alternative splicing provides an essential means of expanding the proteome, enabling a single gene to encode multiple, distinct isoforms by selective inclusion or exclusion of exons from mature mRNA. However, mis-regulation of this process is associated with most human diseases

Efficient quality control and export of procollagen from the cell is crucial for extracellular matrix homeostasis, yet it is still incompletely understood. One of the debated questions is the role of a collagen-specific ER chaperone HSP47 in these processes. Most ER chaperones preferentially bind to unfolded polypeptide chains, enabling selective export of natively folded proteins from the ER after

Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth and metastasis. We have utilized mice over-expressing (Hpa-tg)

Extracellular matrix (ECM) is the foundation on which all cells and organs converge to orchestrate normal physiological functions. In the setting of pathology, the ECM is modified to incorporate additional roles, with modifications including turnover of existing ECM and deposition of new ECM. The fibroblast is center stage in coordinating both normal tissue homeostasis and response to disease. Understanding

Collective cell behaviour during embryogenesis and tissue repair requires the coordination of intercellular junctions, cytoskeleton-dependent shape changes controlled by Rho GTPases, and integrin-dependent cell-matrix adhesion. Many different integrins are simultaneously expressed during wound healing, embryonic development, and sprouting angiogenesis, suggesting that there is extensive integrin/integrin

It is well accepted that the tumor microenvironment plays a pivotal role in cancer onset, development, and progression. The majority of clinical interventions are designed to target either cancer or stroma cells. These emphases have been directed by one of two prevailing theories in the field, the Somatic Mutation Theory and the Tissue Organization Field Theory, which represent two seemingly opposing

Cardiac wound healing after myocardial infarction (MI) evolves from pro-inflammatory to anti-inflammatory to reparative responses, and the cardiac fibroblast is a central player during the entire transition. The fibroblast mirrors changes seen in the left ventricle infarct by undergoing a continuum of polarization phenotypes that follow pro-inflammatory, anti-inflammatory, and pro-scar producing profiles

The cardiac stroma plays essential roles in health and following cardiac damage. The major player of the stroma with respect to extracellular matrix deposition, maintenance and remodeling is the poorly defined fibroblast. It has long been recognized that there is considerable variability to the fibroblast phenotype. With the advent of new, high throughput analytical methods our understanding and appreciation

Fibroblasts are the primary regulator of cardiac extracellular matrix (ECM). In response to disease stimuli cardiac fibroblasts undergo cell state transitions to a myofibroblast phenotype, which underlies the fibrotic response in the heart and other organs. Identifying regulators of fibroblast state transitions would inform which pathways could be therapeutically modulated to tactically control maladaptive

During lung development, the mesenchyme and epithelium are dependent on each other for instructive morphogenic cues that direct proliferation, cellular differentiation and organogenesis. Specification of epithelial and mesenchymal cell lineages occurs in parallel, forming cellular subtypes that guide the formation of both transitional developmental structures and the permanent architecture of the adult

Complex intercellular interactions as well as biomolecular and biomechanical cues from the extracellular matrix (ECM) profoundly affect cellular functions. Traditional transcriptomic and proteomic approaches have provided insight into disease progression by identifying discrete cellular subpopulations or microenvironmental signatures characteristic of normal or pathological tissues, however these techniques

Tumor progression is marked by dense collagenous matrix accumulations that dynamically reorganize to accommodate a growing and invasive tumor mass. Cancer-associated fibroblasts (CAFs) play an essential role in matrix remodeling and influence other processes in the tumor microenvironment, including angiogenesis, immunosuppression, and invasion. These findings have spawned efforts to elucidate CAF functionality

Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in

The growth factor progranulin plays a critical role in bladder cancer by modulating tumor cell motility and invasion. Progranulin regulates remodeling of the actin cytoskeleton by interacting with drebrin, an actin binding protein that regulates tumor growth. We previously discovered that progranulin depletion inhibits epithelial-to-mesenchymal transition and markedly reduces in vivo tumor growth.

Inflammation contributes to the development of heart failure (HF) through multiple mechanisms including regulating extracellular matrix (ECM) degradation and deposition. Interactions between cells in the myocardium orchestrates the magnitude and duration of inflammatory cell recruitment and ECM remodeling events associated with HF. More recently, studies have shown T-cells have signficant roles in

The architectural complexity of the lung is crucial to its ability to function as an organ of gas exchange; the branching tree structure of the airways transforms the tracheal cross-section of only a few square centimeters to a blood-gas barrier with a surface area of tens of square meters and a thickness on the order of a micron or less. Connective tissue comprised largely of collagen and elastic

Alterations in the composition of the extracellular matrix (ECM) critically regulate the cellular responses in tissue repair, remodeling, and fibrosis. After injury, proteolytic degradation of ECM generates bioactive ECM fragments, named matricryptins, exposing cryptic sites with actions distinct from the parent molecule. Matricryptins contribute to the regulation of inflammatory, reparative, and fibrogenic

The fibroblast is a key mediator of wound healing in the heart and other organs, yet how it integrates multiple time-dependent paracrine signals to control extracellular matrix synthesis has been difficult to study in vivo. Here, we extended a computational model to simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction (MI) in response to time-dependent data for nine

The involvement of fibrosis as an underlying pathology in heart diseases is becoming increasingly clear. In recent years, fibrosis has been granted a causative role in heart diseases and is now emerging as a major contributor to Atrial Fibrillation (AF) pathogenesis. AF is the most common arrhythmia encountered in the clinic, but the substrate for AF is still being debated. Consensus in the field is

Heparan sulfate (HS) regulates the activity of many signaling molecules critical for the development of endochondral bones. Even so, mice with a genetically altered HS metabolism display a relatively mild skeletal phenotype compared to the defects observed in other tissues and organs pointing to a reduced HS dependency of growth-factor signaling in chondrocytes. To understand this difference, we have

Prolyl 3-hydroxylation is a rare collagen type I post translational modification in fibrillar collagens. The primary 3Hyp substrate sites in type I collagen are targeted by an endoplasmic reticulum (ER) complex composed by cartilage associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1) and prolyl cis/trans isomerase B, whose mutations cause recessive forms of osteogenesis imperfecta with impaired

Fibrotic posterior capsular opacification (PCO), one of the major complications of cataract surgery, occurs when lens epithelial cells (LCs) left behind post cataract surgery (PCS) undergo epithelial to mesenchymal transition, migrate into the optical axis and produce opaque scar tissue. LCs left behind PCS robustly produce fibronectin, although its roles in fibrotic PCO are not known. In order to

Cells have evolved mechanisms to sense the composition of their adhesive microenvironment. Although much is known about general mechanisms employed by adhesion receptors to relay signals between the extracellular environment and the cytoskeleton, the nuances of ligand-specific signalling remain undefined. Here, we investigated how glomerular podocytes, and four other basement membrane-associated cell

Null mutations in CRTAP or P3H1, encoding cartilage-associated protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate

Hyaluronan plays a key role in regulating inflammation and tumor angiogenesis. Of the three transmembrane hyaluronan synthases, HAS2 is the main pro-angiogenic enzyme responsible for excessive hyaluronan production. We discovered that HAS2 was degraded in vascular endothelial cells via autophagy evoked by nutrient deprivation, mTOR inhibition, or pro-autophagic proteoglycan fragments endorepellin and

Versican is a large extracellular matrix (ECM) chondroitin sulfate (CS) proteoglycan found in most soft tissues, which is encoded by the VCAN gene. At least four major isoforms (V0, V1, V2, and V3) are generated via alternative splicing. The isoforms of versican are expressed and accumulate in various tissues during development and disease, where they contribute to ECM structure, cell growth and migration

The transcriptional events that promote invasive and metastatic phenotypes in renal cell carcinoma (RCC) remain poorly understood. Here we report that the decreased expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) and the increased expression of several genes encoding collagen family members are associated with RCC tumor progression. PGC1α restoration attenuates

Although the molecular mechanisms behind tendon disease remain obscure, aberrant stromal matrix turnover and tissue hypervascularity are known hallmarks of advanced tendinopathy. We harness a tendon explant model to unwind complex cross-talk between the stromal and vascular tissue compartments. We identify the hypervascular tendon niche as a state-switch that gates degenerative matrix remodeling within

The coordinated spatial and temporal regulation of gene expression in the murine hindlimb determines the identity of mesenchymal progenitors and the development of diversity of musculoskeletal tissues they form. Hindlimb development has historically been studied with lineage tracing of individual genes selected a priori, or at the bulk tissue level, which does not allow for the determination of single

β4GalT7 is a transmembrane Golgi enzyme, encoded by B4GALT7, that plays a pivotal role in the proteoglycan linker region formation during proteoglycan biosynthesis. Defects in this enzyme give rise to a rare autosomal recessive form of Ehlers-Danlos syndrome (EDS), currently known as ‘spondylodysplastic EDS (spEDS-B4GALT7)’. This EDS subtype is mainly characterized by short stature, hypotonia and skeletal