Cell Turnover: 20/01/2025 Theme 2.1 PDF

CELL TURNOVER Dr N Buthelezi Department of Anatomical Pathology Date: 20/01/2025 LEARNING OBJECTIVES Definitions: Growth, differentiation, morphogenesis Cell cycle Types of stem cells Tissue types GROWTH, DIFFERENTIATION AND MORPHOGENESIS Growth is the process of increase in size r...

CELL TURNOVER Dr N Buthelezi Department of Anatomical Pathology Date: 20/01/2025 LEARNING OBJECTIVES Definitions: Growth, differentiation, morphogenesis Cell cycle Types of stem cells Tissue types GROWTH, DIFFERENTIATION AND MORPHOGENESIS Growth is the process of increase in size resulting from the synthesis of specific tissue components. Type of growth in tissue are: Multiplicative: Increase in the number of cells by mitosis. Present in all tissues during embryogenesis Auxetic: Increase size of individual cells (eg. Skeletal muscle) Accretionary: An increase in intercellular tissue components (eg. Bone and cartilage) Combined GROWTH, DIFFERENTIATION AND MORPHOGENESIS Differentiation is the process whereby a cell develops an overt specialized function or morphology that distinguished it from its parent cell. In this process, genes are expressed selectively, and gene products act to produce a cell with a specialised function. GROWTH, DIFFERENTIATION AND MORPHOGENESIS Morphogenesis is the highly complex process of development of structural shape and form of organs, limbs, facial features etc. from primitive cells masses during embryogenesis. This involves growth and differentiation with movement of cell groups relative to others, and focal apoptosis to remove unwanted features MAINTAINING CELL POPULATIONS Cell proliferation is fundamental to: Development Maintenance of steady-state tissue homeostasis Replacement of dead or damaged cells The size of a cell population depends on the rate of cell proliferation and death by apoptosis: Cell proliferation can be stimulated by pathological or physiological conditions MAINTAINING CELL POPULATIONS Physiological: Endometrial tissue during the menstrual cycle Thyroid tissue during pregnancy Pathological: After cell death or tissue injury MAINTAINING CELL POPULATIONS Cell proliferation is controlled by signals from the microenvironment that either inhibit or stimulate cell proliferation. Growth can be increased by increasing the rate or shortening the cell cycle. MAINTAINING CELL POPULATIONS The key elements of cellular proliferation are: Accurate DNA replication Coordinated synthesis of all other cellular constituents Equal apportionment of DNA and cellular constituents to daughter cells through mitosis MAINTAINING CELL POPULATIONS The cell cycle is a sequence of events that results in cell division. It consists of the following phases: G1 = Presynthetic growth phase Restriction point G1/S checkpoint S = DNA synthesis G2 = Premitotic growth G2/M checkpoint M = Mitosis CELL CYCLE CELL CYCLE MAINTAINING CELL POPULATIONS The cell cycle checkpoints ensure that cells with genetic imperfections do not complete replication. The G1/S checkpoint monitors the integrity of DNA before irreversibly committing cellular resources to DNA replication. The G2/M checkpoint ensures accurate genetic replication before the cell divides. If DNA damage is beyond repair, the cell will either undergo apoptosis or senescence. MAINTAINING CELL POPULATIONS The cell cycle is regulated by activators and inhibitors: Cyclins Cyclin-dependent kinases (CDKs) Cyclin-dependent kinase inhibitors (CDKIs) CDKs acquire the ability to phosphorylate protein substrates by forming complexes with the relevant cyclins. MAINTAINING CELL POPULATIONS Increased synthesis of a particular cyclin leads to increased kinase activity of the appropriate CDK binding partner. As the cyclin completes its round of phosphorylation, the associated cyclin is degraded and the CDK activity abates. Therefore, CDK levels wax and wane with corresponding cyclin levels. CYCLIN-DEPENDENT KINASE INHIBTIORS p21 (CDKN1A) p27 (CDKN1B) p57 (CDKN1C)  Broadly inhibit CDKs CYCLIN-DEPENDENT KINASE INHIBTIORS p15 (CDKN2B) p16 (CDKN2A) p18 (CDKN2C) p19 (CDKN2D) Selective effects on CDK4 and CDK6 STEM CELLS Stem cells are undifferentiated cells that can differentiate into multiple types of other cells. Stem cells are characterized by two important properties: Self-renewal: allows maintenance of stem cell pool Asymmetric division: one daughter cell enters the differentiation pathway and gives rise to mature cells, whilst the other cell remains undifferentiated and retains its self-renewal capacity. STEM CELLS STEM CELLS Embryonic stem cells: Most undifferentiated Present in the inner mass of the blastocyst Virtually limitless self-renewal capacity Can give rise to any cell in the body = totipotent STEM CELLS Tissue (adult) stem cells Found within differentiated tissues Can only produce cells that are constituents of that particular tissue Protected within stem cell nicches STEM CELLS Bone marrow Bulge of the hair follicle Limbus of the eye The canals of herring in the liver Supraventricular zone in the brain STEM CELLS Labile Proliferate continuously in postnatal life The cells have a short life span with a rapid turnover time Cells are frequently lost and replaced by stem cell division This high cell turnover renders the tissue susceptible to the toxic effects of radiation and drugs Haemopoietic cells of the bone marrow, skin, GIT, exocrine gland ducts, urinary tract, vagina, cervix and endometrium STEM CELLS Stable Divide very infrequently under normal conditions Stem cells may be stimulated to divide rapidly when cells are lost Liver, endocrine glands, bone, renal tubules STEM CELLS Permanent Active stem cells in these tissues do NOT persist long into postnatal life Cells cannot be replaced when they lost Neurons, cardiac muscle, photoreceptors. REFERENCES Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran pathologic basis of disease. Cross S. Underwood's Pathology: A Clinical Approach. Elsevier Health Sciences; 2018 Mar 9.