7 Cell-Cell/Matrix Interactions

  1. Connective Tissue Matrix
    • • where mesenchymal cells live
    • • composed of elastic fibers, proteoglycans, hyaluronan, type I collagen
    • • highly organized: orthogonal arrays of collagens I & III in the ECM create a plywood-like structure that’s very strong
    • Image Upload 1
  2. Basal Lamina/Membrane
    • separating epithelial cells from underlying stroma or connective tissue (in picture, fibroblasts + collagen fibers)
    • Image Upload 2
  3. What are 2 examples where fundamental processes are carried out via the basement membrane?
    • 1. Glomerular Filtration: basement lamina consists of a lot of proteoglycans + laminins
    • • cells are fenestrated so only some ions & water (NOT protein) pass through the membrane into the urinary space to be excreted
    • • proteoglycans of the BM carry out this function
    • Image Upload 3

    • 2. Lung Alveoli: BM (co-synthesized by endothelium on the blood side & pneumocytes on the inhaled-air side) is specially designed to only allow gasses to go through - how oxygen & carbon dioxide are exchanged (eg. prevents water from ever getting into the lung & drowning it)
    • Image Upload 4
  4. Types of ECM Molecules
    • Collagens
    • Proteoglycans
    • Matricellular Proteins (Adhesive Glycoproteins)
    • Integrins
    • Cadherins
    • CAMs (Cell Adhesion Molecules)
    • Elastic fibers (Elastin)
    • Matrix Metalloproteases (MMPs)
  5. Difference between Basal Lamina & Basement Membrane
    • • basal lamina: very thin, can really only be seen via electron microscope
    • • basement membrane: thicker, can see via light microscope
    • • no difference in composition, just by how they can be visualized
  6. Collagens
    • provide structural integrity for bone & cartilage; are also a major component of basement membranes
    • • Type I: fibril-forming & found almost everywhere - accounts for 90% of body collagen (bONE)
    • • Type II: fibril-forming & almost exclusively in cartilage (car-TWO-lage)
    • • Type IV: network/sheet-forming that plays a role in basement membranes
    • • Type XVIII: basal lamina around blood vessels
  7. • Type I + II: fibrilar collagens; connective tissue collagens
    • Type II: cartilage collagen

    • Type IV: epithelial basement membrane/basal lamina collagens
  8. What is the one place type I collagen isn’t found?
    cartilage - because type II collagen is specialized to be in cartilage
  9. Collagen I Diseases
    1. Scurvy: Vitamin C (ascorbic acid) deficiency prevents cross-linking of collagens

    2. Ehler-Danlos Syndrome: genetic defects in collagen synthesis/assembly causes impaired musculoskeletal & vascular systems
  10. Scurvy
    Vitamin C deficiency prevents cross-linking of collagens; deficiency leads to spots on the skin, spongy (scorbutic) gums & bleeding from mucous membranes
  11. Ehler-Danlos Syndrome
    a connective tissue disorder that results from a defect in collagen synthesis & assembly

    • • without the collagen to stabilize the connective tissue, tissues become more elastic (bendy fingers)
    • • has consequences in both the musculoskeletal & vascular system
  12. Osteogenesis Imperfecta
    autosomal dominant disorder that causes a defect in type I collagen

    • mutated collagen in bones results in brittle bones & multiple fractures (case study where girl was taken away from her parents)
  13. Menke’s Disease
    • • X-linked recessive disease that causes a deficiency in copper utilization & results in faulty collagen cross-linking
    • • causes developmental delays, seizures, failure to thrive + characteristically kinky, colorless, & easily broken hair
  14. Alport Syndrome
    • genetic defect in which type IV collagen is absent or non-functional
    • • main defect is in the basement membrane of the kidneys
    • • is the 2nd most common inherited cause of kidney failure (PKD is #1)
  15. Goodpasture’s Syndrome
    • autoimmune disease in which antibodies to type IV collagen (made by the body) destroy the basement membrane in the lungs AND kidneys
    • • this is the one where you have to consider which is worse, losing kidney or lung function?
    • • treatment = corticosteroids, immunosuppressants
  16. Endostatin
    • • 20 Kd fragment of type XVIII (18) collagen that inhibits angiogenesis
    • • is cleaved by a MMP from collagen XVIII
    • • is specific for “immature” vascular endothelial cells
    • • likely anti-cancer mechanism is that it induces apoptosis in endothelial cells
    • • is now used in 3 million cancer patients (with angiostatin)
  17. How was endostatin discovered?
    • • it was hypothesized that primary tumors were secreting something inhibiting metastases because after primary tumor removal with no evidence of metastases, patients would show up post-removal with metastases everywhere
    • • 1 inhibitor discovered was endostatin
    • • is an internal peptide fragment of collagen XVIII (18)
    • • inhibits blood vessel formation → preventing tumor growth (by withholding access to blood supply)
  18. Metastatic Cancer
    • clinical correlate: MMPs (+ fibronectin, laminin, matrix-degrading enzymes)
    • • cancer that has spread from the place where it first started to another place in the body via angiogenesis
  19. Diseases of Collagen Defects
    • 1. Goodpasture’s Syndrome
    • 2. Alport Syndrome
    • 3. Menke’s Disease
    • 4. Ehler-Danlos Syndrome
    • 5. Scurvy
    • 6. Osteogenesis Imperfecta
  20. Major Functions of Proteoglycans:
    • 1. regulate hydration state of tissues, especially cartilage
    • 2. provide resistance to impact in cartilage (shock absorbers)
    • 3. act as reservoirs for growth factors & cytokines (eg. heparan sulfate proteoglycans (HSPGs))
    • 4. provide selectively permeable filters in kidney & lung
    • • consist of a little bit of protein & a TON of carbohydrate - carbohydrates that are doing the FUNCTION
    • • are very negatively charged molecules
    • Image Upload 5
  21. Chondrodysplasias
    • • can be caused by either defective 1. chondriotin sulfate proteoglycans or 2. collagen type II
    • • flattened nose bridge + malformed legs, feet, toes, forearm & fingers
    • • when you see “chondro” think cartilage
  22. Matricellular Proteins (Adhesive Glycoproteins)
    • • are secreted by cell & remain tightly bound to the cell surface (don’t just disseminate into the matrix)
    • • often act as co-receptors to help regulate adhesion & signal
    • transduction pathways for proliferation, motility & differentiation
    • • help attach cells to each other & the ECM
    • • classics: laminin, fibronectin
    • • integrins = receptors
  23. What does a defect in the matricellular protein CCN6 cause?
    a rare and severe form of chondromalasia
  24. CCN5
    • may be useful in treating restenosis, fibroids, asthma, PPHN, & other SMC hyperproliferation diseases
  25. What are 3 examples of matricellular proteins?
    • 1. fibronectin
    • 2. laminin
    • 3. CCN proteins

    • • they all bind to integrin or some other transmembrane receptor
    • • integrin is bound to cytoskeletal proteins
    • • induce signal transduction pathways
    • • link between ECM & cell membrane; that’s why these proteins are so important for signal transduction
  26. Fibronectin
    type of matricellular protein found in connective tissue/mesenchymal matrices (glue for attaching cells)

    • connective tissue matrix
  27. What are the binding sites of Fibronectin (+ other matricellular proteins)?
    • besides an integrin binding site, fibronectin also has
    • 1. a site to bind to cells (aka a heparin sulfate binding site - proteoglycan on basically every cell surface)
    • 2. a collagen binding site
    • Image Upload 6
  28. Laminin
    matricellular protein that is a a major component of basement membranes

    • is another common adhesive protein that binds to integrins, heparan sulfates & collagens
  29. Integrins
    • • bind to matricellular proteins & activate signaling pathways inside the cell
    • • receptors for fibronectin, laminins, CCN proteins + other molecules
    • • connect to cell signaling & cytoskeletal machinery via tightly complexed proteins on cytoplasmic side of membranes
    • • "they're everywhere"
  30. What disease is associated with a defect in integrin?
    Glanzmann's Thrombasthenia
  31. Glanzmann's Thrombasthenia
    • a defect in platelet integrins results in the inability to form blood clots correctly
    • • autosomal recessive
    • • (“thromba” refers to platelets → know there will be a clotting or platelet issue)
  32. Elastic Fibers (Elastin)
    • major component of the elastic laminae of large artery walls; cross-linked by fibrillin
    • • composed of a protein called elastin, which is highly insoluble
    • • elastin fibers are incredibly strong yet flexible
    • • are very prominent in the wall of arteries
    • • the thicker the vessel & the more force it has to withstand → the more elastin present
    • • eg. between a vein & artery of the same diameter, the artery has more elastin because it goes through more pressure changes)
  33. Fibrillin
    • cross-links elastin to provide flexibility
    • • acts like a spring attaching the elastin fibers
    • • elastin is the strong part; flexibility comes from elastin binding protein (eg. Fibrillin) cross-linking
    • Image Upload 7
  34. What disease state results when Fibrillin can’t function as a ‘spring’?
    Marfan’s Syndrome
  35. Marfan’s syndrome
    • • defective fibrillin fails to cross-link elastin
    • • upon overexertion aneurism can occur in athletes with Marfan's
    • • analogy: blowing up a balloon & deflating it over & over, eventually elasticity is lost
    • • clinical correlate: fibrillin
    • • key physical symptom: depression of the sternum (breast bone)
    • • only ~50% of people with Marfan's are really tall → seen in a few basketball players
  36. Matrix Metalloproteinases (MMPs)
    • • enzymes in the matrix that bind metal ions (eg. cobalt, nickel, copper, magnesium) & are responsible for breaking down collagen & the ECM
    • • their job is to CLEAVE proteins
    • • required for stimulating & inhibiting angiogenesis, cancer cell metastasis, tissue remodeling, & wound healing
  37. What are MMPs required for?

    • • eg. if a tumor cell signals for a blood supply to be built around it, local endothelial cells will have to ‘elaborate’ MMPs to migrate & create that new blood supply
    • • EC needs to break attachment to neighboring cells & also change the matrix so it can migrate → MMPs facilitate this
  38. Cadherins
    • cell adhesion molecules important in maintaining tissue (eg. skin) integrity by connecting desmosomes of adjacent skin cells
    • • defects in Cadherins connecting desmosomes can weaken/destroy integrity of the skin & cause sloughing/blistering
    • • Calcium dependent
  39. Pemphigus
    • • autoimmune blistering disease, therefore clinical correlate: cadherins
    • • antibodies against cadherins destroy desmosomes & hemidesmosomes, resulting in blisters
  40. Besides skin, where else are desmosome critically important?
    Cardiac muscle

    • defects in desmosomes (or cadherins) can lead to fatal arrhythmias
  41. Progression of Atherosclerosis: inflammatory disease involving complex cell-cell & cell-matrix interactions
    • • starts with endothelial dysfunction: anything that disrupts an endothelial cell causes it to no longer be non-thrombogenic
    • • start to see adhesion of cells like leukocytes, generally cells that are part of the inflammatory response
    • • when they bind they move into the ‘middle’ (muscle) layer & secrete cytokines + GFs
    • • this causes the smooth muscle to proliferate
    • • if the patient is hyperlipidemic, fats begin to soak into artery wall
    • • smooth muscle cells + macrophages become foam cells
    • • causes more immune cell response; leukocytes will start entering the artery wall
    • • fatty streak results & usually intensifies to the point where a plaque forms & eventually become necrotic & calcified
    • • fibrous cap formation is dangerous because it’s a labile structure
    • • unstable plaques are the real danger
  42. CAMs (Cell Adhesion Molecules)
    • • play a role in bringing immune response to an infected EC
    • • leukocytes roll along endothelium by sticking weakly to P-selectin (a matricellular protein) during times of infection
    • - P-selectin is not present on cell surface unless an immune response is needed; it’s kept in vesicles
    • - leukocytes constitutively express receptors for P-selectin
    • • if a tissue is inflamed, the endothelial cells in that area express Platelet Activating Factor (PAF), which binds to the PAF receptor ON the leukocyte → stronger binding
    • • this binding additionally activates an integrin ON the leukocyte which itself binds tightly to ICAM-1 on the EC membrane
    • • leukocyte stops & invades the tissue
    • • CAMs are NOT calcium dependent
Card Set
7 Cell-Cell/Matrix Interactions
Cell Biology Exam 2