Intro to Pathology Spring 2025 PDF

Intro to Pathology Dr. Danny Mora Oral and Maxillofacial Pathologist Dr. Danny Mora, Oral and Maxillofacial Pathologist  Dr DannyMora sina dcesisiastst.mg'reEmine lunes mierales 8...

Intro to Pathology Dr. Danny Mora Oral and Maxillofacial Pathologist Dr. Danny Mora, Oral and Maxillofacial Pathologist  Dr DannyMora sina dcesisiastst.mg'reEmine lunes mierales 8 00 1000am enprontuario idicker 3 partialexams us nafinal upregideam in.EE scaYeMnistology parial Quizzes 15.1 Pattiparticipation 51 Disclosure: Most photos are from Copyright © 2017, by Elsevier Inc. All rights reserved. Dr. Danny Mora, Oral and Maxillofacial Pathologist  General pathology Systemic pathology Pathology is Studies the basic Examines the specific the study of reactions of cells and responses of specialized suffering or tissues to abnormal organs and tissues to disease stimuli that underlie all more or less well- diseases defined stimuli Dr. Danny Mora, Oral and Maxillofacial Pathologist THE CELL Dr. Danny Mora, Oral and Maxillofacial Pathologist  - The human genome contains roughly 3.2 billion DNA base pairs. - 80% of the human genome either binds proteins, involved in regulating gene expression, or can be assigned some functional activity, mostly related to the regulation of gene expression, often in a cell-type specific fashion. - The noncoding regions of the genome provide the critical “architectural planning.” N ONCODING DNA - The major classes of functional non–protein-coding sequences found in the human genome are the following: - Promoter and enhancer regions that provide binding sites for transcription factors - Binding sites for factors that organize and maintain higher order chromatin structures - Noncoding regulatory RNAs - Mobile genetic elements (e.g., transposons) - Special structural regions of DNA, telomeres (chromosome ends) and centromeres (chromosome “tethers”) Dr. Danny Mora, Oral and Maxillofacial Pathologist  Many genetic variations or polymorphisms associated with diseases So, non–protein-coding regions of the genome. Variation in gene regulation may prove to be more important in the cause of disease than structural changes in specific proteins. The genome sequencing for any two humans is typically more G ENETIC than 99.5% DNA-identical. VARIATIONS So, the individual variation, including susceptibility to diseases and environmental stimuli, is encoded in less than 0.5% of our DNA, this represents about 15 million base pairs. The two most common forms of DNA variation in the human genome are single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). Dr. Danny Mora, Oral and Maxillofacial Pathologist   SNPs are variants at single nucleotide positions and biallelic (only two choices exist, such as A or T).  Over 6 million human SNPs have been identified.  SNPs occur across the genome—within exons, introns, intergenic regions, and coding regions.  SNPs located in noncoding regions can occur within genomic regulatory elements, thereby altering gene expression;  SNPs influence disease susceptibility directly.  Even “neutral” SNPs may be useful markers if they happen to S INGLE be coinherited with a disease- associated polymorphism as a result of physical proximity. NUCLEOTIDE  The effect of most SNPs on disease susceptibility is weak, and it remains to be seen if identification of such variants, alone or in combination, can be used to develop effective strategies to POLYMORPHISMS identify those at risk and prevent disease. (SNPS) Dr. Danny Mora, Oral and Maxillofacial Pathologist  CNVs are a form of genetic variation consisting of different numbers of large contiguous stretches of DNA; CNVs can range from 1000 base pairs to millions of base pairs. COPY N UMBER CNVs can be biallelic and simply duplicated or, alternatively, deleted in some individuals. VARIATIONS CNVs are responsible for between 5 million and 24 million base pairs of sequence difference between any two individuals. Dr. Danny Mora, Oral and Maxillofacial Pathologist   Epigenetics is defined as heritable changes in gene expression that are not caused by alterations in DNA sequence.  Histones and histone modifying factors.  Histone is a protein that has nucleosomes wrapped around. E PIGENETICS  The resulting DNA-histone complex is called FACTORS chromatin.  Nuclear chromatin exists in two basic forms:  Cytochemically dense and transcriptionally inactive heterochromatin  Cytochemically dispersed and transcriptionally active euchromatin that regulates gene expression and dictates cellular identity and activity. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Histones are not static Chromatin remodeling complexes can reposition nucleosomes on DNA, exposing (or obscuring) gene regulatory elements to promoters. Histone marks are reversible through the activity of E PIGENETICS “chromatin erasers.” FACTORS Histone methylation Histone acetylation Histone phosphorylation DNA methylation. Chromatin organizing factors. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Deciphering the mechanisms that allow epigenetic factors to control genomic organization and gene expression in a cell-type- specific fashion is an extraordinarily complex proposition. Despite the intricacies, there is already ample evidence that dysregulation of the “epigenome” has a central role in malignancy. HISTONES Emerging data indicate that many other diseases are associated with inherited or acquired epigenetic alterations. Epigenetic alterations (e.g., histone acetylation and DNA methylation) are reversible and amenable to therapeutic intervention; HDAC and DNA methylation inhibitors are already being tested in the treatment of various forms of cancer. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Another mechanism of gene regulation depends on the functions of noncoding RNAs Micro-RNA (miRNA) Do not encode proteins. They modulate the translation of target mRNAs into their corresponding M ICRO -RNA proteins. AND LONG Act on gene regulation miRNAs appear to regulate multiple protein-coding genes, allowing each miRNA to co- NONCODING regulate entire programs of gene expression Small interfering RNAs (siRNAs) RNA Short RNA sequences that can be introduced experimentally into cells Serve as substrates for Dicer and interact with the RNA-Induced Silencer Complex in a manner analogous to endogenous miRNAs Developed as possible therapeutic agents to silence pathogenic genes, such as oncogenes involved in neoplastic transformation Dr. Danny Mora, Oral and Maxillofacial Pathologist  Recent studies have further identified an untapped universe of lncRNAs—by some calculations, the number of lncRNAs may exceed coding mRNAs by 10-fold to 20- fold. lncRNAs modulate gene expression by several mechanisms. lncRNAs can bind to chromatin and restrict RNA polymerase LONG from accessing coding genes within that region. N ONCODING RNA The best-known example is XIST, which is transcribed from the X chromosome and plays an essential role in the physiologic X regula la gran mayoria chromosome inactivation that occurs in females. de las accionesgenéricas XIST itself escapes X inactivation but forms a repressive “cloak” on the X chromosome from which it is transcribed, resulting in gene silencing. Many enhancers are actually sites of lncRNA synthesis. Dr. Danny Mora, Oral and Maxillofacial Pathologist  High-fidelity genome editing is part of the next era of the molecular revolution due to the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR- associated genes (Cas), such as the Cas9 nuclease Gene editing repurposes this process by using artificial 20-base guide RNAs (gRNAs) that bind Cas9 and are complementary to a targeted DNA sequence. Cas9 then induces double-stranded DNA breaks at the site of gRNA binding. Repair of the highly specific cleavages can lead to random disruptive mutations (through nonhomologous end joining) or can introduce new genetic material with precision (by homologous recombination). GENE EDITING Both the guide sequences and the Cas enzyme, either as a coding DNA (cDNA) or a protein, can be easily estoes constantemente todos introduced into cells. 105dias The potential application to genetic engineering, due to the impressive specificity of the Cas9 system, has led to great excitement. regeneration constants Applications for CRISPR: Inserting specific mutations in cells and tissues Model cancers Selectively edit mutations that cause hereditable disease, cloud eliminate less “desirable” traits. Predictably the technology has inspired a vigorous debate regarding the ethics of its use. Dr. Danny Mora, Oral and Maxillofacial Pathologist  The viability and normal activity of cells depend on a variety of fundamental housekeeping functions that all differentiated cells must perform. Include: Protection from the environment- cell membrane C ELL Nutrient acquisition- cell membrane Communication- cell junctions HOUSEKEEPING Movement- cytoskeleton constantemente do limpian roomba Renewal of senescent molecules- endoplasmic partemaisimp es la reticulum and Golgi membranacelular Molecular catabolism- mitochondria Energy generation- mitochondria Dr. Danny Mora, Oral and Maxillofacial Pathologist  Mitochondria also regulate the balance of cell survival and death. There are two major pathways of cell death Necrosis: External cellular injury (toxin, ischemia, trauma) can damage mitochondria, inducing the formation of C ELL DEATH mitochondrial permeability transition pores in the outer membrane. cil noesta esperateesta tuncionando These channels allow the dissipation of the proton potential so that mitochondrial ATP generation fails and IEEnosisexterna the cell dies apoptosis endogeno P.fidtiEiswricamente Dr. Danny Mora, Oral and Maxillofacial Pathologist  celc umplesufuncionbammussemurer Apoptosis: Programmed cell death is a central feature of normal tissue development and turnover and can be triggered by extrinsic signals (including cytotoxic T cells and inflammatory cytokines), or intrinsic pathways (including DNA damage and intracellular stress). Mitochondria play a central role in the intrinsic pathway of apoptosis. If mitochondria are damaged (a sign of irreversible cell injury or stress) or C ELL DEATH the cell cannot synthesize adequate amounts of survival proteins (because of deficient growth signals), mitochondria become leaky. Cytochrome c, which is normally sequestered inside the mitochondria, leaks into the cytosol, where it forms a complex with other proteins that ultimately activate caspases, the enzymes that induce apoptosis. Failure of apoptosis can contribute to malignancy and too much apoptosis can lead to premature cell death, as occurs in some neurodegenerative disorders. apoptosisocumdsp Dr. Danny Mora, Oral and Maxillofacial Pathologist  The cell is exposed to a remarkable variety of signals Some signals may induce a given cell type to differentiate, others may stimulate proliferation, and yet others may direct the cell to perform a specialized function. The absence of appropriate exogenous signals, they die by apoptosis. C ELL The signals that most cells respond to: SIGNALING Damage to neighboring cells and pathogens Contact with neighboring cells Contact with ECM Secreted molecules Growth factors, cytokines, and hormones Dr. Danny Mora, Oral and Maxillofacial Pathologist  Extracellular cell-cell signaling pathways are classified into different types, based on the distance over which the signal functions: Paracrine signaling 4 FORMASPRINCIPALESDECELLSIGNALING Autocrine signaling Synaptic signaling C ELL Endocrine signaling endo hormonal SIGNALING P9gñaifngso glides In iaminatiina Dr. Danny Mora, Oral and Maxillofacial Pathologist  Cells respond to the signaling molecules that they themselves secrete, thus establishing an autocrine loop. Autocrine growth regulation plays a role in liver regeneration, proliferation of antigen stimulated lymphocytes, and the growth of some tumors. A UTOCRINE SIGNALING Dr. Danny Mora, Oral and Maxillofacial Pathologist  Hormones are synthesized by cells of endocrine organs and act on target cells distant from their site of synthesis, being usually carried by the blood. E NDOCRINE S IGNALING Edo hormonal Dr. Danny Mora, Oral and Maxillofacial Pathologist  One cell type produces the ligand The ligand acts on adjacent target cell that express the appropriate receptors. Seen in tissue repair: Macrophages produces a factor that has growth effects on fibroblasts Liver regeneration PARACRINE Common in connective tissue repair of healing wounds S IGNALING Dr. Danny Mora, Oral and Maxillofacial Pathologist  Activated neurons secrete neurotransmitters at specialized cell junctions (synapses) onto target cells. Paracrine S YNAPTIC SIGNALING nuncailegan a tocarse ej Herpesoval Dr. Danny Mora, Oral and Maxillofacial Pathologist Dr. Danny Mora, Oral and Maxillofacial Pathologist  It is increasingly clear that any initial signal impacts multiple processes, each of which contributes to the final outcome. This is particularly true of signaling pathways that rely on enzymatic activity. M ODULAR For example, specific phosphorylation of any given protein can S IGNALING allow it to associate with a host of other molecules, resulting in : P ROTEINS , H UBS, Enzyme activation or inactivation. Nuclear or cytoplasmic localization of transcription factors. AND NODES Transcription factor activation or inactivation. Actin polymerization or depolymerization. Patamatgrandedela ULOS Protein degradation or stabilization. Activation of feedback inhibitory or stimulatory loops. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Growth factors stimulate the activity of signaling pathways and genes that augment cell survival, growth, and division. A major role of growth factors is to stimulate the activity of genes that are required for cell growth and cell division. They bind to specific receptors to: Promote entry of cells into the cell cycle Relieve blocks on cell cycle progression (thus promoting G ROWTH replication) Prevent apoptosis FACTORS Enhance biosynthesis of cellular components (nucleic acids, proteins, lipids, carbohydrates) paramandymaxilla Uncontrolled proliferation can result when the growth factor activity is esmodular dysregulated, or when growth factor signaling pathways are altered Many growth factor pathway genes are proto-oncogenes; gain-of- function mutations in these genes can convert them into oncogenes capable of tumor formation. Dr. Danny Mora, Oral and Maxillofacial Pathologist Growth Factor Sources Functions Activated macrophages, salivary Mitogenic for keratinocytes and fibroblasts; stimulates keratinocyte Epidermal growth factor (EGF) glands, keratinocytes, and many migration; stimulates formation of granulation tissue other cells Activated macrophages, Stimulates proliferation of hepatocytes and many other epithelial Transforming growth factor-α (TGF-α) keratinocytes, many other cell cells types Hepatocyte growth factor (HGF) Fibroblasts, stromal cells in the Enhances proliferation of hepatocytes and other epithelial cells; (scatter factor) liver, endothelial cells increases cell motility Vascular endothelial growth factor Stimulates proliferation of endothelial cells; increases vascular Mesenchymal cells (VEGF) permeability Platelets, macrophages, Chemotactic for neutrophils, macrophages, fibroblasts, and smooth Platelet-derived growth factor (PDGF) endothelial cells, smooth muscle muscle cells; activates and stimulates proliferation of fibroblasts, cells, keratinocytes endothelial, and other cells; stimulates ECM protein synthesis Fibroblast growth factors (FGFs), Macrophages, mast cells, Chemotactic and mitogenic for fibroblasts; stimulates angiogenesis including acidic (FGF-1) and basic endothelial cells, many other cell and ECM protein synthesis (FGF-2) types Platelets, T lymphocytes, macrophages, endothelial cells, Chemotactic for leukocytes and fibroblasts; stimulates ECM protein Transforming growth factor-β (TGF-β) keratinocytes, smooth muscle synthesis; suppresses acute inflammation cells, fibroblasts Keratinocyte growth factor (KGF) (i.e., Fibroblasts Stimulates keratinocyte migration, proliferation, and differentiation FGF-7) gotransformedeuntejidoa que Dr. Danny Mora, Oral and Maxillofacial Pathologist  The Extracellular Matrix (ECM) is a protein network that constitutes a significant proportion of any tissue. Cell interactions with the ECM are critical for development, healing, and maintenance of normal tissue architecture. The ECM functions as a: - Mechanical support for cell anchorage, cell migration, and maintenance of cell polarity. - Regulator of cell proliferation by binding and displaying growth factors and by signaling via cellular integrin family receptors. - The ECM provides a depot for latent growth factors that can be activated within foci E XTRACELLULAR of injury or inflammation. - Scaffolding for tissue renewal. MATRIX - Maintenance of normal tissue structure requires a basement membrane or stromal scaffolds, integrity of the basement membrane or the stroma of parenchymal cells is critical for organized tissue regeneration. estoquenosdael - ECM disruption prevents effective tissue regeneration and repair. coreIvelleno - Foundation for establishment of tissue microenvironments. - Basement membrane acts as a boundary between epithelium and underlying connective tissue but often does more than just provide structural support; for example, in the kidney, it forms part of the filtration apparatus. The ECM is constantly being remodeled. Dr. Danny Mora, Oral and Maxillofacial Pathologist  T HE ECM OCCURS IN TWO BASIC FORMS: INTERSTITIAL MATRIX AND BASEMENT MEMBRANE  Interstitial matrix.  Interstitial matrix occupies the spaces between stromal cells within connective tissue and between parenchymal epithelium and the underlying supportive vascular and smooth muscle structures in some organs.  Interstitial matrix is synthesized by mesenchymal cells (e.g., fibroblasts), forming a three-dimensional, relatively amorphous, semi-fluid gel.  In some tissues, such as the gastrointestinal tract, urinary bladder, and periarterial soft tissues, fluid within  matrix cushions tissue compression associated with peristalsis, urination, and pulsatile arterial blood flow.  The major nonfluid constituents of the interstitial matrix are fibrillar and nonfibrillar collagens, as well as fibronectin, elastin, proteoglycans, hyaluronate, and other constituents.  Basement membrane.  Interstitial matrix within connective tissues becomes highly organized around epithelial cells, endothelial cells, and smooth muscle cells, where it forms basement membranes, specialized surfaces for cell growth. Basement membrane components, which are synthesized by the overlying epithelium and underlying mesenchymal cells, form a flat lamellar mesh.  The major constituents are nonfibrillar type IV collagen and laminin. Dr. Danny Mora, Oral and Maxillofacial Pathologist  ECM components fall into three families: Fibrous structural proteins such as collagens and elastin that confer tensile strength and recoil Water-hydrated gels such as proteoglycans and hyaluronan that permit compressive resistance and lubrication Adhesive glycoproteins that connect ECM elements C OMPONENTS OF to one another and to cells THE EXTRACELLULAR MATRIX Dr. Danny Mora, Oral and Maxillofacial Pathologist  Collagens are composed of three separate polypeptide chains braided into a ropelike triple hélix. About 30 collagen types have been identified, some of which are unique to specific cells and tissues. estabilidad Fibrillar collagens: Some collagen types (e.g., types I, II, III, and V) form linear fibrils stabilized by interchain hydrogen bonding; A major proportion of the connective tissue in bone, tendon, cartilage, blood vessels, and skin, as well as in healing wounds and scars. COLLAGENS  The tensile strength of the fibrillar collagens derives from lateral cross-linking of the triple helices via covalent  bonds that follow lysine hydroxylation.  The responsible enzyme, lysyl hydroxylase, is dependent on vitamin C, explaining why children with ascorbate deficiency have skeletal deformities and why individuals of any age with vitamin C deficiency heal poorly and bleed easily.  Genetic defects, including collagen and lysyl hydroxylase mutations, cause diseases such as osteogenesis imperfecta and certain forms of Ehlers-Danlos syndrome. Nonfibrillar collagens: apanienciama's oilu npocomasestivada estetical Type IV collagen contribute to structures of planar basement membranes; Type IX collagen in cartilage help regulate collagen fibril diameters and collagen-collagen interactions via so- called fibril-associated collagen with interrupted triple helices (FACITs); Type VII collagen mutations lead to blistering skin diseases. It provides anchoring fibrils that maintain structure of stratified squamous epithelium Dr. Danny Mora, Oral and Maxillofacial Pathologist  The ability of tissues to elastically recoil and return to a baseline structure after physical stress is conferred by elastin Elasticity is especially important in cardiac valves and large blood vessels, which need to accommodate recurrent pulsatile flow, as well as in the uterus, skin, and ligaments. ELASTIN The elastic fibers consist of a central core of elastin with an associated mesh like network of fibrillin glycoprotein. The latter relationship partially explains why fibrillin synthetic defects lead to skeletal abnormalities and weakened aortic walls, as in patients with Marfan syndrome; Fibrillin also controls the availability of free TGF-β, and this function plays a role in pathogenesis of Marfan syndrome. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Proteoglycans form highly hydrated compressible gels that confer resistance to compressive forces; in joint cartilage, proteoglycans also provide a layer of lubrication between adjacent bony surfaces. Proteoglycans are named according to the structure of their principal repeating disaccharide. Heparan sulfate Chondroitin/dermatan sulfate Keratan sulfate PROTEOGLYCANS Hyaluronan (HA) Proteoglycans consist of long polysaccharides, called glycosaminoglycans attached to a core AND protein; HYALURONAN These are then linked to a long hyaluronic acid polymer called hyaluronan, The highly negatively charged nature of the densely packed sulfated sugars attracts cations (mostly sodium) and with them, abundant osmotically attracted water—producing a viscous, gel-like matrix. Besides providing compressibility to tissues, proteoglycans also serve as reservoirs for growth factors secreted into the ECM (e.g., FGF and HGF). Some proteoglycans are integral cell membrane proteins that have roles in cell proliferation, migration, and adhesion (e.g., by binding and concentrating growth factors and chemokines) Dr. Danny Mora, Oral and Maxillofacial Pathologist   HA is a polysaccharide of the Glycosaminoglycans  Found in ECM, abundant in heart valves, skin and skeletal tissues, synovial fluid, the vitreous of the eye, and the umbilical cord  Inhibits cell to cell adhesion HYALURONIC  Facilitates cell motility ACID  It binds a large amount of water (about 1000-fold its own weight), 5112grabacion forming a viscous hydrated gel that gives connective tissue the ability to resist compression forces.  HA helps provide resilience and lubrication to many types of connective tissue, notably for the cartilage in joints. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Prototypical adhesive glycoproteins include fibronectin (a major component of the interstitial ECM) and laminin (a major constituent of basement membrane). Integrins are representative of the adhesion receptors, also known as cell adhesion molecules (CAMs); also include immunoglobulin family members, cadherins, and selectins. Fibronectin exists in tissue and plasma forms. Synthesized by fibroblasts, monocytes, and endothelium. A DHESIVE Can bind to distinct ECM components (e.g., collagen, fibrin, heparin, and proteoglycans), and attach to cell integrins. GLYCOPROTEINS In healing wounds, tissue and plasma fibronectin provide the scaffolding for subsequent ECM deposition, angiogenesis, and reepithelialization. AND A DHESION Laminin is the most abundant glycoprotein in basement membranes. Connects cells to underlying ECM components such as type IV collagen and heparan RECEPTORS sulfate. Also modulate cell proliferation, differentiation, and motility. Integrins are glycoproteins composed of α- and β-subunits Allows cells to attach to ECM constituents such as laminin and fibronectin, linking the intracellular cytoskeleton. Integrins also facilitate cell-cell adhesive interactions; Important role in platelet aggregation. Binding through the integrin receptors it can trigger signaling cascades that regulate cell locomotion, proliferation, shape, and differentiation Dr. Danny Mora, Oral and Maxillofacial Pathologist Dr. Danny Mora, Oral and Maxillofacial Pathologist  Cell proliferation is fundamental to organism development, to maintenance of steady-state tissue P ROLIFERATION homeostasis, and to replacement of dead or damaged cells. AND THE The sequence of events that results in cell proliferation is CELL CYCLE called the cell cycle: G1 (gap 1) S (DNA synthesis) G2 (gap 2) M (mitotic) phases Quiescent cells that are not actively cycling are in the G0 (gap 0) state. Cells can enter G1 either from the G0 quiescent cell pool or after completing a round of mitosis. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Self-renewal, which permits stem cells to maintain their numbers. Asymmetric division, in which one daughter cell enters a differentiation pathway and gives rise to mature cells, while the other remains undifferentiated and retains its self-renewal capacity. Embryonic Stem Cells (ES) STEM CELLS Embryos contain pluripotent ES cells, which can give rise to all the tissues of the human body. formadeltejidoregenerause Adult Stem Cells constantement Adult animals have been shown to contain reservoirs of stem cells Adult stem cells have a more restricted differentiation capacity and are usually lineage-specific. Dr. Danny Mora, Oral and Maxillofacial Pathologist S TEM CELLS Dr. Danny Mora, Oral and Maxillofacial Pathologist  Stem cells are located in sites called niches Isthmus of stomach glands, and at the base of the crypts of the colon Base of hair follicles Limbus of the cornea Bone marrow. The bone marrow contains HSCs and stromal cells STEM CELLS IN Hematopoietic stem cells (HSCs) Generate all of the blood cells T ISSUE At bone marrow, from umbilical cord blood, and from circulating blood of individuals receiving cytokines. HOMEOSTASIS HSCs may be capable of giving rise to neurons, hepatocytes, and other cell types Bone marrow stromal cells, depending on the tissue environment, can generate chondrocytes, osteoblasts, adipocytes, myoblasts, and endothelial cell precursors. Stem cells may produce growth factors and cytokines that act on the cells of the tissue to which they migrate, promoting repair and cell replication. Dr. Danny Mora, Oral and Maxillofacial Pathologist Stem cells in skin Dr. Danny Mora, Oral and Maxillofacial Pathologist Stem cells in GI epithelium Dr. Danny Mora, Oral and Maxillofacial Pathologist  Liver. The liver contains stem cells in the canals of Hering, the junction between the biliary ROLE OF STEM ductular system and parenchymal hepatocytes. CELLS Cells located in this niche can give rise to a population capable of differentiating into hepatocytes and biliary cells. In contrast to stem cells in proliferating tissues, liver stem cells function as a secondary or reserve compartment activated only when hepatocyte proliferation is blocked. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Brain Neurogenesis from neural stem cells (NSCs) occurs in the brain of adult rodents and humans. Thus, the long-established dogma that no new neurons are generated in the brain of normal adult mammals is now known to be incorrect. ROLE OF STEM NSCs (also known as neural precursor cells), capable of generating neurons, astrocytes, and oligodendrocytes, have been CELLS identified in two areas of adult brains, the subventricular zone (SVZ) and the dentate gyrus of the hippocampus. There is much hope that stem cell transplantation, or the induction of differentiation of endogenous NSCs, may be used in treatment of stroke, neurodegenerative disorders such as Parkinson and Alzheimer diseases, and spinal cord injury. Dr. Danny Mora, Oral and Maxillofacial Pathologist  Cytokines have important functions as mediators of inflammation and immune responses Some are considered growth factors because of their growth promoting activities. CYTOKINES CD4 Employees's titmmune Dr. Danny Mora, Oral and Maxillofacial Pathologist  The ability to identify, isolate, expand, and transplant stem cells Differentiated progeny of adult stem cells can be used to repopulate damaged tissues, or to construct entire organs for replacement. Opportunity for restoring damaged tissues that have low intrinsic regenerative capacity Myocardium after a myocardial infarct Neurons after a stroke REGENERATIVE Potential problem is the immunogenicity of most stem cells; although mesenchymal stem cells may be weakly immunogenic, most other adult MEDICINE stem cells, as well as Embryonic Stem cells express histocompatibility (HLA) molecules of the sperm and egg donors that provoke immunologic rejection by the host “stem-ness” of ES cells, when such genes are introduced into fully differentiated cells (e.g., fibroblasts), induced pluripotent stem cells (iPS cells) are generated Since these cells are derived from the patient, their differentiated progeny (e.g., insulin- secreting β-cells in a patient with diabetes) can be engrafted without eliciting a rejection reaction. Dr. Danny Mora, Oral and Maxillofacial Pathologist Tissue Repair Dr. Danny Mora, Oral and Maxillofacial Pathologist   Define tissue repair, regeneration, and scarring.  Explain the difference between labile, stable, and permanent Tissue Repair tissues, and give examples of each. Objectives  Explain the importance of stem cells in regeneration, and list the two types of tissues in which regeneration can occur.  Outline the main steps involved in scarring, and be sure you know what granulation tissue is. Dr. Danny Mora, Oral and Maxillofacial Pathologist   Describe what you’d need to know in order to predict whether a wound will heal by regeneration or scarring.  Compare and contrast first-intention and second-intention Tissue Repair healing, and know the rough timeline for first-intention healing of small wounds. Objectives  Describe in general how strong a wound is at suture removal, and explain how that wound strength changes over time.  Explain how the wound healing process is abnormal in keloid scars and proud flesh. Dr. Danny Mora, Oral and Maxillofacial Pathologist   Introduction and definitions  Three types of tissues Tissue Repair  Repair by regeneration Outline  Repair by scarring  A couple things about skin wounds  Abnormal wound healing Dr. Danny Mora, Oral and Maxillofacial Pathologist  Tissue repair is defined as the restoration of tissue architecture and function after an injury. Tissue Repair It involves two processes:  Regeneration (full restoration to normal)  Connective tissue deposition (scarring) Dr. Danny Mora, Oral and Maxillofacial Pathologist Dr. Danny Mora, Oral and Maxillofacial Pathologist  Labile (continuously proliferating) tissues Composed of cells that are constantly being Three Types of lost and replaced Replacement comes from stem cells and Tissues also from proliferation of some mature cells Labile, Stable, Permanent Can easily regenerate after injury Examples: skin, bone marrow, GI epithelium Dr. Danny Mora, Oral and Maxillofacial Pathologist Stem cells in GI epithelium Dr. Danny Mora, Oral and Maxillofacial Pathologist  Stable (quiescent) tissues Composed of cells that have a minimal Three Types of ability to proliferate Tissues Can undergo some regeneration after injury Labile, Stable, Permanent Examples: liver, kidney, pancreas Dr. Danny Mora, Oral and Maxillofacial Pathologist  Permanent tissues Composed of cells that cannot proliferate Three Types of Cannot regenerate in response to injury Tissues Injury always results in scarring Labile, Stable, Permanent Examples: brain, heart tejido no seregenera Dr. Danny Mora, Oral and Maxillofacial Pathologist Dr. Danny Mora, Oral and Maxillofacial Pathologist  Occurs all the time in labile tissues! Occurs in limited form in stable tissues Remove one kidney: the other one Regeneration undergoes hypertrophy and hyperplasia Remove half of the liver: it will grow back Doesn’t occur at all in permanent tissues. Dr. Danny Mora, Oral and Maxillofacial Pathologist Liver right lobe before to be resection resected left lobe Liver now 1 week enlarged after resection Dr. Danny Mora, Oral and Maxillofacial Pathologist  If full regeneration isn’t possible, then you need to make a scar. What determines whether regeneration is possible? Type of tissue Scarring Extent of extracellular matrix damage Scarring involves creating new blood vessels (angiogenesis), laying down collagen (which is made by fibroblasts), and eventually remodeling the collagen so the scar is just right. Dr. Danny Mora, Oral and Maxillofacial Pathologist  1. New blood vessels 2. Fibroblasts 3. Extracellular matrix collagen Dr. Danny Mora, Oral and Maxillofacial Pathologist  Summary: 1. Make granulation tissue Scarring 2. Turn it into a chunk of collagen Dr. Danny Mora, Oral and Maxillofacial Pathologist  Fibroblasts New blood vessels Collagen Granulation tissue Extracellular matrix Dr. Danny Mora, Oral and Maxillofacial Pathologist  Blood vessels Scar Collagen Dr. Danny Mora, Oral and Maxillofacial Pathologist  Q. Is “granulation tissue” the same thing as “granuloma”? no son 2cosasdifeventes Dr. Danny Mora, Oral and Maxillofacial Pathologist Granuloma Multinucleated Dr. Danny Mora, Oral and Maxillofacial Pathologist Skin Wounds: Two Types of Healing First intention healing Second intention healing etquequeremos lameta etcachete Dr. Danny Mora, Oral and Maxillofacial Pathologist First Intention Healing Second Intention Healing Small wounds that close easily Large open wounds Regeneration > scarring Scarring > regeneration Healing is fast Healing is slower Minimal inflammation and scarring More inflammation and scarring, Examples: greater risk of infection Paper cuts Examples: Well-approximated surgical Burns incisions External-bevel Replaced periodontal flaps gingivectomies Extraction sockets Dr. Danny Mora, Oral and Maxillofacial Pathologist  notTHATIMPfortest Rough timeline for first intention healing of small wounds sammthf.glet What rejido (scar) Dr. Danny Mora, Oral and Maxillofacial Pathologist Pressure ulcer of skin rejidodefibrinaenel centro Dr. Danny Mora, Oral and Maxillofacial Pathologist  muchakerating usesanormalenla boca Skin ulcer: “large gap between edges” Dr. Danny Mora, Oral and Maxillofacial Pathologist Skin ulcer: granulation tissue ulceras re venignal en la pied y en laboca Dr. Danny Mora, Oral and Maxillofacial Pathologist Skin ulcer: re-epithelialization abajotodavia estrien regeneration Dr. Danny Mora, Oral and Maxillofacial Pathologist  100% 75% Skin Wound 50% Strength 25% al pasar 105 Suture 3 months Years arsos ese tejido removal NUNCA Ilega al 1001de strength Dr. Danny Mora, Oral and Maxillofacial Pathologist  as citoquinasprostaglandin Not enough granulation tissue/scarring Abnormalities in Too much scarring (keloid scar) cito q uinasmuyactivadas Tissue Repair Too much granulation tissue (proud flesh) I PE.maieiiisinamintnagia.in fuman que Dr. Danny Mora, Oral and Maxillofacial Pathologist Keloid Scar Dr. Danny Mora, Oral and Maxillofacial Pathologist Proud Flesh Dr. Danny Mora, Oral and Maxillofacial Pathologist Questions? Dr. Danny Mora, Oral and Maxillofacial Pathologist