Cells to Tissues
Cell Surfaces
Apical & Basolateral
- The apical surface of a cell faces the outside of the organism and the basolateral surface faces the inside
- In the case of intestinal epithelial cells, the apical surface refers to the microvilli and the rest forms the basolateral surface. We can remember the "baso-" part because it abuts the "basal" lamina.
- As we address in our GI physiology tutorials, the finger-like projections of the apical faces the intestinal lumen where it picks up nutrients and the basolateral surface faces the intestinal vasculature and tissue, where they are absorbed into the body.
Transport
Paracellular
- Paracellular transport is the extracellular passage of molecules between adjacent cells.
Transcellular
- Transcellular transport, in which molecules are taken up on one side of the cell (the apical surface) and ultimately released from the opposite side of the cell (the basolateral surface) into the surrounding vasculature and tissues.
Cell-Cell Junctions
Tight Junctions
Structure
- Form an essential barrier between discrete body regions: the region outside of the apical surface of the cell and the region underlying the basolateral surface. For instance, they separate the intestinal lumen (cavity) from the intestinal tissue and absorptive vasculature.
Function
- Tight junctions prevent varying degrees of paracellular solute diffusion depending on the organ, which is determined by the needs of the environment.
- They can create a total impermeability to macromolecules; small, water-soluble substances; and even ions, such that these substances are completely unable to cross the extracellular space between cells (as in the case of the blood-brain barrier) OR they can have varying degrees of permeability to small-water soluble molecules and ions (as in the case of the kidneys).
Proteins & Pathological Correlates
- Four transmembrane protein particles involved in the formation of tight junctions and some representative pathologies are:
- Claudin (hypomagnesemia can occur in claudin defect).
- Hypomagnesemia occurs because a defect in claudin (claudin 16) can produce hypomagnesemia from dysfunction in paracellular reabsorption of magnesium in the thick ascending loop of Henle of the kidney where the majority of magnesium and calcium passage is driven by paracellular (rather than transcellular) transport.
- Occludin (inflammatory bowel disease and alcoholic injury can impact occludin expression and performance).
- Junctional adhesion molecule (JAM) (is implicated in angiogenesis in cancer).
- Tight junctions play a key role in endothelial cells and thus dysregulation in them can promote pathological vessel formation.
- Tricellulin (deafness occurs due to cochlear compartmentalization defects).
- The cochlea comprises perilymphatic and endolymphatic fluid spaces that necessitate optimized compartmentalization.
Gap Junctions
Structure
- Gap junctions comprise cylindrical channels that are formed from the alignment of connexin hemichannels attached to each membrane.
- Note that connexins comprise gap junctions in vertebrates whereas in invertebrates, innexins form the gap junctions.
Function
- Gap junctions allow for rapid ion passage between cells (eg, in neuronal transmission, rapid ion passage is essential to expedite nerve transmission).
- Note that just as tight junctions have varying degrees of permeability, so too, there are many forms of connexins, which leads to different degrees of gap junction permeability.
- Gap junction expression can even augment to meet various physiological demands. For instance, childbirth requires forceful uterine contractions, which necessitates high amounts of ionic transport for the spike in action potentials during delivery. Thus, the amount of uterine (specifically, myometrial) connexin increases during childbirth, to create enough channels to meet this demand.
Clinical Correlates: Connexin Mutations
- Connexin gene mutations are responsible for many different pathologies, including genetic forms of cataracts, neuronal sensory deafness, atrial fibrillation, skeletal dysplasias, Charcot-Marie Tooth X (an X-linked hereditary peripheral neuropathy), and other numerous other diseases.
Anchoring Junctions
Adherens Junctions & Desmosomes
- Cell-cell anchoring junctions comprise adapter proteins, which are connected by cell adhesion molecules, known as CAMs.
- For both, show that cadherins constitute the CAMs (the cell adhesion molecules).
- But for the adherens junction, the cadherins bind to adapter receptors, which bind to intracellular actin.
- Adherens junctions are typically located beneath the tight junctions to help create the tension necessary to keep tight junctions together, and they form a circumferential tension cable to help maintain the epithelial tissue structure.
Desmosomes
- For the desmosome, the cadherins bind to cytoplasmic plaques, which bind to intracellular intermediate filaments.
- Desmosomes form snap junctions between the cells; this allow for various forces to be distributed throughout the rows of cells, protecting them from shear injury.
Clinical correlate: Pemphigus vulgaris
- Pemphigus vulgaris is an autoimmune disorder wherein an autoantibody to a certain cadherin, called desmoglein (think: desmosome), disrupts the linkage between adjacent cells and results in skin and mucous membrane breakdown (blistering).
Cell-Matrix Adhesions: Hemidesmosomes
Hemidesmosomes
- Hemidesmosomes comprise an anchoring junction attached to adhesion receptors, called integrins.
- Integrins bind directly and indirectly to intermediate filaments and to ligands (eg, fibronectin and laminin).
- Consider that hemidesmosomes are required to attach basal epidermal keratinocytes to the basement membrane to maintain skin structure.
Clinical Correlates: Epidermolysis bullosa (EB) & Bullous pemphigoid
- Hemidesmosome defects (acquired or inherited) can lead to various forms of epidermolysis bullosa (EB), a skin blistering disorder, and bullous pemphigoid.
Extracellular Matrix Proteins
Proteoglycans
- Glycoproteins serve to cushion and bind together ECM molecules.
- As an example, perlecan binds and links extracellular molecules.
Collagens
- Collagens, via a triple-helix shape, provide tissue strength and integrity.
- Although there are at least 28 types of collagen, the first four types constitute the vast majority of them.
- Fibrillar collagen comprises collagen types 1, 2, and 3 in triple-stranded helical shape.
- Sheet-forming collagen, collagen type 4, comprises a noncollagenous globular domain attached to long triple helical collagenous strands.
Multiadhesive Matrix Proteins
- Multiadhesive matrix proteins bind and link adhesion receptors to underlying ECM molecules.
- Laminin is cross-shaped, fibronectin wire-like, and entactin (aka nidogen-1) is rod-like.
Basal Lamina
- Formed from Type IV Collagen (Sheet-forming), Perlecan, Laminin, Entactin
Clinical Correlates: Goodpasture's syndrome & Alport's syndrome
- As clinical correlates, basal lamina defects occur in:
- Goodpasture's syndrome, which is an autoimmune disorder involving a type 4 collagen autoantibody, and results in rapidly progressive glomerulonephritis as well as pulmonary hemorrhage.
- Alport's syndrome, which is secondary to a type 4 collagen genetic defect that produces kidney disease, sensorineuronal hearing loss, and various ocular abnormalities (anterior lenticonus (cone-shaped lens), retina discoloration (dot-and-fleck retinopathy), and maculopathy (affects central vision).
Connective Tissue
Types I, II, III Collagen (Fibrillar)
Structure
- Connective tissue is primarily formed from fibrillar collagen, which gets its strength through the formation of cross-striated collagen fibrils from procollagen alpha chains.
Clinical Correlate: Scurvy
- In scurvy, there is a vitamin C deficiency that leads to unstable procollagen triple helix formation, resulting in fragile connective tissue.
- Specifically, after several weeks of vitamin C deficiency, several collagen deficiencies manifest: poor wound healing, gingival swelling and tooth loss, mucocutaneous petechiae and other blood vessel abnormalities and capillary fragility (causing "woody edema"), hyperkeratosis, nail abnormalities, brittle bones, ocular abnormalities, and eventually anasarca, hemolysis, jaundice, and eventually seizures.