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Connective Tissue Biology Juan Pablo Olano M.D. Associate Professor Director, Residency Training Program Member, Center for Biodefense and Emerging Infectious.

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Presentation on theme: "Connective Tissue Biology Juan Pablo Olano M.D. Associate Professor Director, Residency Training Program Member, Center for Biodefense and Emerging Infectious."— Presentation transcript:

1 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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4 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.) Downloaded from: StudentConsult (on 19 May :34 PM) © 2005 Elsevier

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9 Stem cells Asymetric replication Asymetric replication Self renewal capacity Self renewal capacity Types: Types: Embryonic stem cells (pluripotent)Embryonic stem cells (pluripotent) Four transcription factors: Four transcription factors: Oct3/4, Sox 2, c-myc, Kfl4Oct3/4, Sox 2, c-myc, Kfl4 Nanog (Tir na n’Og) homeobox protein Nanog (Tir na n’Og) homeobox protein Adult stem cellsAdult stem cells Lineage specific Lineage specific Might have broad plasticity (bone marrow) Might have broad plasticity (bone marrow) Transdifferentiation and developmental plasticity Transdifferentiation and developmental plasticity Multipotent adult stem cells (MAPCs) Multipotent adult stem cells (MAPCs)

10 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: , 2003.) Downloaded from: StudentConsult (on 19 May :34 PM) © 2005 Elsevier

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16 Extracellular matrix Framework of the vertebrate body Framework of the vertebrate body Roles in vertebrate animals: Roles in vertebrate animals: SurvivalSurvival DevelopmentDevelopment MigrationMigration ProliferationProliferation ShapeShape FunctionFunction

17 Extracellular matrix and cell-matrix interactions Fibrous structural proteins Fibrous structural proteins Collagen, elastins, microfibrilsCollagen, elastins, microfibrils Adhesive glycoproteins Adhesive glycoproteins Fibronectin, lamininFibronectin, laminin Matrix gel Matrix gel Glycosaminoglycans, proteins.Glycosaminoglycans, proteins. Compartments Compartments Interstitial matrixInterstitial matrix Basement membranesBasement membranes

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19 Extracellular matrix Elastin: Resilience Elastin: Resilience Collagen: Tensile strength Collagen: Tensile strength Matrix gel: Compressive forces Matrix gel: Compressive forces

20 Extracellular matrix GAG’s: Unbranched polysaccharides with repeating disaccharides. GAG’s: Unbranched polysaccharides with repeating disaccharides. N-acetylglucosamine or N- acetylgalactosamineN-acetylglucosamine or N- acetylgalactosamine Uronic acid: Iduronic, glucuronicUronic acid: Iduronic, glucuronic Types:Types: Hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate. Hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate. <10% of dry weight of ECM<10% of dry weight of ECM

21 GAGs

22 Extracellular matrix Hyaluronan: Hyaluronan: No protein linkagesNo protein linkages No sulfatesNo sulfates Interactions with proteoglycans and proteins.Interactions with proteoglycans and proteins. Very high molecular weightsVery high molecular weights Fetal developmentFetal development Joints and other connective tissuesJoints and other connective tissues

23 Extracellular matrix Proteoglycans Proteoglycans Sugar chains are GAG (as opposed to glycoproteins).Sugar chains are GAG (as opposed to glycoproteins). Attached to serine by tetrasaccharide (xylose-galactose-galactose-glucuronic acid).Attached to serine by tetrasaccharide (xylose-galactose-galactose-glucuronic acid). >60% of dry weight is GAG>60% of dry weight is GAG ExamplesExamples Aggrecan, betaglycan, decorin, perlecan, syndecan Aggrecan, betaglycan, decorin, perlecan, syndecan

24 Extracellular matrix Functions of proteoglycans Functions of proteoglycans Selective sievesSelective sieves Signaling: Enhance or inhibit signaling molecules.Signaling: Enhance or inhibit signaling molecules. Protein immobilization Protein immobilization Steric block Steric block Protein reservoir: delayed release Protein reservoir: delayed release Degradation protection Degradation protection Alter binding of signaling molecules to cell surface receptors Alter binding of signaling molecules to cell surface receptors

25 Extracellular matrix Cell surface proteoglycans Cell surface proteoglycans Lipid bilayer or anchored through GPI.Lipid bilayer or anchored through GPI. Co-receptors.Co-receptors. SyndecansSyndecans FGF, TGF-β. FGF, TGF-β. Actin cytoskeleton and Integrins. Actin cytoskeleton and Integrins.

26 Extracellular matrix

27 Extracellular matrix and cell-matrix interactions Collagen Collagen 25% of protein mass in mammals25% of protein mass in mammals Three α-chains: Glycine and proline rich.Three α-chains: Glycine and proline rich. 41 different genes (14 chromosomes) and 27 collagens. 41 different genes (14 chromosomes) and 27 collagens. Several typesSeveral types Fibrillar: I, II, III, V, VI. Fibrillar: I, II, III, V, VI. Network-forming (amorphous): IV, VII Network-forming (amorphous): IV, VII Transmembrane: XVII. Transmembrane: XVII. Fibril-associated collagens: IX, XII Fibril-associated collagens: IX, XII Others Others

28 Extracellular matrix Collagen (cont) Collagen (cont) Complex synthesisComplex synthesis Hydroxylation Hydroxylation Cleavage Cleavage Fibril formation and cross-linking Fibril formation and cross-linking Syndromes: Ehlers-Danlos (type III), scurvy, osteogenesis imperfecta (type I), chondrodysplasias (type II)Syndromes: Ehlers-Danlos (type III), scurvy, osteogenesis imperfecta (type I), chondrodysplasias (type II)

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32 Extracellular matrix and cell-matrix interactions Elastin, microfibrils. Elastin, microfibrils. Allow tissues to recoil. Strength given by collagenAllow tissues to recoil. Strength given by collagen Central core (elastin) and microfibril network sheathing central core.Central core (elastin) and microfibril network sheathing central core.

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37 Extracellular matrix and cell-matrix interactions Basal Laminae Basal Laminae LamininLaminin Basement membranes Basement membranes Binds to cells and ECM proteins (Type IV collagen, perlecan and nidogen). Binds to cells and ECM proteins (Type IV collagen, perlecan and nidogen). Structural and filtering functions Structural and filtering functions Cell polarity, proliferation, migration, healing, neurotransmission. Cell polarity, proliferation, migration, healing, neurotransmission. Diseases: Alport syndrome, minimal change disease. Diseases: Alport syndrome, minimal change disease.

38 Basement membrane structure

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42 Extracellular matrix and cell-matrix interactions Adhesive glycoproteins and integrins Adhesive glycoproteins and integrins Four groups: Immunoglobulin superfamily “CAM’s”, cadherins, integrins and selectinsFour groups: Immunoglobulin superfamily “CAM’s”, cadherins, integrins and selectins Binding to cell membranes and ECMBinding to cell membranes and ECM FibronectinFibronectin Attachment, spreading and migration of cells (tenascins and thrombospondins) Attachment, spreading and migration of cells (tenascins and thrombospondins) Attaches cells to matrix Attaches cells to matrix Coagulation, healing and phagocytosis Coagulation, healing and phagocytosis Plasma fibronectin and insoluble fibronectin. Plasma fibronectin and insoluble fibronectin. Assembly affected by actin cytoskeleton Assembly affected by actin cytoskeleton

43 Extracellular matrix and cell-matrix interactions Integrins Integrins Transmembrane heterodimersTransmembrane heterodimers α(24 types) andβ (9 subtypes) subunits. α(24 types) andβ (9 subtypes) subunits. Link extracellular matrix to cells and cell-cell interactions.Link extracellular matrix to cells and cell-cell interactions. Activation regulated from within the cells (inside-out signaling).Activation regulated from within the cells (inside-out signaling). Intracellular signaling via FAK, talin and paxillinIntracellular signaling via FAK, talin and paxillin

44 “Inside out” signaling

45 Integrins

46 Cell ECM interactions

47 Cell-matrix and cell-cell interactions

48 Repair by connective tissue Angiogenesis Angiogenesis Fibroplasia Fibroplasia Deposition of ECM Deposition of ECM Remodeling Remodeling

49 Repair by connective tissue Angiogenesis Angiogenesis Proteolytic degradation of BMProteolytic degradation of BM Migration of endothelial cellsMigration of endothelial cells Proliferation of endothelial cellsProliferation of endothelial cells Maturation of endothelial cellsMaturation of endothelial cells Recruitment of periendothelial cellsRecruitment of periendothelial cells

50 Repair by connective tissue Angiogenesis Angiogenesis VEGFVEGF Increases vascular permeability Increases vascular permeability EC migration EC migration EC proliferation EC proliferation Regulates coagulation/fibrinolytic system Regulates coagulation/fibrinolytic system Receptors Receptors VEGF-R1 and R2VEGF-R1 and R2 Inducers: PDGF, Hypoxia, TGF-β, TGF-α. Inducers: PDGF, Hypoxia, TGF-β, TGF-α. Angiopoietins (Ang1 and 2)Angiopoietins (Ang1 and 2) Receptor: Tie2 Receptor: Tie2 ECM protein regulators: Integrins, thrombospondin 1, SPARC, tenascin C, endostatin.ECM protein regulators: Integrins, thrombospondin 1, SPARC, tenascin C, endostatin.

51 Angiogenesis Vascularv proliferation: VEGF Vascularv proliferation: VEGF Stabilization: Stabilization: Pericyte recruitment: Angiopoietins Pericyte recruitment: Angiopoietins SMCs: PDGF SMCs: PDGF ECM deposition: TGF-β ECM deposition: TGF-β

52 Angiogenesis

53 Repair by connective tissue Fibrosis Fibrosis Fibroblast proliferation and migration:Fibroblast proliferation and migration: PDGF, TGF-β, FGF, EGF, IL-1, TNF-α. PDGF, TGF-β, FGF, EGF, IL-1, TNF-α. ECM depositionECM deposition Fibrillar collagens and others Fibrillar collagens and others Tissue remodeling Tissue remodeling Matrix metalloproteinasesMatrix metalloproteinases Interstitial collagenases Interstitial collagenases Gelatinases Gelatinases Stromelysins Stromelysins Membrane bound matrix proteinases Membrane bound matrix proteinases Inhibitors: Tissue inhibitor of matrix metalloproteinases Inhibitors: Tissue inhibitor of matrix metalloproteinases

54 Matrix metalloproteinases

55 Control factors Control factors Local activationLocal activation Confinement by cell surface receptorsConfinement by cell surface receptors Secretion of inhibitors (TIMPs)Secretion of inhibitors (TIMPs)

56 Extracellular matrix and cell- matrix interactions Other proteins Other proteins Secreted protein acidic and and rich in cysteine (SPARC or osteonectin): Angiogenesis inhibitor and tissue remodeling.Secreted protein acidic and and rich in cysteine (SPARC or osteonectin): Angiogenesis inhibitor and tissue remodeling. Thrombospondins: Angionesis inhibitorsThrombospondins: Angionesis inhibitors Osteopontin: Calcification regulator and leukocyte migrationOsteopontin: Calcification regulator and leukocyte migration Tenacin: Morphogenesis and cell adhesionTenacin: Morphogenesis and cell adhesion

57 Wound healing Acute inflammation Acute inflammation Regeneration of parenchymal cells Regeneration of parenchymal cells Migration and proliferation of parenchymal and mesenchymal cells Migration and proliferation of parenchymal and mesenchymal cells Synthesis of ECM proteins Synthesis of ECM proteins Remodeling Remodeling Collagenization Collagenization

58 Wound healing

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65 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.) Downloaded from: StudentConsult (on 19 May :58 PM) © 2005 Elsevier

66 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.) Downloaded from: StudentConsult (on 19 May :58 PM) © 2005 Elsevier

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69 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. Downloaded from: StudentConsult (on 19 May :58 PM) © 2005 Elsevier

70 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). Downloaded from: StudentConsult (on 19 May :01 PM) © 2005 Elsevier

71 Let us take a break!


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