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Cells to Tissues

Notes

Cells to Tissues

Sections




Overview

Overview

  • Here, we will learn how cells integrate to form tissues.
  • To begin, start a table.
  • Denote that we will learn about tissue formation from cells and extracellular matrix proteins.

Cell surfaces & Transport

  • We will address cell surfaces and basics of transepithelial transport, specifically the apical and basolateral cell surfaces and transcellular and paracellular transport.

Adhesions

  • We'll address cell-cell and cell-matrix adhesions, specifically the forms of junctions and types of adhesions.

Basal lamina

  • We'll address the basal lamina, focusing on type IV collagen, (aka sheet-forming collagen).

Connective tissue

  • We'll address connective tissue; focusing on types I, II, and III collagen (fibrillar collagen).

Cell Surfaces & Transport

Overview

  • Let's begin with cell surfaces and transepithelial transport.
  • First, draw a pair of intestinal epithelial cells; show that they have finger-like microvilli on the top.

Cell Surfaces

Apical & Basolateral

  • The apical surface of a cell faces the outside of the organism and the basolateral surface faces the inside
  • So, indicate that 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

  • Next, show two forms of transport:

Paracellular

  • Paracellular transport, which is the extracellular passage of molecules between adjacent cells.
    • As shown in our diagram, however, cells are connected via junctions to provide strength and rigidity, thus paracellular transport is limited by the permeability of the tight junctions that connect adjacent cells – we will discuss this permeability in detail soon.

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 & Cell-Matrix Adhesions

Overview

  • Now, that we know about cell surfaces and transport, let's turn to cell-to-cell and cell-to-extracellular matrix connections. Our goal is to understand how cells interrelate to form tissues.

Cell-Cell Junctions

  • First, draw a row of intestinal cells.
  • Show two sets of cell-cell junctions:
  • A set of tight junctions just beneath the apical surface.
  • A set of gap junctions, lower down.
  • Divide the extracellular matrix beneath the cells into a thin layer of basal lamina directly underneath the cell and then a larger swath of connective tissue beneath it.
  • Indicate some generic protein constituents of the extracellular matrix, which we'll define at the end.

Tight Junctions

Structure

  • Now, draw a magnified section of the tight junctions.
  • Draw plasma membranes near one another at the site of the tight junctions – the tight junctions pull the membranes close to one another.
  • Indicate the intercellular space.
  • Then, show that at each junction there are rows of protein particles.
  • Indicate that the tight junctions form a link between protein particles in the adjacent cells.
    • They 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

  • Make a notation that tight junctions prevent varying degrees of paracellular solute diffusion depending on the organ, which is determined by the needs of the environment.
    • Meaning, 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).
    • In the brain, neuronal pools require stable electrochemical extracellular environments to operate efficiently, so unregulated paracellular transport would be disastrous, thus the tight junctions must create a high degree of impermeability. Tight junctions form a key element in the blood-brain barrier: they join endothelial cells to wall off the vasculature from the brain tissue.
    • The kidney is responsible for gating the urinary excretion or reabsorption of various solutes. When we are dehydrated or starved, the kidneys are tasked with holding onto vital nutrients and solutes, and the kidney relies on paracellular transport across tight junctions for the rapid reabsorption of essential nutrients and ions.

Proteins & Pathological Correlates

  • Tight junctions are divided into transmembrane, cytoskeletal, and cytoplasmic plaque proteins.
  • Indicate that four transmembrane protein particles involved in the formation of tight junctions and some representative pathologies that they are implicated in:
  • 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

  • Next, draw a magnified view of the gap junctions.
  • Draw plasma membranes of adjacent cells.
  • Show that 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

  • Show ions pass through the channels and write that 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

  • Now, indicate that 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

  • Now, let's address anchoring junctions, which comprise cell-cell adhesions and cell-matrix adhesions.
  • First, the cell-cell adhesions.
  • Draw an adherens junction and a desmosome.

Cell-Cell Anchoring Junctions: Adherens Junctions & Desmosomes

  • Now, let's show a representative magnified view of a cell-cell anchoring junction.
  • Draw the plasma membranes of neighboring cells and indicate the intercellular space.

Adherens Junctions & Desmosomes

  • Show that cell-cell anchoring junctions comprise adapter proteins, which are connected by cell adhesion molecules, known as CAMs.
  • Let's look at some simplified specifics for adherens junctions and desmosomes: re-draw adjacent cells for both.
  • For both, show that cadherins constitute the CAMs (the cell adhesion molecules).
    #Adherens Junctions
  • But for the adherens junction, show that the cadherins bind to adapter receptors, which bind to intracellular actin.
    • As shown in the diagram, 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

  • Next, for the desmosome, show that 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

  • As a clinical correlate, indicate that 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

  • Next, let's look at cell-matrix adhesions.

Hemidesmosomes

  • Draw a hemidesmosome at the junction of the basal membrane and the basal lamina.
  • Window out a magnified view of this region.
  • Show that hemidesmosomes comprise an anchoring junction attached to adhesion receptors, called integrins.
  • The numerous interactions between integrins and the extracellular matrix are beyond our scope, here, but show a couple of important examples.
  • Show that 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

  • Indicate that hemidesmosome defects (acquired or inherited) can lead to various forms of epidermolysis bullosa (EB), a skin blistering disorder, and bullous pemphigoid.

Extracellular Matrix

Extracellular Matrix Proteins

  • Now, let's turn to the extracellular matrix.
  • Let's form a table so we can keep track of some of the various kinds of extracellular matrix proteins. Note that we will simplify the functions of these substances and show a small number of examples.

Proteoglycans

  • First, the proteoglycans.
  • Indicate that these glycoproteins serve to cushion and bind together ECM molecules.
  • As an example, draw perlecan, which binds and links extracellular molecules.

Collagens

  • Next, include the collagens, which, 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.
  • First, draw fibrillar collagen, which comprises collagen types 1, 2, and 3, in triple-stranded helical shape.
  • Then, draw sheet-forming collagen, collagen type 4, which comprises a noncollagenous globular domain attached to long triple helical collagenous strands.

Multiadhesive Matrix Proteins

  • Now, include the multiadhesive matrix proteins, which bind and link adhesion receptors to underlying ECM molecules: we drew this when we showed the hemidesmosome attach to fibronectin.
  • Show that laminin is cross-shaped, fibronectin wire-like, and entactin (aka nidogen-1) is rod-like.
    • We already indicated that laminin and fibronectin serve as ligands that hemidesomosomal integrins bind to link cells to the underlying basal lamina.
    • We'll see, momentarily, the role that entactin plays in forming the basal lamina.

Basal Lamina

  • So, now, let's show a simple representation of the major proteins of the basal lamina.

Type IV Collagen (Sheet-forming)

  • Indicate that it is built upon a type 4 collagen backbone and held together with various other proteins.

Perlecan, Laminin, Entactin

  • They include: the proteoglycan perlecan and the multiadhesive matrix proteins laminin and entactin.

Clinical Correlates: Goodpasture's syndrome & Alport's syndrome

  • Indicate that, 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

  • Finally, let's address connective tissue.
  • Show that it 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

  • Indicate that 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.