Apoptosis Mechanisms and Functions

Cell Function: Cell Death and Differentiation

• The course is Fundamentals of Human Biology (FUNBIO.15)
• The lecturer is Tom Hodgkinson
• The date is 29/10/24
• Learning Outcomes:
  • Describe the process of cell death or apoptosis.
  • Define the role of mitochondria in apoptosis.
  • Understand cell differentiation, and the concept of unipotent and pluripotent cells.
  • Describe the role of organelles in cell differentiation and tissue formation.
  • Explain cellular processes triggered in cancer cell formation.
  • Define mesenchymal cells and their differentiation into muscle and connective tissue.
  • Differentiate between adult and embryonic stem cells.
  • Discuss the ethical issues involved in stem cell research.

Circumstances for Cell Death (Apoptosis)

• Genetic mutation/damage
• Irreparable damage (radiation, chemical injury, pathogenic attack)
• Cell stress (e.g., heat, pH changes)
• Cell death induced by cytotoxic T cells or death receptors
• Mitochondrial stress/injury
• Injury to cell membrane
• Growth factor/hormone gradients (e.g., embryonic development)
• Cell cycle dysregulation (e.g., cancer)

Apoptosis- Programmed Cell Death

• Necrosis is traumatic cell death from acute cellular injury.
• Apoptosis is a highly regulated, controlled process of cell death.
• Nobel Prize (2002) awarded to Brenner, Horvitz, and Sulston for work identifying genes controlling apoptosis
• Occurs in multicellular and some single-celled eukaryotic organisms, like yeast.
• Biochemical events produce characteristic cell morphology changes leading to death.
• Involves cell shrinkage, chromatin condensation, blebbing, DNA condensation, mRNA decay, nuclear fragmentation, and organelle collapse.
• Results in apoptotic bodies that are engulfed by phagocytes preventing cell contents release and damage to surrounding cells.
• An average adult loses 50-70 billion cells daily due to apoptosis.
• Apoptosis is crucial during development (e.g., separation of fingers and toes).

Mechanisms of Apoptosis

• Apoptosis can occur via two pathways:
  • Intrinsic pathway: the cell senses internal stress and kills itself.
  • Extrinsic pathway: the cell kills itself due to signals from other cells.
• Both pathways activate proteases called caspases.
• Caspases lead to indiscriminate protein degradation.

Intrinsic Pathway (Mitochondrial Pathway)

• Mitochondria are vital for multicellular life, especially aerobic respiration.
• Some apoptotic pathways centre on mitochondria.
• Mitochondrial changes include increased membrane pores, pore formation, and dissipation of mitochondrial membrane potential.
• Important proteins in this pathway include Bax, Bak, cytochrome C. Also involved are Apaf-1/apoptosome procaspase 9, and caspase 3.

Extrinsic Pathway

• An external signal (typically from immune cells) triggers this pathway.
• Two main models are present: TNFP-induced and Fas-FasL-mediated.
• FAS receptor binds to the Fas ligand (FasL), forming a death-inducing signaling complex (DISC). This activates caspase 8.
• Caspase-8 can then truncate Bid, leading to apoptosis.
• There's a connection between TNF-α and apoptosis, significant in autoimmune diseases.

Cancer Cell Formation

• Normal cells have tightly regulated mechanisms preventing uncontrolled growth and division.
• Disruption of these mechanisms are factors in cancer formation.
• Cancer cells divide and grow unchecked, forming tumors or neoplasms.
• Metastasis is the spread of cancer cells to different parts of the body.
• Gene mutations can occur in proto-oncogenes (activating genes) and tumor suppressor genes.

Same Genome - Diverse Function

• Cells with the same genome can have very different structures and functions depending on gene expression.
• Gene expression differs based on the proteins produced by specific genes.

Differential Gene Expression

• Gene expression means genes code for a protein.
• Differential expression means different proteins are made in different cells, even from the identical DNA structure.
• "Housekeeping genes" are essential for basic cellular functions.

How Does a Cell Decide?

• Micro-environment (cell-cell/cell-extracellular matrix interactions, soluble factors, mechanical factors) plays a role.
• Lineage commitment of parent cells, and DNA packaging/epigenetics, are key processes in controlling gene expression.

Stem Cell Determination & Differentiation

• Stem cells are undifferentiated: they can self-renew and differentiate into other cells.
• Potency describes the stem cell's differentiation potential.
• Totipotent stem cells can form any cell type; Pluripotent cells potentially any body cell type and Embryonic stem cells are an example.
• Multipotent cells can form specialized cell types within a specific lineage.
• Unipotent cells differentiate into a single, specified cell type.
• Differentiation is a genetic commitment to a specific cell type progression.

Different Types of Stem Cells

• Adult stem cells in various tissues (bone marrow, adipose, etc.) are used clinically.
• They can replace damaged cells and maintain tissue, however have limited differentiation potential.
• Induced pluripotent stem cells (iPSCs): researchers can reprogram mature cells into a pluripotent state using transcription factors.
• iPSCs share many properties with embryonic stem cells but with potential differences.

Stem Cells in the Clinical Scenario

• Stem cells are used in autologous/allogeneic transplantations.
• Autologous (most common) is using your own stem cells; allogeneic is using someone else's.
• Treatments like chemotherapy use stem cells to replace destroyed blood cells.

Human Embryonic Stem Cells

• ES cells are pluripotent and can differentiate into many cell types potentially.
• Potential applications include regenerative medicine, disease modeling (for drug testing and development), and drug discovery.
• However, ethical concerns (embryo destruction), and immune rejection are present.

Unregulated ES Application and Teratoma Formation

• Teratomas are tumors consisting of cells from multiple germ layers.
• Uncontrolled growth in pluripotent cells (e.g., ES cells) can result in teratoma formation.

Ethical Questions in Human Cloning

• Human reproductive cloning attempts to create a genetically identical person.
• Human therapeutic cloning aims to make ES cells or iPSCs for medical purposes.
• Ethical issues include human dignity violations, unpredictable outcomes, and embryo destruction.

Induced Pluripotent Stem Cells (iPSCs)

• iPSCs can be generated from adult cells like skin cells, urine cells, or blood cells, not from an embryo directly.
• Re-programming them back to earlier states allows for creation of potentially valuable tools, therapies, and resources for research.
• iPSCs face some limitations: factors such as genomic instability and tumorigenic potential exist and are a concern.

Learning Resources

• Solomon Chapter 17, p362 (Developmental Genetics)
• Science Articles (cited below)
• Other online resources (cited below)