Stem Cells and Biomolecules of Life Notes

CORE IDEA 1: THE CELL AND BIOMOLECULES OF LIFE

STEM CELLS

Stem Cell Characteristics

• Definition: Stem cells are unspecialized cells capable of self-renewal through mitosis and differentiation into various specialized cell types upon stimulation.
• Regulation: Stem cell behavior is regulated by the immediate environment (stem cell niche).
• Unique Features:
  • Unspecialized:
    • Stem cells are not terminally differentiated, meaning they aren't at the end of a differentiation pathway.
    • They lack tissue-specific structures for performing tissue-specific functions.
  • Self-Renewing:
    • Stem cells maintain their population through self-renewal.
    • Types of Cell Division:
      • Asymmetric Division: Produces one daughter stem cell (self-renewal) and a committed cell that differentiates into a specialized cell.
      • Symmetric Division:
        • Gives rise to two identical daughter cells.
        • Can be symmetric self-renewal (two identical stem cells) or symmetric differentiation (two cells committed for differentiation).
  • Differentiation:
    • Signals from the stem cell's environment trigger differentiation. These signals can include:
      • Chemicals secreted by other cells.
      • Physical contact with neighboring cells.
      • Molecules in the microenvironment.
    • Stem cells replace worn-out or damaged cells in multicellular organisms.
  • Regulation by Stem Cell Niche:
    • Stem cells reside in a specific microenvironment (niche) that controls their division and differentiation.
    • Extracellular signals from surrounding cells and the extracellular matrix lead to intracellular changes that regulate stem cell behavior.

Levels of Potency

• Potency Definition: The differentiation potential of a stem cell. Higher potency means the cell can differentiate into more cell types.
• Types of Potency:
  • Totipotency:
    • Definition: Capacity to differentiate into all cell types, including extra-embryonic tissues (e.g., placenta), and develop into an entire organism.
    • Examples: Fertilized egg (zygote) and the first 4 to 8 cells in mammals.
  • Pluripotency:
    • Definition: Potential to differentiate into almost any cell type of an organism (except extra-embryonic tissues); lacks self-organizing ability to form an entire organism.
    • Examples: Embryonic stem cells (ESCs) derived from the inner cell mass (ICM) of a blastocyst.
  • Multipotency:
    • Definition: Capable of differentiating into several related cell types for the tissue in which they reside.
    • Examples: Lymphoid and myeloid stem cells that differentiate into different types of blood cells.
  • Unipotency:
    • Definition: Generates only one cell type.
    • Examples: Spermatogonia, which only generates sperm cells.

Normal Functions of Stem Cells

• General Functions:
  • Self-renewal to maintain a constant pool of stem cells.
  • Support growth and development through division and differentiation.
  • Repair by replenishing cells lost from tissue injury or cell death due to normal wear-and-tear or disease.

Embryonic Stem Cells (ESCs)

• Derivation: Derived from the inner cell mass (ICM) of a blastocyst.
• Blastocyst Structure:
  • Inner cell mass (ICM): A cluster of cells.
  • Blastocoel: A fluid-filled cavity.
  • Trophoblast: An outer layer of cells.
• Differentiation: Can differentiate into different types of cells that develop from the three germ layers:
  • Ectoderm:
    • Generates the outer layer of the embryo.
    • Produces the epidermis of the skin.
    • Forms the brain and nervous system.
  • Endoderm:
    • Becomes the innermost layer of the embryo.
    • Produces the epithelium of the digestive tube and associated organs (including the lungs).
  • Mesoderm:
    • Located between the ectoderm and endoderm.
    • Generates blood, heart, kidney, gonads, bones, muscles, and connective tissues.

Blood Stem Cells (Lymphoid and Myeloid)

• Definition: Adult stem cells or somatic stem cells found in different tissues of a developed organism (including infants and children).
• Function: Critical roles in organogenesis in the embryo and regeneration in adult tissues lost through disease, tissue injury, or normal wear-and-tear.
• Example: Lymphoid and myeloid stem cells differentiate into different types of blood cells.

Application of Stem Cells – Hope or Hype?

• Vision: Regenerative medicine, where diseased organs can be regrown and replaced using a patient's own stem cells.

Introduction to Bioethics

• Ethics Definition: Determining the best course of action and provides reasons why.
• Bioethics Definition: A subfield of ethics that explores ethical questions related to the life sciences. It helps people make decisions about behavior and policy questions related to biomedical knowledge and innovations.
• Key Principles of Bioethics:
  • Respect for Autonomy:
    • Involves the capacity to make informed and voluntary decisions without external interference.
    • Informed consent is a key way to respect autonomy.
  • Nonmaleficence:
    • The duty to avoid causing harm intentionally and to minimize harm, including through negligence or unreasonable risk.
    • Foreseeable unintended harm necessary to bring about a good effect is acceptable.
  • Beneficence:
    • Working to the best interests of individuals, promoting positive outcomes.
  • Justice (or Fairness):
    • Treating others equitably and distributing benefits/burdens fairly.
    • Distributive justice ensures each individual receives their fair share of scarce resources (e.g., organ donation).

Application of Stem Cells

• Research Applications:
  • Studying developmental biology
  • Modeling diseases
  • Screening drugs
  • Advancing understanding of genetic and epigenetic factors
• Medical Applications:
  • Regenerative purposes
  • Treating blood disorders through hematopoietic stem cell transplants
  • Addressing neurological conditions
  • Repairing cardiac tissue
  • Exploring therapies for diabetes
  • Orthopaedics, ophthalmology, autoimmune disease treatment, cancer therapy, dental medicine, liver regeneration, wound healing, and vascular diseases

Controversies in the Use of Stem Cells

• Source of Embryos: Human ESCs are derived from the inner cell mass (ICM) of blastocysts (formed 4 to 5 days after fertilization), commonly obtained from spare embryos from in vitro fertilization (IVF).
• Ethical Concerns (using bioethics):
  • Informed Consent
  • Equitable Access
  • Commercialization and Exploitation
  • Regulatory Oversight

Induced Pluripotent Stem Cells (iPSCs)

• Definition: Normal adult cells that are ‘reprogrammed’ to an embryonic stem cell-like state.
• Reprogramming: Involves erasing and remodeling epigenetic marks, such as DNA methylation or histone modification, to reverse the potency level of adult somatic cells.
• Advantages:
  • Can be made from a patient's own cells, eliminating the risk of immune rejection.
  • Can be produced from any type of specialized somatic cell (e.g., skin cell) without invasive procedures.
  • Avoids controversies related to the use of embryonic stem cells as it does not destroy embryos.
  • Allows for research using pluripotent cells generated from patients to better understand the development of diseases.
• Disadvantages:
  • Low efficiency of reprogramming.
  • The reprogramming process can involve genetic modifications and introduce the risk of tumor development.
  • Somatic cells might have accumulated mutations through the years.
  • Other ethical concerns relating to the creation of embryos from iPSC-derived sex cells.

Nobel Prize in Physiology or Medicine 2012

• Awarded to Sir John B. Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent.
• John B. Gurdon's Discovery (1962): Demonstrated that cell specialization is reversible by replacing the immature cell nucleus in a frog egg cell with the nucleus from a mature intestinal cell, which then developed into a normal tadpole.
• Shinya Yamanaka's Discovery (2006): Showed how intact mature cells in mice could be reprogrammed to become immature stem cells by introducing only a few genes (Oct4, Sox2, Klf4, and cMyc).
• Oct4 and Sox2 are part of the core pluripotency network of transcription factors in ES cells.
• Klf4 is an ancillary transcription factor also associated with pluripotency.
• cMyc is a transcription factor that increases cell division rate, assisting the reprogramming process.

Overcoming Ethical Concerns

• Human iPSCs overcome ethical concerns related to the application of ESCs because they do not require the destruction of embryos.
• New ethical concerns can arise due to the creation of iPSCs, such as those related to genetic modifications and potential tumor development, and the creation of embryos from iPSC-derived sex cells.

Producing iPSCs Without Genetic Modification

• Methods have been developed to produce induced pluripotent cells from adult cells without genetic modification, addressing the concern of uncontrolled integration of viral DNA into the host cell's genome when using retroviruses as delivery vectors.

Glossary