Life Sciences I - Cell Biology - Apoptosis - PDF

Life Sciences I Cell biology Cellular Differentiation, Aging, Apoptosis, Regeneration  Cellular Differentiation Within multicellular organisms, tissues are organized communitie...

Life Sciences I Cell biology Cellular Differentiation, Aging, Apoptosis, Regeneration  Cellular Differentiation Within multicellular organisms, tissues are organized communities of cells that work together to carry out a specific function. The exact role of a tissue in an organism depends on what types of cells it contains. For example, the endothelial tissue that lines the human gastrointestinal tract consists of several cell types. Some of these cells absorb nutrients from the digestive contents, whereas others (called goblet cells) secrete a lubricating mucus that helps the contents travel smoothly. When a cell differentiates (i.e., becomes more specialized), it may undertake major changes in its size, shape, metabolic activity, and overall function. https://www.nature.com/scitable/topicpage/cell-differentiation-and-tissue-14046412/  Stem cells are cells with the potential to develop into many different types of cells in the body. There are two main types of stem cells: embryonic stem cells and adult stem cells. Stem cells are different from other cells in the body in three ways:  They can divide and renew themselves over a long time  They are unspecialized, so they cannot do specific functions in the body  They have the potential to become specialized cells, such as muscle cells, blood cells, and brain cells https://medlineplus.gov/stemcells.html  Stem cells typically have the capacity to mature into many different cell types. Transcription factors — proteins that regulate which genes are transcribed in a cell — appear to be essential to determining the pathway particular stem cells take as they differentiate. For example, both intestinal absorptive cells and goblet cells arise from the same stem cell population, but divergent transcriptional programs cause them to mature into dramatically different cells. https://www.nature.com/scitable/topicpage/cell-differentiation-and-tissue-14046412/ https://www.nature.com/scitable/ebooks/  Mechanism of differentiation The primary mechanism by which genes are turned “on” or “off” is through transcription factors. A transcription factor is one of a class of proteins that bind to specific genes on the DNA molecule and either promote or inhibit their transcription. The primary mechanism that determines which genes will be expressed and which ones will not is through the use of different transcription factor proteins, which bind to DNA and promote or hinder the transcription of different genes. Through the action of these transcription factors, cells specialize into one of hundreds of different cell types in the human body. Transcription Factors Regulate Gene Expression: While each body cell contains the organism’s entire genome, different cells regulate gene expression with the use of various transcription factors. Transcription factors are proteins that affect the binding of RNA polymerase to a particular gene on the DNA molecule. https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/16%3A_Gene_Expression/16.4%3A_Regulating_Gene_Expression_in_Cell_Development/16.4C%3A_Mechanics_of _Cellular_Differentation  Cell potency refers to the varying ability of stem cells to differentiate into specialized cell types. Cells with the greatest potency can generate more cells types than those with lower potency. 1. Totipotent Stem Cells Totipotent (omnipotent) stem cells can give rise to any of the 220 cell types found in an embryo as well as extra-embryonic cells (placenta). 2. Pluripotent Stem Cells Pluripotent stem cells can give rise to all cell types of the body (but not the placenta). 3. Multipotent Stem Cells Multipotent stem cells can develop into a limited number of cell types in a particular lineage. Hima Bindu A, Srilatha B (2011) Potency of Various Types of Stem Cells and their Transplantation. J Stem Cell Res Ther 1:115. doi:10.4172/2157-7633.1000115  Proliferative capability Labile cells are continuously dividing and include surface epithelial cells of the skin and epithelial cells of the gastrointestinal tract. Stabile cells are nondividing under normal circumstances but can be induced to reenter the cell cycle by exposure to growth factors. Stabile cells include parenchymal cells of the liver, kidney, and pancreas and mesenchymal cells such as fibroblasts. Permanent nondividing cells have lost all capacity for proliferation and include nerve cells and cardiac muscle cells.  Key Points Different types of stem cells exhibit varying abilities to differentiate into specialized cells (from the most unlimited stem cell to the most restricted): totipotent, pluripotent, multipotent to oligopotent. Totipotent cells have the potential to differentiate into any of the cells needed to enable an organism to grow and develop; pluripotent cells have the potential to differentiate into any type of human tissue but cannot support the full development of an organism. A multipotent stem cell has the potential to differentiate into different types of cells within a given cell lineage or small number of lineages, while an oligopotent stem cell is limited to becoming one of a few different cell types. The process of cellular differentiation is under strict regulation by transcription factors which can either activate or repress expression of genes that will affect the proteome of the cell and thus, provide the necessary components it needs to become a specialized cell. All cells contain the same complement of DNA, or genome, but once differentiation occurs, it is the changes in the proteome that will distinguish one cell type from another. https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology  Cellular Aging Modern biological theories of aging in humans fall into two main categories: Programmed. Damage or error theories.  The programmed theories imply that aging follows a biological timetable, perhaps a continuation of the one that regulates childhood growth and development. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defense responses. The damage or error theories emphasize environmental assaults to living organisms that induce cumulative damage at various levels as the cause of aging. The programmed theory has three sub-categories: 1) Programmed Longevity. Aging is the result of a sequential switching on and off of certain genes, with senescence being defined as the time when age- associated deficits are manifested. 2) Endocrine Theory. Biological clocks act through hormones to control the pace of aging. 3) Immunological Theory. The immune system is programmed to decline over time, which leads to an increased vulnerability to infectious disease and thus aging and death. For example, as one grows older, antibodies lose their effectiveness, and fewer new diseases can be combated effectively by the body, which causes cellular stress and eventual death. Dysregulated immune response has been linked to cardiovascular disease, inflammation, Alzheimer’s disease (AD), and cancer. Jin K. Modern Biological Theories of Aging. Aging Dis. 2010;1(2):72-74. The damage or error theory include: 1) Wear and tear theory. Cells and tissues have vital parts that wear out resulting in aging. Like components of an aging car, parts of the body eventually wear out from repeated use, killing them and then the body. 2) Rate of living theory. The greater an organism’s rate of oxygen basal metabolism, the shorter its life span. The rate-of-living theory of aging while helpful is not completely adequate in explaining the maximum life span. 3) Cross-linking theory. According to this theory, an accumulation of cross-linked proteins damages cells and tissues, slowing down bodily processes resulting in aging. Jin K. Modern Biological Theories of Aging. Aging Dis. 2010;1(2):72-74. The damage or error theory include: 4) Free radicals theory. This theory proposes that superoxide and other free radicals cause damage to the macromolecular components of the cell, giving rise to accumulated damage causing cells, and eventually organs, to stop functioning. The macromolecules such as nucleic acids, lipids, sugars, and proteins are susceptible to free radical attack. 5) Somatic DNA damage theory. DNA damages occur continuously in cells of living organisms. While most of these damages are repaired, some accumulate, as the DNA Polymerases and other repair mechanisms cannot correct defects as fast as they are apparently produced. Genetic mutations occur and accumulate with increasing age, causing cells to deteriorate and malfunction. In particular, damage to mitochondrial DNA might lead to mitochondrial dysfunction. Jin K. Modern Biological Theories of Aging. Aging Dis. 2010;1(2):72-74. Cell death Apoptosis (A) The paw in this mouse embryo has been stained with a dye that specifically labels cells that have undergone apoptosis. The apoptotic cells appear as bright green dots between the developing digits. (B) This interdigital cell death eliminates the tissue between the developing digits, as seen one day later, when few, if any, apoptotic cells can be seen. (From W. Wood et al., Development 127:5245–5252, 2000. © The Company of Biologists.)  Apoptosis during the metamorphosis of a tadpole into a frog As a tadpole changes into a frog, the cells in the tadpole tail are induced to undergo apoptosis; as a consequence, the tail is lost. All the changes that occur during metamorphosis, including the induction of apoptosis in the tail, are stimulated by an increase in thyroid hormone in the blood. Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002. In many other cases, cell death helps regulate cell numbers.  apoptosis pathways Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death. Two major pathways can elicit cell apoptosis: the intrinsic (or mitochondrial) pathway extrinsic (or death receptor) pathway  https://www.creative-biolabs.com/drug-discovery/therapeutics/apoptosis-and-programmed-cell-death-assessment.htm The extrinsic and intrinsic cell death pathways: 1.- The extrinsic and intrinsic cell death pathways. Signals from other cells are the triggers of extrinsic pathway. The intrinsic pathway is activated by internal surveillance mechanisms. 2.- Intrinsic pathway of cell death. Bax and Bak form a pore that releases cytocrhome c. Released cytochrome c induces the forma tion of apoptosome, which binds and activates procaspase 9. Activated caspase 9 activates downstream effectors caspases, leading to death of the cell. Caspases disassemble the cellular cortex (actin microfilaments) and the nucleus. Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death.  One common pathway bringing about apoptosis is activation of caspases, a group of cysteine proteases. Many of these have been characterized to date in mammals; 14 have been found in humans. They exist in cells as inactive proenzymes (procaspases) until activated by the cellular machinery. The net result is DNA fragmentation, cytoplasmic and chromatin condensation, and eventually membrane bleb formation, with cell breakup and removal of the debris by phagocytes Overview of cellular physiology. Barrett K.E., & Barman S.M., & Brooks H.L., & Yuan J.J.(Eds.), (2019). Ganong's Review of Medical Physiology, 26e. McGraw- Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2525&sectionid=204290456  four stages of the apoptotic process Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death.  four stages of the apoptotic process 1. Induction/signalling phase: - molecular systems are activated by: * Bcl-2 family proteins (Bax, Bad, Bak, Bid, Bcl-XS) * initiator caspases (2, 8, 9 and 10) - cellular survival mechanisms are activated * Bcl-2 family proteins (Bcl-2, Bcl-XL, Bcl-w). * p53 - absence of morphologic changes - reversible stage Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death.  four stages of the apoptotic process 2. Effector phase. - “no return” point. - determined by the loss of mitochondrial transmembrane potential, that causes the “opening” of a large ionic channel called “permeability transition pore complex” or “megachannel” which through mitochondrial substances are released into the cytosol: *cytochrome C, that bound to APAF-1 (Apoptosis Protease Activating Factor 1) and caspase 9 form the apoptosome. Aposptosome, subsequently activates the effector caspases: caspase-3 and -7. *endonuclease G causes DNA fragmentation. *AIF (Apoptosis Inducing Factor) controls the nucleus for the chromatin condensation and DNA fragmentation. - permeability transition pore complex in the mitochondrial membranes leads to depolarization, uncoupling of oxidative phosphorylation, mitochondrial swelling, ATP depletion and cell death. Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death.  four stages of the apoptotic process 3. Degradation phase - several enzymatic mechanisms are activated (the main mechanisms are effectors caspases 3, 6 and 7). *cross links among proteins are broken or established *DNA degradation *phosphatidyl serine is exhibited in the outer cell membrane - morphological changes appear: *cell surface specializations and cell-cell junctions are broken *chromatin is condensed and the endonucleases fragment the chromatin into separated nucleosomes *subsequently the nucleus is fragmented and the cell breaks into several fragments (apoptotic bodies). This process lasts only a few minutes *organelles are undamaged Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death.  four stages of the apoptotic process 4. Phagocytic phase - the phosphatidyl serine position in the outer cell membrane and the thrombospondine-vitronectin junction over the cellular surface provide the recognition by macrophage phagocytosis - absence of inflammatory response Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death.  Sequential events observed in apoptosis. Usually apoptosis affects to single cells. Hilario, E & Cañavate, M & Lacalle, Jaione & Alonso-Alconada, D & Lara, Idoia & Alvarez-Granda, L & Alvarez, A. (2020). Cell death. A comprehensive approximation. Delayed cell death. Major steps of apoptosis: Cell shrinks Cell fragments Cytoskeleton collapses Nuclear envelope disassembles Cells release apoptotic bodies https://www.semanticscholar.org/paper/Histamine-Receptor-4-(H4R)-in-Pathogenesis-of-Stegajev/4a1b5aef9d9080471396d806ee94ffb7d54082cf/figure/10  Regulation of Apoptosis https://teachmephysiology.com/biochemistry/cell-growth-death/apoptosis/ Necrosis  inflammatory responses (necrosis) Wäster, Petra. (2007). UVA/B induced redox alterations and apoptosis in human melanocytes /. 14. https://www.cureffi.org/2013/04/28/cell-biology-11-apoptosis-necrosis/  Cellular Renewal / Regeneration Regeneration is a process by which the remaining cells of an injured organ regrow to offset the missed cells. https://biomedres.us/pdfs/BJSTR.MS.ID.002663.pdf AČIŪ UŽ DĖMESĮ www.lsmu.lt