Transcript Connective Tissue Biology: Cell Growth and Repair

Connective Tissue
Biology
Juan Pablo Olano M.D.
Associate Professor
Director, Residency Training Program
Member, Center for Biodefense and Emerging
Infectious Diseases
UTMB, 2010
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Figure 3-3 Cell-cycle landmarks. The figure shows the cell-cycle phases (G0, G1,G2, S, and M), the location of the G1 restriction point, and the G1/S
and G2/M cell-cycle checkpoints. Cells from labile tissues such as the epidermis and the gastrointestinal tract may cycle continuously; stable cells
such as hepatocytes are quiescent but can enter the cell cycle; permanent cells such as neurons and cardiac myocytes have lost the capacity to
proliferate. (Modified from Pollard TD and Earnshaw WC: Cell Biology. Philadelphia, Saunders, 2002.)
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Stem cells
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Asymetric replication
Self renewal capacity
Types:
• Embryonic stem cells (pluripotent)
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Four transcription factors:
• Oct3/4, Sox 2, c-myc, Kfl4
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Nanog (Tir na n’Og) homeobox protein
• Adult stem cells
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Lineage specific
Might have broad plasticity (bone marrow)
Transdifferentiation and developmental plasticity
Multipotent adult stem cells (MAPCs)
Figure 3-7 Differentiation of embryonic cells and generation of tissue cells by bone marrow precursors. During embryonic development the three
germ layers-endoderm, mesoderm, and ectoderm-are formed, generating all tissues of the body. Adult stem cells localized in organs derived from
these layers produce cells that are specific for the organs at which they reside. However, some adult bone marrow stem cells, in addition to
producing the blood lineages (mesodermal derived), can also generate cells for tissues that originated from the endoderm and ectoderm (indicated
by the red lines). (Modified from Korbling M, Estrov Z: Adult stem cells for tissue repair-a new theropeutic concept? N Engl J Med 349:570-582,
2003.)
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Extracellular matrix
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Framework of the vertebrate body
Roles in vertebrate animals:
• Survival
• Development
• Migration
• Proliferation
• Shape
• Function
Extracellular matrix and cell-matrix
interactions
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Fibrous structural proteins
• Collagen, elastins, microfibrils
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Adhesive glycoproteins
• Fibronectin, laminin
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Matrix gel
• Glycosaminoglycans, proteins.
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Compartments
• Interstitial matrix
• Basement membranes
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Extracellular matrix
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Elastin: Resilience
Collagen: Tensile strength
Matrix gel: Compressive forces
Extracellular matrix
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GAG’s: Unbranched polysaccharides
with repeating disaccharides.
• N-acetylglucosamine or Nacetylgalactosamine
• Uronic acid: Iduronic, glucuronic
• Types:
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Hyaluronan, chondroitin sulfate, dermatan
sulfate, heparan sulfate, keratan sulfate.
• <10% of dry weight of ECM
GAGs
Extracellular matrix
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Hyaluronan:
• No protein linkages
• No sulfates
• Interactions with proteoglycans and
proteins.
• Very high molecular weights
• Fetal development
• Joints and other connective tissues
Extracellular matrix
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Proteoglycans
• Sugar chains are GAG (as opposed to
glycoproteins).
• Attached to serine by tetrasaccharide
(xylose-galactose-galactose-glucuronic
acid).
• >60% of dry weight is GAG
• Examples
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Aggrecan, betaglycan, decorin, perlecan,
syndecan
Extracellular matrix
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Functions of proteoglycans
• Selective sieves
• Signaling: Enhance or inhibit signaling
molecules.
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Protein immobilization
Steric block
Protein reservoir: delayed release
Degradation protection
Alter binding of signaling molecules to cell
surface receptors
Extracellular matrix
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Cell surface proteoglycans
• Lipid bilayer or anchored through GPI.
• Co-receptors.
• Syndecans
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FGF, TGF-β.
Actin cytoskeleton and Integrins.
Extracellular matrix
Extracellular matrix and cell-matrix
interactions
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Collagen
• 25% of protein mass in mammals
• Three α-chains: Glycine and proline rich.
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41 different genes (14 chromosomes) and 27
collagens.
• Several types
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Fibrillar: I, II, III, V, VI.
Network-forming (amorphous): IV, VII
Transmembrane: XVII.
Fibril-associated collagens: IX, XII
Others
Extracellular matrix
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Collagen (cont)
• Complex synthesis
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Hydroxylation
Cleavage
Fibril formation and cross-linking
• Syndromes: Ehlers-Danlos (type III),
scurvy, osteogenesis imperfecta (type
I), chondrodysplasias (type II)
Collagen synthesis
Extracellular matrix and cell-matrix
interactions
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Elastin, microfibrils.
• Allow tissues to recoil. Strength given
by collagen
• Central core (elastin) and microfibril
network sheathing central core.
Extracellular matrix and cell-matrix
interactions
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Basal Laminae
• Laminin
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Basement membranes
Binds to cells and ECM proteins (Type IV
collagen, perlecan and nidogen).
Structural and filtering functions
Cell polarity, proliferation, migration,
healing, neurotransmission.
Diseases: Alport syndrome, minimal change
disease.
Basement membrane structure
Extracellular matrix and cell-matrix
interactions
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Adhesive glycoproteins and integrins
• Four groups: Immunoglobulin superfamily
“CAM’s”, cadherins, integrins and selectins
• Binding to cell membranes and ECM
• Fibronectin
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Attachment, spreading and migration of cells
(tenascins and thrombospondins)
Attaches cells to matrix
Coagulation, healing and phagocytosis
Plasma fibronectin and insoluble fibronectin.
Assembly affected by actin cytoskeleton
Extracellular matrix and cell-matrix
interactions
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Integrins
• Transmembrane heterodimers
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α(24 types) andβ (9 subtypes) subunits.
• Link extracellular matrix to cells and
cell-cell interactions.
• Activation regulated from within the
cells (inside-out signaling).
• Intracellular signaling via FAK, talin and
paxillin
“Inside out” signaling
Integrins
Cell ECM interactions
Cell-matrix and cell-cell
interactions
Repair by connective tissue
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Angiogenesis
Fibroplasia
Deposition of ECM
Remodeling
Repair by connective tissue
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Angiogenesis
• Proteolytic degradation of BM
• Migration of endothelial cells
• Proliferation of endothelial cells
• Maturation of endothelial cells
• Recruitment of periendothelial cells
Repair by connective tissue
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Angiogenesis
• VEGF
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Increases vascular permeability
EC migration
EC proliferation
Regulates coagulation/fibrinolytic system
Receptors
• VEGF-R1 and R2
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Inducers: PDGF, Hypoxia, TGF-β, TGF-α.
• Angiopoietins (Ang1 and 2)
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Receptor: Tie2
• ECM protein regulators: Integrins, thrombospondin 1,
SPARC, tenascin C, endostatin.
Angiogenesis
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Vascularv proliferation: VEGF
Stabilization:
• Pericyte recruitment: Angiopoietins
• SMCs: PDGF
• ECM deposition: TGF-β
Angiogenesis
Repair by connective tissue
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Fibrosis
• Fibroblast proliferation and migration:
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PDGF, TGF-β, FGF, EGF, IL-1, TNF-α.
• ECM deposition
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Fibrillar collagens and others
Tissue remodeling
• Matrix metalloproteinases
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Interstitial collagenases
Gelatinases
Stromelysins
Membrane bound matrix proteinases
Inhibitors: Tissue inhibitor of matrix
metalloproteinases
Matrix metalloproteinases
Matrix metalloproteinases
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Control factors
• Local activation
• Confinement by cell surface receptors
• Secretion of inhibitors (TIMPs)
Extracellular matrix and cellmatrix interactions
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Other proteins
• Secreted protein acidic and and rich in
cysteine (SPARC or osteonectin):
Angiogenesis inhibitor and tissue
remodeling.
• Thrombospondins: Angionesis inhibitors
• Osteopontin: Calcification regulator and
leukocyte migration
• Tenacin: Morphogenesis and cell
adhesion
Wound healing
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Acute inflammation
Regeneration of parenchymal cells
Migration and proliferation of
parenchymal and mesenchymal cells
Synthesis of ECM proteins
Remodeling
Collagenization
Wound healing
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Figure 3-23 A, Keloid. Excess collagen deposition in the skin forming a raised scar known as keloid. (From Murphy GF, Herzberg AJ: Atlas of
Dermatopathology. Philadelphia, Saunders, W.B. 1996, p. 219.) B, Note the thick connective tissue deposition in the dermis. (Slide courtesy of Z.
Argenyi, M.D., University of Washington, Seattle, WA.)
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Figure 3-23 A, Keloid. Excess collagen deposition in the skin forming a raised scar known as keloid. (From Murphy GF, Herzberg AJ: Atlas of
Dermatopathology. Philadelphia, Saunders, W.B. 1996, p. 219.) B, Note the thick connective tissue deposition in the dermis. (Slide courtesy of Z.
Argenyi, M.D., University of Washington, Seattle, WA.)
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Growth Factors
Figure 3-24 Development of fibrosis in chronic inflammation. The persistent stimulus of chronic inflammation activates macrophages and
lymphocytes, leading to the production of growth factors and cytokines, which increase the synthesis of collagen. Deposition of collagen is enhanced
by decreased activity of metalloproteinases.
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Figure 3-25 Repair responses after injury and inflammation. Repair after acute injury has several outcomes, including normal tissue restitution and
healing with scar formation. Healing in chronic injury involves scar formation and fibrosis (see text).
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