Cell Death and Homeostasis

Homeostasis of Cell Populations

  • Determining Factors of Cell Population Size:

    • The size of a cell population is influenced by three main rates:

    • Cell Differentiation: The process whereby a less specialized cell becomes a more specialized cell type.

    • Cell Proliferation: The process through which cells divide and reproduce.

    • Cell Death: The process of cell losing life, which can be through various mechanisms like apoptosis or necrosis.

  • Different Tissues and Their Cell Population Rates:

    • Continuously Dividing Tissues:

    • Examples include gut, skin, and haemopoietic cells of the bone marrow.

    • Stable (Quiescent) Tissues:

    • Cell proliferation is normally low, e.g., pancreas, liver, and kidney.

    • Proliferation can be increased in response to certain stimuli, e.g. liver regeneration after partial hepatectomy.

    • Non-Dividing Tissues:

    • Examples include brain and cardiac muscle.

Definition of Homeostasis

  • Homeostasis:

    • The ability of an organism or a cell to maintain a constant internal state despite external changes.

    • Cells adapt to various stimuli to preserve homeostasis.

    • Examples of Homeostatic Changes in Cells:

    • Hypertrophy: Increase in cell size.

    • Hyperplasia: Increase in cell number.

    • Atrophy: Decrease in cell size.

    • Metaplasia: Change of one cell type to another.

Programmed Cell Death (PCD)

  • Importance of PCD:

    • PCD is crucial during both development and adulthood.

    • Billions of cells die in tissues like bone marrow and intestine every hour, but cell division balances cell death maintaining tissue size.

    • This cell death is controlled and primarily occurs through apoptosis.

Apoptosis

  • Morphological Changes in Apoptotic Cells:

    • Cells undergoing apoptosis exhibit the following changes:

    • Cell Shrinkage and Condensation

    • Collapse of Cytoskeleton

    • Disassembly of Nuclear Envelope

    • Condensation and Fragmentation of Nuclear Chromatin

    • Bleb Formation on Cell Surface:

      • If blebs are large, they break off into membrane-enclosed fragments known as apoptotic bodies.

    • Chemical Alteration of Cell Surface: Ensures a neighboring cell or a macrophage can engulf the apoptotic cell before it spills its contents.

  • Importance of Engulfment:

    • It is critical for apoptotic cells to be engulfed before spilling their contents to prevent triggering an unwanted inflammatory response.

Necrosis

  • Characteristics of Necrosis:

    • Cells typically die by necrosis in response to sudden insults such as trauma or lack of blood.

    • Process involves necrotic cells swelling and bursting, releasing their contents which leads to an inflammatory response.

Injury and Necrosis

  • Causes of Necrosis:

    • Death due to unexpected and accidental cell damage. Examples include:

    • Chemical toxins

    • Radiation

    • Heat

    • Trauma

    • Hypoxia due to blood flow blockage

    • These insults disrupt cellular structure and activity, leading to necrosis.

Loss of Homeostasis During Necrosis

  • As necrotic cells begin to die, they swell and exhibit membrane holes causing intracellular materials to spill out.

  • Intracellular Environment Regulation Loss:

    • The normal cytosolic concentration of calcium ions ([Ca^{2+}]_{cytosolic} < 10^{-7} M).

    • The typical extracellular concentration of calcium ions ([Ca^{2+}]_{extracellular} ext{ is } 10^{-3} M).

    • Intracellular calcium homeostasis requires energy to maintain as calcium needs to be pumped out from the cytoplasm.

Breakdown During Necrosis

  • As cells disassemble, various breakdown products are released, including:

    • Membrane Phospholipid Derivatives: Such as arachidonic acid (a free fatty acid).

    • These breakdown products signal to neighboring cells that damage has occurred, prompting a defensive response.

Eicosanoids and Inflammatory Responses

  • FFAs as Substrates:

    • Free fatty acids generated by damaged cells are substrates for cyclooxygenases, enzymes that convert them into prostaglandins and other molecules collectively termed eicosanoids, mediators of inflammation.

    • Chronic inflammation may lead to conditions such as rheumatoid arthritis.

Inflammatory Response to Injury

  • Necrosis results in the release of cellular breakdown products that act as inflammatory signals:

    • These signals cause capillary dilation and increased local blood flow.

    • Symptoms include:

      • Increased tissue temperature

      • Tissue reddening

    • Release of histamines leads to pain by stimulating pain-sensing neurons.

    • Increased capillary permeability allows white blood cells (leukocytes and macrophages) to infiltrate the damaged area.

    • Fluid shifts from blood into tissue (edema) leading to swelling.

  • White Blood Cell Action:

    • Engulf and digest debris, bacteria, and foreign materials. Dying white blood cells may form pus.

  • Healing Process:

    • Tissues regenerate and wounds heal.

Comparative Overview of Apoptosis and Necrosis

  • Histological Differences:

    • Apoptosis:

    • Involves single cells, no tissue structure disruption.

    • Cytological features include shrunken cells, fragmentation, condensed chromatin, and intact mitochondria.

    • Necrosis:

    • Involves groups of cells, disrupts tissue structure.

    • Cytological features include swollen cells, pyknotic or fragmented nuclei, dilated endoplasmic reticulum, and swollen mitochondria.

Physiological Effects on Tissue

  • Apoptosis:

    • No inflammation occurs; neighboring cells perform phagocytosis.

  • Necrosis:

    • Causes disruption of membrane permeability and leakage of cellular products into blood.

    • Triggers acute inflammation and potential scar formation.

Purpose of Programmed Cell Death (PCD)

  • PCD occurs via apoptosis.

  • Magnitude of PCD:

    • A significant amount of cell death occurs, especially in the developing nervous system, where over half of nerve cells may die shortly after formation.

Induction of Apoptosis

  • Various signals can initiate apoptosis:

    • UV or gamma radiation

    • Chemotherapeutic agents

    • Withdrawal of growth factors

    • Cytokines

  • Selective Process:

    • Apoptosis serves to selectively remove unnecessary, infected, or genetically malfunctioning cells.

Role of PCD in Homeostasis

  • Role of Apoptosis in Bone Marrow:

    • PCD occurs at a high rate, especially in human bone marrow where neutrophils are produced in large numbers but most die through apoptosis within days.

    • Purpose of maintaining a pool of ready neutrophils for rapid infection response.

Quality Control in Development through PCD

  • In development, apoptosis eliminates:

    • Abnormal, misplaced, non-functional, or potentially harmful cells (e.g., self-reactive lymphocytes).

  • Post-Infection Response:

    • After infection, most activated lymphocytes are eliminated via apoptosis.

  • Cell Damage Recognition:

    • Damaged cells can recognize their condition and undergo apoptosis if repair is impossible (e.g., due to damaged DNA that could lead to cancer).