The Human Epidermal Basement Membrane -A Shaped and Cell Instructive Platform That Aging Slowly Alters Eva Roig-Rosello, Patricia Rousselle

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The Human Epidermal Basement Membrane -A Shaped and Cell Instructive Platform That Aging Slowly Alters Eva Roig-Rosello, Patricia Rousselle The human epidermal basement membrane -a shaped and cell instructive platform that aging slowly alters Eva Roig-Rosello, Patricia Rousselle To cite this version: Eva Roig-Rosello, Patricia Rousselle. The human epidermal basement membrane -a shaped and cell instructive platform that aging slowly alters. Biomolecules, MDPI, 2020, 10 (12), pp.1607. 10.3390/biom10121607. hal-03037856 HAL Id: hal-03037856 https://hal.archives-ouvertes.fr/hal-03037856 Submitted on 3 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 Review 2 The human epidermal basement membrane – a 3 shaped and cell instructive platform that aging 4 slowly alters 5 Eva Roig-Rosello 1,2 and Patricia Rousselle 1,* 6 1 Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, UMR 5305, CNRS - Université Lyon 1, 7 Institut de Biologie et Chimie des Protéines, SFR BioSciences Gerland-Lyon Sud, 7 passage du Vercors, 8 Lyon, 69367, France 9 2 Roger Gallet SAS, 4 rue Euler, 75 008 Paris, France 10 * Correspondence: [email protected] 11 Received: date; Accepted: date; Published: date 12 Abstract: One of the most important functions of skin is to act as a protective barrier. To fulfill this 13 role, the structural integrity of the skin depends on the dermal–epidermal junction, a complex 14 network of extracellular matrix macromolecules that connect the outer epidermal layer to the 15 underlying dermis. This junction provides both a structural support to keratinocytes and a specific 16 niche that mediates signals influencing their behavior. It displays a distinctive microarchitecture 17 characterized by an undulating pattern, strengthening dermal–epidermal connectivity and cross- 18 talk. The optimal stiffness arising from the overall molecular organization together with 19 characteristic anchoring complexes keeps the dermis and epidermis layers extremely well connected 20 and capable of proper epidermal renewal and regeneration. Because of intrinsic and extrinsic 21 factors, a large number of structural and biological changes accompany skin aging. These changes 22 progressively weaken the dermal–epidermal junction substructure and affect its functions, 23 contributing to the gradual decline in overall skin physiology. Most changes involve reduced 24 turnover or altered enzymatic or nonenzymatic posttranslational modifications, compromising the 25 mechanical properties of matrix components and cells. This review combines recent and older data 26 on organization of the dermal–epidermal junction, its mechanical properties and role in 27 mechanotransduction, its involvement in regeneration, and its fate during the aging process. 28 Keywords: extracellular matrix; basement membrane; dermal-epidermal junction, skin, epidermal 29 rete-ridge, dermal papilla, aging, mechanical properties 30 31 1. Introduction 32 One of the most important functions of skin is to act as a protective barrier. To fulfil this role, 33 the structural integrity of the skin depends on the basement membrane, a complex network of 34 extracellular matrix (ECM) macromolecules that connect the outer epidermal layer to the 35 underlying dermis. The epidermis, which consists primarily of keratinocytes, is continuously 36 renewed by the proliferation of stem cells and the differentiation of their progeny. These cells 37 undergo terminal differentiation as they exit the basal layer and move toward the surface, where 38 they die and slough off [1]. Basal keratinocytes adjoin the dermal–epidermal junction (DEJ), a cell 39 surface–associated ECM that acts in concerted action by both epidermal and dermal cells [2]. The 40 DEJ provides both structural support to keratinocytes and a specific niche that mediates signals 41 influencing their behavior. Biomolecules 2020, 10, x; doi: FOR PEER REVIEW www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x FOR PEER REVIEW 2 of 32 42 Much progress has been made in understanding the molecular structure and functions of 43 extracellular macromolecules at the DEJ. Similar to all archetypal thin planar basement membranes, 44 the DEJ consists primarily of laminins, collagen IV, nidogens, and the heparan sulfate (HS) 45 proteoglycan perlecan, all of which are necessary for tissue organization and structural integrity 46 [3,4,5]. Electron microscopy evaluation of the DEJ following conventional fixation protocols has 47 revealed a lamina densa and lamina lucida much like those of other basement membranes. In 48 addition, the DEJ contains numerous regular structures known as anchoring complexes [6,7]. These 49 anchoring complexes consist of electron-dense thickenings of the basolateral plasma membrane, 50 which are called hemidesmosomes because of their resemblance to half of the desmosome plaques 51 present on the plasma membranes at sites of cell–cell contact. Cytoskeletal keratin filaments insert 52 into the hemidesmosomes, bridging the plasma membranes and providing a continuous 53 intercellular network throughout the entire epidermis. Thin filaments known as anchoring 54 filaments appear to traverse the lamina lucida and insert into the lamina densa, tethering the 55 hemidesmosomes to the basement membrane [8,9]. Other structures, the anchoring fibrils, originate 56 within the lamina densa and project into the upper regions of the papillary dermis. They either loop 57 back and reinsert into the lamina densa or extend perpendicularly from the basement membrane 58 and insert into anchoring plaques. Anchoring plaques are electron-dense condensations of the ends 59 of anchoring fibrils together with other intrinsic constituents of the basal lamina [10,11]. Additional 60 anchoring fibrils originate in the plaques and extend further into the papillary dermis. The 61 complexity of these structures probably serves to increase the frictional resistance of external 62 epithelia to applied forces [12]. 63 In addition, the DEJ provides a highly dynamic microenvironment to the keratinocytes by 64 participating in epidermal renewal under physiological conditions and taking part in repair 65 processes during skin healing [13,14,15,16]. In both scenarios, the DEJ serves as an adhesive 66 scaffold, and its constituents may be part of signaling events that vary depending on maturation 67 processes driven by ECM-modifying enzymes [17,18]. Basement membranes can function as 68 signaling platforms by sequestering growth factors and other ligands. Perlecan, agrin, and collagen 69 XVIII bind to many growth factors via HS glycosaminoglycan chains [19,20]. Through binding and 70 sequestering of soluble growth factors in the presence of appropriate cell-mediated forces or 71 proteolytic degradation, basement membranes can also enable spatial-temporal regulation of 72 receptor–ligand interactions. Furthermore, these ECMs can generate and transduce mechanical 73 signals. Through interactions with cell surface receptors, these ECMs modulate a remarkably wide 74 range of signaling processes. 75 2. General organization of the interfollicular DEJ 76 The originally inferred thickness of the DEJ, around 100 nm, was based on measurements made 77 on transmission electron microscopy images taken of human skin cross-sections. The development 78 of imaging approaches that require less or no chemical treatment of samples, such as atomic force 79 microscopy (AFM) and super-resolution light microscopy, consistently have allowed re-evaluation 80 of basement membrane thickness values, yielding results that double those obtained by transmission 81 electron microscopy [5,21]. 82 2.1. The DEJ undulating pattern and the rete ridges 83 84 The DEJ displays a distinctive microarchitecture characterized by an undulating pattern arising 85 from epidermal rete ridges that are downgrowths of the epidermis within the papillary dermis, 86 leading to the characteristic varying number of strata along the epidermis [22] (Figure 1). These 87 nipple-like elevations indent the epidermis layer and substantially increase the surface area of the 88 DEJ, strengthening dermal–epidermal connectivity and keeping the dermis and the epidermis layer 89 well connected. In addition, they increase the overall number of hemidesmosomes at the DEJ and 90 subsequently improve the strength of the interface and of the mechanical properties of skin [23,24]. Biomolecules 2020, 10, x FOR PEER REVIEW 3 of 32 A Epidermis Rete-ridges Dermal papillae Dermis B Micro-vessels 91 92 93 Figure 1. Histological section of human skin showing the undulated structure of the dermal-epidermal 94 junction with epidermal rete-ridges and dermal papillae. Section of a paraffin‐embedded skin biopsy from the 95 abdomen of a 30 years old donor was processed for HES staining. (A) Epidermis, dermis, rete-ridges and dermal 96 papillae are shown. (B) Micro-vessels are shown within dermal papillae. Scale bars = 100 μm. 97 98 Rete ridges surround the dermal papillae, which can be seen as small extensions protruding 99 from the papillary dermis within the epidermis. These two structures are perfectly embedded; the 100 alternation of a rete ridge with a dermal papilla creates
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