MED100-I Medical Biology: Basal Laminae

Basal Laminae

• A sheet-like meshwork of ECM components that provides a foundation for assembly of cells into tissue
• Only 60-120 nm thick
• Found in columnar and other epithelia, such as intestinal lining and skin, where it is a foundation on which one surface of the cells rests
• Surrounds each cell in other tissues, such as muscle or fat
• Important in regeneration after tissue damage and in embryonic development
• Helps four- and eight-celled embryos adhere together in a ball
• Plays a role in the development of the nervous system, where neurons migrate along ECM pathways that contain basal laminal components

Functions of Basal Laminae

• Organizes cells into tissues and distinct compartments
• Repairs tissues
• Forms permeability barriers
• Guides migrating cells during development
• Components have been highly conserved throughout evolution

Diseases Associated with Basal Laminae

• Mutations in the gene for the α5 chain of type IV collagen are associated with Alport syndrome, a disease that involves nephritis and deafness
• Junctional EB, a severe blistering disease of the skin, is associated with mutations in the genes that encode the laminin-5 chains
• Dystrophic EB, a severely debilitating blistering disease, is due to mutations in collagen VII genes and consequent absence of anchoring fibrils
• Autoantibodies to type IV collagen α3 chain are associated with Goodpasture syndrome

Basement Membrane and Angiogenesis

• The basement membrane inhibits the proliferation and migration of endothelial cells, preventing them from branching out to produce new vessels
• During tumor growth, inflammatory and stromal cells within the matrix near the tumor produce matrix metalloproteinases that degrade the vascular basement membrane, enabling the endothelial cells to proliferate, migrate, and form new blood vessels to supply the tumor

Type-IV Collagen

• A major structural component of basal laminae
• Can bind to adhesion receptor including integrins
• All collagens are trimeric proteins made from three polypeptides, each encoded by one of at least 43 genes in humans
• The three α chains in a collagen molecule can be identical (forming a homotrimer) or different (forming a heterotrimer)
• The chains twist together into a special triple helix called the collagenous triple helix

Cell-Surface Receptors for Collagen IV

• Integrins
• Discoidin domain receptors 1 and 2 (which are tyrosine kinase receptors)
• Glycoprotein VI (on platelets)
• Leukocyte-associated Ig-like receptor-1
• Members of the mannose receptor family
• A modified form of the protein CD44

Perlecan

• A crosslink component of basal laminae
• A major secreted proteoglycan in basal laminae
• Consists of a large multidomain core protein (~470 kDa) to which polysaccharides are covalently attached
• The core protein is made up of multiple repeats of five distinct domains
• Contains three types of covalent polysaccharide chains: N-linked chains, O-linked chains, and glycosaminoglycans (GAGs)

ECM in Pathogenesis and Treatment of Human Diseases

• Mutations in ECM component genes can affect the architecture of the ECM, leading to bone formation defects
• The composition and architecture of the ECM fibers control migration of immune cells and tumor cells
• Loose ECM areas facilitate cell motility, whereas dense ECM areas impede migration
• ECM serves as a reservoir for growth factors, such as VEGF, PDGF, and TGF-β, whose release due to ECM remodeling further modulates tumor growth and progression
• Directly targeting disease-associated ECM molecules is an attractive therapeutic strategy