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Cell division, death and specialisation Lecture 4, Apoptosis, cell…
Cell division, death and specialisation Lecture 4
Chromatin density and organisation. Euchromatin
- DNA is in active use
- Genes are being transcribed.
- Proteins need space to work.
Heterochromatin.
- DNA is not in active use.
- Genes are silenced.
- Condense DNA to protect it
Telomere.
- Ends of chromosomes.
- Protects from attaching to each other.
Cell Division. Mitosis.
- 2 identical daughter cells from 1 parent
cell.
- Diploid (2n, 2 sets of chromosomes)
stays diploid (2n).
- Human 2n: 46 chromosomes.
Meiosis.
- 4 genetically diverse cells from one
parent cell.
- Diploid (2n) turns into 4 x 1n haploid (1
set of chromosomes)
- Human 1n: 23 Chromosomes.
- Only happens in gametes (sperm and
egg cells)
Chromosome duplication and
distribution. Centromere:
- Region of repetitive DNA sequences.
- Each sister chromatid has its own,
- Place where sister chromatids
attached most closely.
- Kinetochore is a specialised structure on the centromere where spindle fibres attach during mitosis.
Mitosis
Interphase
- G2 of interphase:
- Nucleus membrane intact
- 2 centrosomes with centriole pairs
(microtubule organising centre)
- Chromatin duplicated
Prophase
Undefined transition between G2 and M.
- Chromosome condensation.
- Spindle begins to form.
- Centrosomes separate to poles of cell.
- Nucleus appears more granular
- Nuclear Envelope breaks down.
- 2 Sister chromatids held
together by centromer
Prometaphase
- Abrupt disruption of nuclear envelope (nucleus membrane
gone) and spindle moves into nuclear region.
- Kinetochores (specialised structure on centromers) mature
and attach to spindle fibres.
- Chromosomes move to metaphase plate.
- Each chromatid has its own kinetochore
Metaphase
- Kinetochores align chromosomes in one plane at equator
of cell.
- Chromosomes held in tension on spindle by paired
kinetochores.
- Each sister chromatid on 1 side
- Sudden separation of sister kinetochores begins anaphase
Anaphase
- Triggered by separation of sister kinetochores.
- Kinetochore microtubules shorten as chromosomes
separate and sister chromatids move towards the poles.
- All chromosomes move at same speed (approx’ 1 μm/min)
- Sister chromatids are now called daughter chromosomes.
- Polar microtubules elongate and the poles of the spindle
move further apart
Telophase
- Daughter chromosomes arrive at the poles.
- Kinetochore microtubules disappear.
- Polar microtubules continue to elongate.
- Nuclear envelope reforms around daughter chromosomes.
- Chromatin expands (chromosomes unwind) and nuclei reappear
Cytokinesis (cytoplasmic division)
- Cytoplasm divides by cleavage (begins in anaphase)
- Membrane drawn in by contractile ring to form
cleavage furrow.
- Furrow deepens until it encounters the remains of
the mitotic spindle (known as the “thin bridge” or “mid-body”) and finally breaks
Apoptosis
Programmed cell death.
- Essential in formation, maintenance and moulding of normal tissue with minimal disruption to surrounding tissues.
- Membrane integrity is usually retained.
- Normally involves single cells.
- cell engulfed by macrophages or adjacent cells.
- Not accompanied by inflammatory responses.
The process of apoptosis.
- Nucleus shrinks. - Chromatin condenses
- DNA fragments.
- Cells detaches from neighbouring cells.
- Cell " round up"
- cells shrinks.
cell fragments (apoptotic bodies containing intact
organelles and plasma membranes)
- Neighbouring cells and/or macrophages rapidly engulf and destroy apoptosis bodies.
Intrinsic pathways.
- In response to internal damage.
- Mitochondria release cytochrome c.
Cytochrome C activates caspase cascade for programmed cell death.
Extrinsic pathway - triggered by the immune system.
- Activates caspase cascade for programmed cell death.
Necrosis
Common theme of necrosis is disruption of membranes by:
- O2 Deprivation (ischaemia, COPD, altitude, heart attack, anaemia, etc)
- Infectious agents.
- Physical agents ( heat, trauma)
- chemical agents ( drugs, alcohol)
- Nutritional imbalance (lack of vitamins, protein deficiency)
- Immunological reactions (e.g. anaphylaxis, complement overreaction, etc)
- DNA disruption (genetic mutation.
Always a consequence of injury.
- Normally involves groups of cells.
-Involves enzymatic destruction of intracellular constituents,
- Usually accompanied by an inflammatory response.
Injury target and molecular processes.
Targets:
- Aerobic respiration in mitochondria
(specifically electron transport chain)
- cell membranes
- Organelle membrane.
- DNA
- protein synthesis pathways,
- cytoskeleton.
Example processes.
- Reactive oxygen species (ROS)
- Complement activation
- Drugs.
Reactive Oxygen Species (ROS)
- By- products of normal cellular respiration.
- Partially reduced oxygen molecules including:
- OH (hydroxide free radical, Oxygen radical, hydrogen peroxide H202)
- Are free radicals (contain a single, unpaired e-)
- Are highly reactive.
- Interact with nearby molecules release energy. potentially altering the molecule.
Normal defence mechanism to oxidative stress.
- Antioxidants ( vitamin E)
- Enzymes (glutathione peroxidase, superoxide dismutase)
Reperfusion injury during ischemia Ischemia:
- Lack of blood supply to a organ or part of the body, especially the heart.
Reperfusion injury;
- Tissue damage caused when blood supply returns to tissue after a period without oxygen.
Complement activation
Part of the immune system. - Lightning fast
- Activates other "slower" immune responses.
- must be activated first.
20 components in a cascade
three distinct pathways of complement activation
- classical pathway.
- Lectin pathway
- alternative pathway.
All converge on the complement component C3 that is cleaved to generate C3a and C3b
- C3b can act to opsonize material (increased susceptibility) for ingestion by phagocytic cells and to enhance clearance of immune complexes.
- C3b can also form part of C5 convertase, which cleaves C5 to generate the chemotactic fragment C5a.
- This cleavage results in assembly of the membrane attack complex (C5b-9), which can insert into cell
membranes and cause lysis of bacteria and damage to nucleated cells
Classical pathway. start with Antigen-antibody complex. Lectin pathway 1
- Start with mannose (carbohydrates) on bacteria surface.
Lectin pathway II
- Start with acetylglucosamine (monosaccharide) on bacteria surface .
- Lectin or ficolin in complex with MASP (Protein in blood)
Binds directly to surface molecules on bacteria.
- activation of complement.
cell differentiation
- Ectoderm (External layer) - Skins cells of epidermis.
- Neuron of brain
- pigment cell.
Mesoderm (middle layer)
- cardiac muscle.
- Skeletal muscle tissue
- tubule cells of the kidney.
- red blood cells
- Smooth muscle cells of the gut
Endoderm (internal layer)
- Pancreatic cells
- thyroid cells
- Lung cells
Gem cells
Human embryonic stem cells.
- Embryonic stem cells are derived from the inner cell mass of the blastocyst.
- The cells of the inner cell mass are pluripotent they can make
every cell type in the human body
- Capable of indefinite self-renewal and can undergo directed
differentiation to cell types from all 3 germ layers
Embryonic: derived from the inner cell mass of pre- implantation embryos (blastocyst), prior to formation of the 3 germ layers (ectoderm, mesoderm an endoderm.Somatic: undifferentiated cells located in "mature" tissues/ Organs (specific locations)Induced pluripotent stem cells (IPSC)
- IPSC generated by reprogramming differentiated cells back to stem cells.
tissues form: example Drosophila (Fruit flies) - Protein diffusion gradient
- certain genes switched on/off depending on the gradient concentration.
Chemotaxis
Tissues form through a concentration gradient.
- Similar concept applies to how cells move.
- Immune system, blood and lymph
- cancer spreading.
Directional cell movement along the concentration gradient.
- not random
- controlled by chemokines and chemokine receptors.
Chemokines and chemokine
receptors.
- Tumour cell express the chemokine receptor CXCR4 .
- Bone marrow is a site of naturally high expression of the chemokine CXCL12.
- Tumour cells naturally migrate towards a high concentration of CXCL12.
- Bone metastasis (bone marrow invasion)
Cell junctions
- Specialised regions of the plasma membrane- cellular junctions.
Three categories:
- Desmosomes- Holds cells together.
Anchoring junctions” - mechanically attach cells to their neighbours and the
extracellular matrix.
Tight Junctions - Hold cells together and seals the space.
- “Occluding junctions” – seal cells together so that even small molecules cannot
move through the group of cells
Gap Junctions- channels of communication allowing for the passage of small molecules or ions.
- Communicating Junctions” – mediate the passage of chemical or electrical signals
from one interacting cell to its partner
Desmosomes widely distributed in animals tissues.
- allows for groups of cells to function as a unit.
- connecting the cytoskeleton of one to another or to the extracellular matrix.
Three types
- **Adherens junctions
- Desmosomes
- Hemidesmosomes**
Adherens junctions:
- cell to cell junction occurs in many forms.
- can be small or form continuous Adherens belts.
composed of actin fibres.
cell- matrix junctions.
Actin filaments connect the cell to the matrix.
Desmosomes
three structural types.
- Spot Desmosomes
act like rivets.
- Hemidesmosomes
Anchor the cell to the surrounding matrix.
- Belt desmosomes.
continuous band between connecting cells.
-
Gap junctions
Spot desmosomes
- membrane contains dense plaques at spot where they occur.
- Plaques link cells together through interconnecting filaments.
- Plasma membrane of two cells held parallel to each other .
- fixed distance at 30nm.
- On the cytoplasmic side the plaques are
connected to tonofilaments – dissipate stress on the tissue stretching.
Hemidesmosomes
- connect the basal surface of epithelial cells to the underlining basal lamina.
Different proteins but attachments occur in a similar manner to desmosomes.
Occluding Junctions: seal cells together.
- seal is not absolute and can vary with different types of epithelia.
- Small molecules may move through.
- Some epithelia cells serve as semi-permeable barriers separating
fluids that have a different composition.
Example – epithelia cells in the intestine:
- Uptake of nutrients from the intestines into the blood occurs across these epithelia cells.
- Transport must not occur between cells as the transported material may diffuse back into the gut
- Tight junctions between epithelial cells are though to prevent this occurring (not even water can get through)
Communicating junctions:
- Mediate the passage of chemical or electrical signals from one interacting cell to its partner.
- Channels of communication allowing for passage of small molecules and ions. e.g. Gap junctions.
Gap Junctions Membranes of cells next to each other are
separated by a uniform narrow gap.
- Gap is spanned by channel proteins called
Connexons.
- Two connexons in line form a continuous
aqueous channel.
- Ions and other water soluble molecules can pass from cytoplasm of one cell to the next
- therefore cell are coupled both electrically and metabolically.
- Channels do not remain open, rapid change from open to close.
- closure allows for individual cells to be isolated if damaged.
Function of gap junctions.
- Can have different properties in different tissues.
- Permeability can vary.
- In tissues whose functions relies on an electrical current being transported, gap junctions are where the movement of ions occurs.
- spread of action potential in nerve cells.
- Contraction of hear muscle.
Meiosis
- Meiosis I results in formation of two cells, each has half the chromosome content of the parent cell.
- However, each still has double the DNA content in that each chromosome comprises two chromatids.
- After meiosis I a short interphase may follow but there is no replication of the DNA.
- Meiosis II (which is similar to mitosis)
halves the DNA content.
Drugs
Hepatic metabolism of paracetamol.
Therapeutic dose:
does not cause liver damage.
- small amounts of hepato-toxic metabolite are rapidly inactivated by conjugation with hepatic glutathione.
- excreted in urine.
Paracetamol overdose.
- conjugate enzymes becomes saturated, the drug is then directed to alternative metabolic pathways.
- the metabolite is detoxified by interaction with hepatic glutathione.
when these reserves are depleted the compound reacts with macromolecules disrupting their structure and function.