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Hyaluronan accumulation in the superficial epidermal layers in CD44-deficient mouse tail epidermis by tape stripping and retinoic acid. Skin specimens from wild-type (a, d, j, l) and CD44-/-(b, c, e, f, g, h, i, k, m) animals were stained for hyaluronan. Panels (a–c) are from ear skin and (d–i) from tail skin of adult animals, whereas (j, k) are from D17 embryonic head skin and (l, m) from tail skin of newborn animals. Specimens in g–i were wounded with tape stripping 2 days (g) or 3 days (h, i) before sample collection; specimens in (c, f) were treated with retinoic acid for 4 days. Untreated adult epidermis from both WT and CD44-/-animals shows just
Source publication
CD44 is a ubiquitous cell surface glycoprotein, involved in important cellular functions including cell adhesion, migration, and modulation of signals from cell surface receptors. While most of these CD44 functions are supposed to involve hyaluronan, relatively little is known about the contribution of CD44 to hyaluronan maintenance and organizatio...
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Objective:
Management and diagnosis of multiple human cancers remains a challenge and search for a common biomarker is still debatable. In this manuscript we have evaluated the use of monoclonal antibody UNIVmAb, to detect the protein (H11) as a common biomarker for all cancers irrespective of the grade and origin. We have shown by both ELISA and...
Tumor necrosis factor-Stimulated Gene 6 protein (TSG-6) is a hyaluronan (HA)-binding glycoprotein containing an HA-binding Link module. Because of its well-defined structure, HA binding properties and small size, TSG-6 is an excellent candidate as an alternative to animal-derived HA-binding protein (HABP) for the detection of HA. The present work d...
Background:
Hyaluronan (HA) is a ligand for the CD44 receptor which is crucial to cancer cell proliferation and metastasis. High levels of CD44 expression in many cancers have encouraged the development of HA-based carriers for anti-cancer therapeutics.
Purpose:
The objective of this study was to determine whether HA conjugation of anticancer dr...
Stabilin-2/HARE is the primary clearance receptor for circulating hyaluronan (HA), a polysaccharide found in the extracellular matrix (ECM) of metazoans. HA has many biological functions including joint lubrication, ocular turgor pressure, skin elasticity and hydration, cell motility, and intercellular signaling, among many others. The regulatory s...
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Citations
... HA binds to the CD44 receptor, expressed by dermal fibroblasts [53], and attenuates MMP1 overexpression [54]. HA can also bind the CD44 receptor on keratinocytes [55] inducing the growth, survival and migration of these epidermis cells [56], which implies an acceleration of the epidermal rejuvenation process. Likewise, the interaction of HA with the CD44 receptor of the keratinocyte also favors the formation and release of lamellar bodies into the extracellular space of the epidermis, which favors the maintenance of the degree of hydration and the rejuvenation of the epidermis [57]. ...
Solar radiation and environmental pollutants are factors that cause changes in the skin that trigger skin aging. The objective of the study is to evaluate the rejuvenating effects of a complex formed by hyaluronic acid supplemented with vitamins, amino acids and oligopeptides in explants of human skin. For this, surplus skin samples have been obtained from donors that have been resected and cultivated on slides with membrane inserts. The complex was administered to some skin explants and the percentage of cells with low, medium and high levels of melanin was evaluated as an indicator of the degree of pigmentation. Other skin segments were irradiated with UVA/UVB, then the product was administered on several slides and the levels of collagen, elastin, sulfated GAG and MMP1 were evaluated. The results show that the administration of the complex significantly reduces the percentage of skin cells with a high melanin content by 16%, and that in skin irradiated with UVA/UVB, there is a decrease in the content of collagen, elastin and sulfate GAGs, and the complex reverses this reduction without changing MMP1 levels. This suggests that the compound has anti-aging and depigmentation effects on the skin, giving a skin rejuvenation appearance.
... HA participates in skin homeostasis and is implicated in keratinocyte differentiation, as recently discussed [14]. Interestingly, it has been shown that CD44 maintains the important skin barrier function, the pericellular keratinocyte matrix [81]. HA, likewise, exerts a vital role in wound healing. ...
Hyaluronan (HA) is a naturally occurring non-sulfated glycosaminoglycan (GAG) localized to the cell surface and the tissue extracellular matrix (ECM). It is composed of disaccharides containing glucuronic acid and N-acetylglucosamine, is synthesized by the HA synthase (HAS) enzymes and is degraded by hyaluronidase (HYAL) or reactive oxygen and nitrogen species (ROS/RNS) actions. HA is deposited as a high molecular weight (HMW) polymer and degraded to low molecular weight (LMW) fragments and oligosaccharides. HA affects biological functions by interacting with HA-binding proteins (hyaladherins). HMW HA is anti-inflammatory, immunosuppressive, and antiangiogenic, whereas LMW HA has pro-inflammatory, pro-angiogenetic, and oncogenic effects. ROS/RNS naturally degrade HMW HA, albeit at enhanced levels during tissue injury and inflammatory processes. Thus, the degradation of endothelial glycocalyx HA by increased ROS challenges vascular integrity and can initiate several disease progressions. Conversely, HA exerts a vital role in wound healing through ROS-mediated HA modifications, which affect the innate immune system. The normal turnover of HA protects against matrix rigidification. Insufficient turnover leads to increased tissue rigidity, leading to tissue dysfunction. Both endogenous and exogenous HMW HA have a scavenging capacity against ROS. The interactions of ROS/RNS with HA are more complex than presently perceived and present an important research topic.
... GAG-CD44 interaction has been found able to enhance the presentation of growth factors to their specific receptors [58]. HA-CD44 interaction allows the formation of a pericellular matrix [93] involved in the regulation of keratinocyte differentiation [6] and in the development of skin barrier [89]. Actually, HA-CD44 binding induces several various signaling pathways, depending on the size of HA polymers. ...
In skin, although the extracellular matrix (ECM) is highly developed in dermis and hypodermis, discrete intercellular spaces between cells of the living epidermal layers are also filled with ECM components. Herein, we review knowledge about structure, localization and role of epidermal hyaluronan (HA), a key ECM molecule. HA is a non-sulfated glycosaminoglycan non-covalently bound to proteins or lipids. Components of the basal lamina maintain some segregation between the epidermis and the underlying dermis, and all epidermal HA is locally synthesized and degraded. Functions of HA in keratinocyte proliferation and differentiation are still controversial. However, through interactions with partners, such as the TSG-6 protein, HA is involved in the formation, organization and stabilization of the epidermal ECM. In addition, epidermal HA is involved in the formation of an efficient epidermal barrier made of cornified keratinocytes. In atopic dermatitis (AD) with profuse alterations of the epidermal barrier, HA is produced in larger amounts by keratinocytes than in normal skin. Epidermal HA inside AD lesional skin is located in enlarged intercellular spaces, likely as the result of disease-related modifications of HA metabolism.
... Interaction between TSG-6 and HA increases the affinity of HA for the CD44 receptor involved in keratinocytes adhesion, proliferation, differentiation and migration (Baranova et al., 2013;Bourguignon et al., 2004Bourguignon et al., , 2014Kavasi et al., 2017;Lesley et al., 2004). CD44 also contributes to maintain a pericellular matrix around keratinocytes (Muto et al., 2019;Pasonen-Seppanen et al., 2012). ...
... A disorganized ECM was described around pre-ovulatory follicles in TSG-6 knockout mice (Fulop et al., 2003). The HA interaction with its CD44 membrane receptor is facilitated by TSG-6 ( Baranova et al., 2013) and this interaction promotes HA internalization together with proliferation and migration Csoka et al., 2001;Pasonen-Seppanen et al., 2012). TSG-6 deficiency may therefore influence the HA-CD44 signaling axis and pathways located downstream of other receptors such as EGFR (Perez et al., 2013). ...
TNFα-stimulated gene 6 (TSG-6) is a soluble protein secreted in the extracellular matrix (ECM) by various cell types in response to inflammatory stimuli. TSG-6 interacts with ECM molecules, particularly hyaluronan (HA), and promotes cutaneous wound closure in mouse. Between epidermal cells, the discrete ECM contains HA and tiny amount of TSG-6. However, challenges imposed to keratinocytes in reconstructed human epidermis (RHE) revealed strong induction of TSG-6 expression, after exposure to Th2 cytokines to recapitulate the atopic dermatitis phenotype, or after fungal infection that causes secretion of cytokines and antimicrobial peptides. Following both types of challenge, enhanced release of TSG-6 happens simultaneously with increased HA production. TSG-6 deficiency in N/TERT keratinocytes was created by inactivating TNFAIP6 using CRISPR/Cas9. Some TSG-6-/- keratinocytes analyzed through scratch assays tend to migrate more slowly, but produce RHE that exhibit normal morphology and differentiation. Few significant alterations were noticed by transcriptomic analysis. Nevertheless, reduced HA content in TSG-6-/- RHE was observed, along with enhanced HA release into culture medium, and this phenotype was even more pronounced following challenging conditions. Reintroduction of cells producing TSG-6 in RHE reduced HA leakage. Our results demonstrate a role for TSG-6 in sequestering HA between epidermal cells in response to inflammation.
... Short fragments of HA (i.e., HA oligomers) can themselves serve as blockers of the interaction of high molecular weight HA (HMW-HA) with CD44, thereby being effective in cancer treatment [53]. Blocking of HA-CD44 interaction by short HA oligomers helped to remove HMW-HA from the surface of both human (HaCaT) and mouse keratinocytes [26,54], to displace HMW-HA from cell surface CD44 [55] and to significantly inhibit the formation of pericellular matrix by ovarian cancer cells [56]. Moreover, exogenously added short HA oligomers have shown the antigrowth effects in lung, mammary, and colon carcinoma cell lines (see Ref. [53] and references therein). ...
Multiple cancer therapies nowadays rely on oxidative stress to damage cancer cells. Here we investigated the biological and molecular effect of oxidative stress on the interaction between CD44 and hyaluronan (HA), as interrupting their binding can hinder cancer progression. Our experiments demonstrated that the oxidation of HA decreased its recognition by CD44, which was further enhanced when both CD44 and HA were oxidized. The reduction of CD44–HA binding negatively affected the proliferative state of cancer cells. Our multi-level atomistic simulations revealed that the binding free energy of HA to CD44 decreased upon oxidation. The effect of HA and CD44 oxidation on CD44–HA binding was similar, but when both HA and CD44 were oxidized, the effect was much larger, in agreement with our experiments. Hence, our experiments and computations support our hypothesis on the role of oxidation in the disturbance of CD44–HA interaction, which can lead to the inhibition of proliferative signaling pathways inside the tumor cell to induce cell death.
... The main markers used for isolation and identification of CSCs include surface cell-adhesion molecules (e.g., CD44, CD133, and EpCAM) and cytoprotective enzymes (such as aldehyde dehydrogenase, ALDH). However, the surface markers that are used to isolate or identify CSCs from diverse malignant tissues are expressed not only by CSCs, but also by many normal tissues [20][21][22][23][24]. Fox et al. revealed that normal human tissues express different CD44 isoforms; for instance, normal epithelial tissues and some tumors express a wide range of variants at high levels. ...
Despite the promise of cancer medicine, major challenges currently confronting the treatment of cancer patients include chemoresistance and recurrence. The existence of subpopulations of cancer cells, known as cancer stem cells (CSCs), contributes to the failure of cancer therapies and is associated with poor clinical outcomes. Of note, one of the recently characterized features of CSCs is augmented mitochondrial function. The cytoskeleton network is essential in regulating mitochondrial morphology and rearrangement, which are inextricably linked to its functions, such as oxidative phosphorylation (OXPHOS). The interaction between the cytoskeleton and mitochondria can enable CSCs to adapt to challenging conditions, such as a lack of energy sources, and to maintain their stemness. Cytoskeleton-mediated mitochondrial trafficking and relocating to the high energy requirement region are crucial steps in epithelial-to-mesenchymal transition (EMT). In addition, the cytoskeleton itself interplays with and blocks the voltage-dependent anion channel (VDAC) to directly regulate bioenergetics. In this review, we describe the regulation of cellular bioenergetics in CSCs, focusing on the cytoskeleton-mediated dynamic control of mitochondrial structure and function.
... The hyaluronan receptor CD44 (Aruffo et al., 1990) binds and organizes pericellular hyaluronan and governs multiple functions at the cell surface (Jokela et al., 2015;Knudson et al., 2018;Pasonen-Seppänen et al., 2012a). CD44 silencing, like HAS2 repression, partially prevented the induction of the inflammatory mediators in melanocytes after UVB, suggesting that hyaluronan-CD44 interaction was involved in the UVB response. ...
Skin is constantly exposed to UVR, the most critical risk factor for melanoma development. Hyaluronan is abundant in the epidermal extracellular matrix and may undergo degradation by UVR. It is hypothesized that an intact hyaluronan coat around the cells protects against various agents including UVR, whereas hyaluronan fragments promote inflammation and tumorigenesis. We investigated whether hyaluronan contributes to the UVB-induced inflammatory responses in primary melanocytes. A single dose of UVB suppressed hyaluronan secretion and the expression of hyaluronan synthases HAS2 and HAS3, the hyaluronan receptor CD44, and the hyaluronidase HYAL2, as well as induced the expression of inflammatory mediators IL6, IL8, CXCL1, and CXCL10. Silencing HAS2 and CD44 partly inhibited the inflammatory response, suggesting that hyaluronan coat is involved in the process. UVB alone caused little changes in the coat, but its removal with hyaluronidase during the recovery from UVB exposure dramatically enhanced the surge of these inflammatory mediators via TLR4, p38, and NF-κB. Interestingly, exogenous hyaluronan fragments did not reproduce the inflammatory effects of hyaluronidase. We hypothesize that the hyaluronan coat on melanocytes is a sensor of tissue injury. Combined with UVB exposure, repeated injuries to the hyaluronan coat could maintain a sustained inflammatory state associated with melanomagenesis.
... 20 CD44 is an abundant cell-surface protein in keratinocytes, important for binding and organizing pericellular hyaluronan, and contributing to its endocytosis. 18,61,62 The Cd44 mRNA level was reduced during epidermal maturation. However, no such trend was found in the CD44 content during immunohistochemical examination of the basal and spinous layers. ...
Epidermis, the surface layer of human skin, is formed by cells called keratinocytes. They divide (making more cells) in the deeper parts of the skin and gradually move towards the surface. Keratinocytes eventually form a layer of dead cells on the skin's surface, and this layer is the main protective barrier against things that might damage or irritate the skin, such as chemicals and germs. A viscous substance called hyaluronan surrounds keratinocytes in the lower, living cell layers. All kinds of injuries to the epidermis, like wounding, infection, and sunburn, trigger a strong inflammatory response by keratinocytes. This response includes increased division of keratinocytes, and their movement to help the injury site recover, as well as increased hyaluronan production and turnover. In many skin diseases the keratinocyte injury‐response is excessive, or even completely unfounded, and harmful. Therefore, factors and treatments that calm down this reaction are potential medicines for some skin diseases. This study from Kuopio, Finland, studied hyaluronan metabolism (i.e. breakdown) in a special model developed in the laboratory, in which keratinocytes separate to produce a normal‐looking epidermis. This model allowed the researchers to demonstrate that vitamin C suppresses both production and degradation of hyaluronan in the epidermis. Since rapid hyaluronan metabolism is an indicator of inflammation, vitamin C – which is an antioxidant ‐ might have a use for suppressing this reaction in keratinocytes. This study calls for more work on the vitamin's mechanism of action, and possible roles in clinical practice.
... 20 CD44 is an abundant cell-surface protein in keratinocytes, important for binding and organizing pericellular hyaluronan, and contributing to its endocytosis. 18,61,62 The Cd44 mRNA level was reduced during epidermal maturation. However, no such trend was found in the CD44 content during immunohistochemical examination of the basal and spinous layers. ...
Background:
Hyaluronan is a large, linear glycosaminoglycan present throughout the narrow extracellular space of the vital epidermis. Increased hyaluronan metabolism takes place in epidermal hypertrophy, wound healing and cancer. Hyaluronan is produced by hyaluronan synthases (HAS1-3) and catabolized by hyaluronidases (HYAL1 and -2), reactive oxygen species (ROS), and the KIAA1199 protein.
Objectives:
To investigate the changes in hyaluronan metabolism during epidermal stratification and maturation, and the impact of vitamin C.
Methods:
Hyaluronan synthesis and expression of the hyaluronan-related genes were analyzed during epidermal maturation from a simple epithelium to a fully differentiated epidermis in organotypic cultures of rat epidermal keratinocytes (REK) using qRT-PCR, immunostainings, and western blotting, in the presence and absence of vitamin C.
Results:
With epidermal stratification, both the production and the degradation of hyaluronan were enhanced, resulting in an increase of hyaluronan fragments of various sizes. While the mRNA levels of Has3 and KIAA1199 remained stable during the maturation, Has1, Has2, and Hyal2 showed a transient upregulation during stratification, Hyal1 remained permanently increased, and the hyaluronan receptor Cd44 decreased. At maturation, Vitamin C downregulated Has2, Hyal2 and Cd44, while it increased high molecular mass hyaluronan in the epidermis, and reduced small fragments in the medium, suggesting stabilization of epidermal hyaluronan.
Conclusions:
Epidermal stratification and maturation is associated with enhanced hyaluronan turnover, and release of large amounts of hyaluronan fragments. The high turnover is suppressed by vitamin C, which is suggested to enhance normal epidermal differentiation in part through its effect on hyaluronan. This article is protected by copyright. All rights reserved.
... 15 In the maturation and remodeling phases of physiologic wound healing, HyA is produced in the wound margin and connective tissue matrix. 16 Chang et al conducted an animals' study to investigate effects of hydroxyapatite/beta-tricalcium phosphate (HA-bTCP) alone and HyA/HA-bTCP combination on bone formation in the calvarial defects of rabbits and concluded that addition of HyA to HA-bTCP particles increase bone formation. 17 Generally, a commercial form of LMW-HyA (Tissue Support; Naturalize, Kassel, Germany) and a biphasic calcium phosphate ceramic combination (MBCPþ; Biomatlante, Nantes, France) are particularly used for surgeries such as periimplant defects and sinus lift augmentation. ...
Hyaluronic acid (HyA) is an outstanding new product in the field of oral and maxillofacial surgery. The aim of this study was to evaluate the effects of HyA on bone regeneration in critical-size calvarial defects. Twenty-four female Sprague-Dawley rats were used in the present study. In each rat, 4 critical-size defects received different treatments: no treatment (control); HyA; Graft; and HyA + Graft combination. New bone formation, defect closure, inflammation, vascular proliferation, immature bone formation, mature bone formation, and bone marrow existence were investigated based on histological findings. The healing parameters related to bone formation (new bone formation, defect closure, immature bone formation) were significantly higher in the HyA group compared with the control group. However, HyA alone was unable to induce sufficient bone regeneration compared with treatments involving graft materials (Graft and HyA + Graft). In the Graft and HyA + Graft groups, prominent enhancement of all healing parameters was noted. The present results demonstrate that HyA alone did not adequately enhance bone regeneration in critical-size defects. Moreover, addition of HyA to a biphasic alloplastic graft material did not result in improved regeneration compared with the graft material alone.
