Connective Tissue PDF 2024

Connective Tissue Louis J. Toth, Ph.D. [email protected] Chobanian and Avedisian School of Medicine at Boston University Cellular Organization of Tissues 2024 1 Outline of Lecture Part I - What is Connective Ti...

Connective Tissue Louis J. Toth, Ph.D. [email protected] Chobanian and Avedisian School of Medicine at Boston University Cellular Organization of Tissues 2024 1 Outline of Lecture Part I - What is Connective Tissue? Part II - Cells, Fibers, Ground Substance Part III - Disorders of Connective Tissue  CT originates from the embryonic Mesoderm layer mesenchyme is embryonic or fetal CT high cellularity (progenitors), fewer fibers, lots of ground substance, Visible Human Project: https://www.nlm.nih.gov/research/visible/image/thorax.jpg 1. What is CT? 3  Mesoderm (layer) and Mesenchyme (tissue) Embryo, 08mm (BUSM Biolucida) 1. What is CT? 4  The Fibroblast Fig 3b. “Bindegewebskörperchen” from Rudolf Virchow (1858) Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Geweblehre (the first modern pathology textbook!) Ovary with Corpus Luteum, Fallopian Tube (BUSM Biolucida) What is a fibroblast? derives from MSC no specific markers scRNA studies have identified several subtypes organ and site-specific types mechanotransduction – responds to external forces responsible for collagen production and maintenance interactions with other cells to maintain local structure – mφs, etc. “myofibroblast” is an activated form, important in wound repair 1. What is CT? 5  Mesenchymal “Stem" Cell (MSC) embryonic stem cell MSC NSC HSC others? adipocyte muscle Myeloid Lymphoid fibroblast RBCs Granulocytes The embryonic stem cell does not exist in humans. The term “stem cell” is therefore commonly used for its progenitors, which are thought of as “tissue-specific” stem cells. 1. What is CT? 6  Trans-differentiation embryonic stem cell MSC NSC PHSC others? adipocyte muscle Myeloid Lymphoid fibroblast RBCs Granulocytes 1. What is CT? 7  De-differentiation embryonic stem cell MSC NSC PHSC others? adipocyte muscle Myeloid Lymphoid fibroblast RBCs Granulocytes 1. What is CT? 8  Muscle tissue derives from MSC 560 Esophagus, lower region (BUSM Biolucida) Embryo, 25mm (BUSM Biolucida) Muscle progenitors are formed during embryonic and fetal development. Muscle always elaborates within a connective tissue compartment Smooth and skeletal (but probably not cardiac) muscle retain tissue-specific stem cells in the adult. 1. What is CT? 9  Adipose tissue derives from MSC adipose tissue is classed as a “special” CT adult adipocytes do not divide, but they do change their volume (amount of stored lipids) Owens B (2014) The Changing Colour of Fat Nature 508:552 1. What is CT? 10  Case Study: A 53-year-old woman with a history of melanoma of the right cheek that was treated 14 months ago with resection and lymph node dissection followed by treatment with ipilimumab. The patient also has a history of invasive ductal right breast cancer that was diagnosed 12 months ago and treated with lumpectomy and adjuvant radiation and hormonal therapies. F-18 FDG PET and PET/CT images are shown: Case courtesy of: Dr. Adam Kayne, University of Pennsylvania Department of Radiology, contributed to AuntMinnie.com 1. What is CT? 11  Thermogenic Fat Owens B (2014) The Changing Colour of Fat Nature 508:552 The presence of UCP-1 (uncoupling protein 1) in mitochondria determines whether fat will be thermogenic. It changes the product of mitochondrial respiration from ATP to heat. 1. What is CT? 12  Adipose Lineage MSC In theory, white fat may be interconvertible with beige fat. Brown fat is a separate lineage. 1. What is CT? 13  Special CTs - bone & cartilage Progenitor cells are derived from MSC: osteoprogenitors and chondroprogenitors Cells: osteocytes & chondrocytes Fibers: Bone is composed of mineralized type I collagen. Type X collagen is used as a scaffold when it’s being first formed. Ground Bone, Ross “Histology” 6th ed. Cartilage matrix is defined by type II collagen as its major component. Addition of type I collagen fibers produces fibrocartilage Addition of elastic fibers produces elastic cartilage Ground substance: lots of proteoglycans in cartilage resists compression Interface: Bone and cartilage are *always* bounded by a collagen sheet (fibrous periosteum or perichondrium) to Hyaline cartilage, xyphoid process (BUSM Biolucida) surrounding CT. This sheet forms the mechanical structure of the joint capsule. 1. What is CT? 14  Would you consider blood to be a CT? Cells: high cellularity Ovary with corpus luteum, fallopian tube (BUSM Biolucida) Fibers: normally zero (but… fibrin) Ground Substance: plasma …but nothing derived from MSC! 1. What is CT? 15  Consider the insects… In humans, the vasculature and the CT are separate compartments. Transfer between the two is highly regulated. human RBCs remain always within the systemic vasculature human WBCs diapedese to CT, and may return to circ via lymphatics interstitial (extracellular) fluid of CT is blood plasma that has been filtered and modified by the endothelium insect blood is called “hemolymph” it circulates in the “hemocoel” compartment blood and interstitial fluid are identical Purdue University “How to Make an Awesome Insect Collection” Youth and Entomology 1. What is CT? 16 Outline of Lecture Part I - What is Connective Tissue? Part II - Cells, Fibers, Ground Substance Part III - Disorders of Connective Tissue  Resident Cells from MSC Fibroblasts fibroblast precursors general fibroblasts location-specific types activated types (myofibroblast) Adipocytes white fat (unilocular) beige fat brown fat (multilocular) 2a. Cells 18  Cells of the Immune System All derive from the hematopoietic stem cell (HSC) Innate Immunity: macrophage - often resident in tissue neutrophil - 1st cellular response & chemotaxis mast cell - enhances leukocyte response through inflammation eosinophil - inflammatory response basophil - ? Adaptive Immunity B-lymphocyte & plasma cell - response to extracellular pathogen T-lymphocyte - response to virus (intracellular pathogen) 2a. Cells 19  Cells of the Immune System Cytokines control the cellular response - all leukocytes migrate & diapedese in response to cytokines inflammatory cytokines include Il-1, TNF-alpha, Il-6 anti-inflammatory cytokines include Il-4, Il-6, Il-10, Il-11, Il-13 Antibodies control the inflammatory response mast cells respond to allergens (IgE) plasma cells produce antibodies appropriate to the environment (IgM, IgG, IgE, IgA, IgD) 2a. Cells 20  Classification of General Connective Tissue General CT is highly diverse in its organization, but is typically classed as loose (areolar) dense - continuum of density dense irregular (3D) dense sheet-like (2D) - continuum of orientation dense regular (1D) Glisson’s Capsule, liver buh_652 Dermis (hand drawing) Eroschenko V (2013) “di Fiore’s Atlas of Histology” 12th ed, Wolters Kluwer, LWW Tendon Kuhnel W (2002) “Color Atlas of Cytology, Histology, and Microscopic Anatomy” Thieme 2b. Fibers 21  Collagens There are (at least) 28 collagens, generally divided into those that form fibers and those that don’t. — Fibrillar Alberts Molecular Biology of the Cell, 6th ed. type II (cartilage matrix) - tiny! type III (reticular fibers) - small type I (“collagen”) - medium Fibrillar anchoring type VII Karsdal (2016) Biochemistry of Collagens, Laminins & Elastin, Academic Press Meshwork type IV Non-fibrillar (many others) Collagen fibers are recognizable in EM. At high-mag, longitudinal fibers show banding, Cross PC, Mercer KL (1993) Cell and Tissue Ultrastructure, WH Freeman characteristic of their fibrillar structure. 2b. Fibers 22  Type I Collagen Assembly III I … is completed extracellularly Type I (but not type III) collagen fibrils continue to aggregate as their density increases Because of this, you can recognize if an area is dominated by type I collagen or by type III collagen. Cross and Mercer “Cell and Tissue Ultrastructure” 1993 2b. Fibers 23  Type I & Type III collagen the structural, “rope-like” collagens SEM, Renal capsule 5000x SEM, Amnion outer surface 5000x.. a mix of type I and type III.. all type III Thieme “Color Atlas of Cytology, Histology and Microscopic Anatomy” 2b. Fibers 24  Elastic Fibers fibers that resist stretch elastic fibers = amorphous elastin core + fibrillin microfibrils Alberts Molecular Biology of the Cell, 6th ed. The elastin fiber component of a tissue is traditionally visualized with Verhoeff’s stain (deep purple to black) wall of a muscular artery in Verhoeff’s, Biolucida 262 2b. Fibers 25  External or Basement Membrane provides a structural connection between tissue types, always contains type IV and contains VII collagen if connecting to CT Muscle & Adipose Epithelia have polarity If the CT compartment cells are surrounded - the basal surface is between two nearby by an external attached to CT via a epithelia is reduced during membrane basement membrane development, a basement membrane may directly connect two epithelia - e.g. lung & kidney. Alberts Molecular Biology of the Cell, 6th ed. 2b. Fibers 26  Structure of External Membrane lamina lucida - glycoproteins, principally laminin, fibronectin lamina densa - type IV collagen lamina reticularis - (present only when connecting to CT) anchoring type VII collagen binds type III collagen of CT to lamina densa “Basement membrane” and “external membrane” are equivalent structures. The term “basement membrane” is used when attached to an epithelium. “Basal lamina” (originally an EM term) is synonymous with “basement membrane” Alberts Molecular Biology of the Cell, 6th ed. 2b. Fibers 27  Proteoglycans Very large PG molecules hydrate the extracellular matrix by providing many (-) charged regions for weak bonding to H20 F Travascio (2016) Composition and Function of the Extracellular Matrix in the Human Body Alberts “Molecular Biology of the Cell” 6th ed. 2c. Ground Substance 28  Proteoglycans In standard preparations, proteoglycans are normally not visible, and ground substance is normally not preserved. F Travascio (2016) Composition and Function of the Extracellular Matrix in the Human Body Alberts “Molecular Biology of the Cell” 6th ed. 2c. Ground Substance 29  Proteoglycans in the brain form PNNs Example of a PNN surrounding a V1 neuron wikipedia: perineuronal nets Disruption of PNNs by chondroitinase can restore plasticity in a visual system model Distribution of PNNs surrounding PV+ neurons Perineuronal nets (PNNs) can serve to ‘label’ neurons, guiding developing Lensjo KK et al (2017) “Removal of perineuronal nets unlocks juvenille plasticity throguh network mechanisms of decreased inhibition and increased axons to form appropriate connections gamma activity” J Neurosci doi:10.1523/jneurosci.2504-16.2016 3c. Component Imbalance Outline of Lecture Part I - What is Connective Tissue? Part II - Cells, Fibers, Ground Substance Part III - Disorders of Connective Tissue  Disorders of CT 1. genetic disorders 2. responses to injury - scarring & cysts 3. component imbalance 3. Disorders of CT 32  Genetic Disorders Osteogenesis imperfecta - “brittle bone disease” - type I collagen mutation Ehlers-Danlos syndrome - mutations in genes that alter collagen structure (I,III,V), production or processing Marfan syndrome - fibrillin mutation Epidermis bullosa - (type VII, XVII) - blistering Alport’s syndrome (type IV, basal lamina) - loss of kidney function Stickler’s syndrome (type II, XI) - retinal detachments these are not listed in your syllabus - you will meet them later in your studies (some with Dr. Symes) 3a. Genetic Disorders 33  Scarring - Keloid and Hypertrophic Scars - areas of high tension - after trauma - elevated type III collagen Keloid scar Hypertrophic scar - raised appearance, sometimes unsightly - flat appearance at margin - collagen overgrows wound margin - may regress, may respond to steroids - perpendicular fibers - collagen parallel to surface - lower myofibroblast count - higher myofibroblast count emedecine.medscape.com 3b. Response to Injury 34  Cyst and Abscess formation gangrene from frostbite - note involvement of all tissue types UTCVM_OP008 cystic apocrine gland - eagle eye 3b. Response to Injury 35  Cyst and Abscess formation squamous epithelium of external cervix Cervical “glands” (plicae palmatae) Nabothian cyst in cervical canal 3b. Response to Injury  Cyst and Abscess formation ovarian cysts buh_751 3b. Response to Injury 37  too many cells - ulcer Ulcerative Colitis (BUSM Biolucida) 3c. Component Imbalance 38  too many fibers - Fibroproliferative Disease Karsdal (2016) Biochemistry of Collagens, Laminins & Elastin, Academic Press Myocardial infarction, healed (BUSM Biolucida) again, just skim the list for now - you’ll study all these disorders extensively later on 3c. Component Imbalance 39  too much fluid - Edema Pulmonary edema, acute, human (BUSM Biolucida) 3c. Component Imbalance 40  All Connective Tissue Cells fibroblast, adipocytes immune system cells Fibers type III, type I, elastic Ground Substance hydrated proteoglycans General Connective Tissue loose (areolar) dense - continuum of density irregular (sheet-like) - continuum of orientation regular 41