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Review
. 2018 Dec;374(3):439-453.
doi: 10.1007/s00441-018-2934-7. Epub 2018 Oct 3.

Basement membranes in the cornea and other organs that commonly develop fibrosis

Paramananda Saikia  1 , Carla S Medeiros  1   2 , Shanmugapriya Thangavadivel  1 , Steven E Wilson  3
Affiliations
Review

Basement membranes in the cornea and other organs that commonly develop fibrosis

Paramananda Saikia et al. Cell Tissue Res. 2018 Dec.

Abstract

Basement membranes are thin connective tissue structures composed of organ-specific assemblages of collagens, laminins, proteoglycan-like perlecan, nidogens, and other components. Traditionally, basement membranes are thought of as structures which primarily function to anchor epithelial, endothelial, or parenchymal cells to underlying connective tissues. While this role is important, other functions such as the modulation of growth factors and cytokines that regulate cell proliferation, migration, differentiation, and fibrosis are equally important. An example of this is the critical role of both the epithelial basement membrane and Descemet's basement membrane in the cornea in modulating myofibroblast development and fibrosis, as well as myofibroblast apoptosis and the resolution of fibrosis. This article compares the ultrastructure and functions of key basement membranes in several organs to illustrate the variability and importance of these structures in organs that commonly develop fibrosis.

Keywords: Basement membrane; Cornea; Fibrosis; Lung; Skin.

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Figures

Fig. 1.
Fig. 1.
Schematic diagram of typical components found in basement membranes, using skin as an example. A basal keratinocyte adheres to the underlying basement membrane and dermis via the focal adhesions that transmit mechanical force and regulatory signals that consist of numerous interacting components such as the hemidesmosome with bullous pemphigoid antigen (BPAG), integrin a6b4, laminin 332, perlecan, anchoring fibrils, and dozens of other components that vary depending on the organ and the status (homeostasis, post-injury, etc.) of the tissues. Many of these components extend into, and are part of, the lamina lucida of the basement membrane. The underling lamina densa of the basement membrane is composed of collagen type IV, nidogens, perlecan, laminin 332, that directly interact with each other, and other components. Lamina lucida is not as wide naturally as it is drawn here for clarity reasons. Illustration by David Schumick, BS, CMI. Reprinted with the permission of the Cleveland Clinic Center for Medical Art & Photography © 2018. All Rights Reserved.
Fig. 2.
Fig. 2.
Transmission electron micrograph from central rabbit cornea of the epithelial basement membrane (EBM) at 36,000X magnification. In the cornea, the EBM functions to adhere basal epithelial cells (e) to the underlying stroma and to modulate growth factor-mediated communications between the epithelium and the keratocytes within the stroma (S). As artifacts of fixation, the lamina lucida (arrows) and lamina densa (arrowhead) can be seen. Although this morphology is an artifact of fixation, it signifies the presence of a mature skin BM. The regular packing of the collagen fibrils, visible as uniform diameter circles, in the stroma contributes to corneal transparency.
Fig. 3.
Fig. 3.
Rabbit cornea Descemet’s basement membrane at 12,600X magnification. Notice the impressive thickness (greater than 6 μm) of Descemet’s basement membrane (DM) in a rabbit only 14 weeks old. Descemet’s basement membrane continues to increase in thickness throughout life. Descemet’s basement membrane provides adhesion for the monolayered corneal endothelial cells (e) that modulate corneal hydration critical to corneal transparency, allows passage of nutrients from the aqueous humor into the stroma, and modulates the passage of TGFβ from the aqueous humor into the corneal stroma that would drive keratocyte differentiation into myofibroblasts and trigger fibrosis. S is the stroma that makes up greater than 90% of the corneal thickness. A stromal fibroblastic cell referred to as a “keratocyte” is indicated by the arrow.
Fig. 4.
Fig. 4.
Transmission electron micrograph of rabbit inner thigh skin basement membrane (BM) at 40,000X magnification. The overlying basal keratinocyte adheres to the dermis (D) via the basement membrane (BM) composed of lamina lucida (arrows) and lamina densa (arrowhead). The BM in skin also regulates growth factor-mediated interactions between the epithelium and skin fibroblasts in the dermis. Note that the basal epithelial cell membrane in skin is much more prominent than in the cornea.
Fig. 5.
Fig. 5.
Transmission electron micrograph of glomerular basement membrane (BM) in rabbit kidney at 45,000X magnification. The BM that functions in the excretion of waste molecules from capillaries into the urine is a “double” BM that provides adhesion of capillary endothelial cells (endo) with fenestrations (arrowheads) on one side and podocyte foot plates (PFP) of podocytes on the other.
Fig. 6.
Fig. 6.
Transmission electron micrograph of alveolar basement membrane (BM) of rabbit lung at 46,000X. Shown is the “thicker side” of the alveolus where the alveolar BM and capillary BM are separated by an interstitial space containing collagen fibrils and other extracellular matrix materials. The alveolar epithelial (AE) type 1 cell rests on the BM with lamina lucida (arrows) and lamina densa (arrowhead). On the “thinner side” of the alveolus (not shown) the alveolar BM and capillary BM fuse, at least focally, to form a single BM separating alveolar epithelial type 1 cells and capillary endothelial cells—a BM morphological variation that is thought to facilitate gas exchange between the alveolar space and the alveolar capillaries (Vaccaro and Brody, 1981).
Fig. 7.
Fig. 7.
Transmission electron micrograph of rabbit liver hepatocyte, sinusoids and spaces of Disse at 30,000X magnification. Hepatocytes are organized into plates separated by the space of Disse (D) from vascular channels termed sinusoids. Hepatocyte processes (arrowheads) extend into the space of Disse. Sinusoids have a discontinuous, fenestrated endothelial cell lining. Of note, there is no basement membrane between either hepatocytes or endothelial cells and the space of Disse—allowing direct cellular contact that is thought to facilitate hepatocyte functions such as detoxification, modification, and excretion of exogenous and endogenous substances.
Fig. 8.
Fig. 8.
Regenerative vs. fibrotic repair of the rabbit cornea after injury. At one month after minor injuries to the rabbit cornea, such as epithelial abrasion or −4.5 diopter photorefractive keratectomy (PRK) that is shown (A to C), in which the EBM and a small amount of the anterior stroma is ablated with the excimer laser and relatively few stromal keratocytes die by apoptosis or necrosis, transmission electron microscopy (TEM) shows that the EBM regenerates normally (A, 22,000X mag., arrows are lamina lucida and arrowheads are lamina densa), keratocytes repopulate the anterior stroma (B, 400X mag., arrows) and few, and in this case no, myofibroblasts are detected by staining for the alpha-smooth muscle actin (SMA) myofibroblast marker (B, 400X mag. showing DAPI stained keratocytes in the stroma (s). The cornea overlying the pupil (arrows) is transparent and iris details are clear when photographed with a slit lamp at one month after −4.5D PRK (C, 20x mag.). After a more severe injury (such as high correction −9 diopter PRK) shown in D to F, the EBM is not regenerated at one month after surgery and no lamina lucida or lamina densa is detected (D, 22,000X mag., arrows note no EBM beneath the epithelium) and myofibroblasts (arrowheads) with large amounts of rough endoplasmic reticulum fill the anterior stroma of the cornea. Note in D the disorganization of the collagen in the stroma surrounding the myofibroblasts compared to A, where the collagen fibrils are uniform diameter and regularly packed—an important contributor to the transparency of the normal corneal stroma. After this level of injury (E, 400X mag.) the anterior stroma beneath the epithelium (the ongoing source of TGFβ that penetrates the stroma to maintain the viability of the myofibroblasts in the absence of normal EBM) has a layer of SMA+ myofibroblasts (arrows). A slit lamp photograph of the cornea at one month after surgery shows fibrosis (F, 20X mag., arrows delineate area of fibrosis that is also called haze) in the area of the previous PRK surgery. e is the epithelium and s is the stroma in panels A, B, D, and E.
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