Cell Differentiation Lecture Review

Cell Differentiation

Introduction

• Cell differentiation is the process by which different types of cells arise during development.
• It is the acquisition during development of the properties of mature functional cells.
• Cell differentiation is essential for development, allowing a single fertilized egg to generate all the diverse cell types in the body.
• Cell differentiation isn't only important during embryogenesis; it continues throughout life for tissue maintenance and repair.

Symmetrical vs. Asymmetrical Cell Division

• During cytokinesis, cells can divide symmetrically or asymmetrically.
• Symmetrical division produces two identical daughter cells with the same fate.
  • Can result in two proliferative cells or two differentiated cells.
• Asymmetrical division produces two daughter cells with different fates.
  • One cell re-enters the cell cycle (proliferative), and the other differentiates.
• The type of division predominates at different times during development.
  • Early development: Symmetric proliferative divisions expand the progenitor pool.
  • Later development: Asymmetric divisions maintain the progenitor pool while generating differentiated cells.
  • Late/end development: Symmetric generative divisions deplete progenitors.
• Plane of division:
  • The plane of division, relative to the apical-basal polarity, determines cell fate.
  • Apical complex proteins accumulate apically.
  • Perpendicular division: Splits the apical complex, resulting in two proliferative cells.
  • Division not splitting the complex: One cell inherits the apical complex (proliferative), and the other differentiates.

Stem Cells

• Stem cells are a special type of proliferative cell.
• A stem cell is:
  • Undifferentiated.
  • Long-lived.
  • Capable of self-renewal (produces more copies of itself).
  • Able to divide to produce differentiated cell types.
• Symmetric division produces two new stem cells.
• Asymmetric division produces one stem cell and a progenitor cell.
• Progenitor cells:
  • Proliferative but may not self-renew.
  • Limited capacity for division before differentiating.
  • Transient amplifying cells are progenitor cells that divide to produce more proliferative cells before differentiation.
• Potency of stem cells:
  • Refers to the number of different cell types a stem cell can differentiate into.
  • Potency becomes restricted over time during development.
• Examples of stem cell potency:
  • Totipotent: Can generate all cells of the embryo and extraembryonic lineages (e.g., zygote).
  • Pluripotent: Can generate all cells of the embryo but not extraembryonic lineages (e.g., embryonic stem cells).
  • Multipotent: Can generate a range of cells within a particular tissue (e.g., ectoderm, mesoderm, endoderm).
  • Unipotent: Can generate only a specific cell type.
• Adult stem cells:
  • Found in adult tissues for cell replacement.
  • Generally multipotent or unipotent.
  • Important for tissue maintenance and repair.
  • May have a limited capacity for self-renewal, contributing to aging.
• Clonal analysis:
  • Labels a single cell with a dye and tracks its progeny to determine cell fate.
  • Early labeling shows many labeled cells; later labeling shows fewer, indicating restriction of developmental potential.

Specification, Determination, and Regulation

• Cell fate is acquired gradually over time.
• Specification:
  • Cells can develop autonomously in a neutral environment.
  • Reversible; can change fate if transplanted to a different environment.
• Determination:
  • Cells develop autonomously and maintain their fate even when transplanted.
  • Irreversible; committed to a specific cell fate.
  • Determined cells may not yet be differentiated.
• Regulation:
  • Refers to the ability of early embryos to compensate for removed or rearranged parts.
  • Demonstrated in sea urchins where removing one cell at the two-cell stage still results in a fully patterned, albeit smaller, sea urchin.
  • Basis of twinning in mammals where separation of cells at early stages, each group of cells continue development to fully formed humans.
  • Used in pre-implantation genetic diagnosis where a cell is removed from the morula for genetic testing without compromising development.

Forming Different Cell Types

• Different cell types arise from different patterns of gene expression, not changes in DNA.
• Genomic equivalence: All cells in the body contain the same DNA.
• Evidence for genomic equivalence:
  • Cloning experiments, such as Dolly the sheep, demonstrate that the nucleus of a differentiated cell contains all the DNA necessary for development.
  • Dolly was created by taking the nucleus from an adult mammary gland cell and transplanting it into a nucleus-free oocyte.
  • The resulting cell was activated, implanted into a surrogate mother, and developed into Dolly, whose genome was identical to the nuclear donor.

Gene Expression Changes

• Cell differentiation involves turning on and off different genes in different cells.
• Transcription, the process of making mRNA from DNA, is a critical control point.
• Different cell types express specific combinations of genes.
• Master regulators:
  • Some genes, like PAX6 (master regulator of eye development), can drive the development of a specific lineage.

Transcription Factors

• Bind to DNA to regulate gene transcription.
• Bind to regulatory regions of DNA, such as promoters and enhancers.
• Control whether genes are turned on or off in a particular tissue.
• A single transcription factor can activate or repress different genes.
• Transcription factors can regulate other transcription factors, creating a cascade of changes.
• Difference between transcription factors and signaling molecules
  • Transcription factors bind to DNA to directly control gene transcription.
  • Signaling molecules bind to receptors and initiate intracellular signaling cascades, indirectly affecting gene expression by influencing transcription factor function.

Muscle Differentiation

• Involves a cascade of transcription factor activation.
• MRF4: Determines mesodermal progenitors to a muscle fate.
• MyoD: Influenced by MRF4.
  • Sets up a positive feedback loop by binding to its own promoter, maintaining the muscle-determined state.
  • Binds to the promoter of p21, an inhibitor of the cell cycle, stopping proliferation.
• Myogenin: Alters expression of muscle-specific proteins, leading to differentiated muscle cells.
• Cell division and differentiation are generally mutually exclusive.

Cytoplasmic Determinants and Extracellular Signals

• Mechanisms that guide cells towards a particular fate:
  • Cytoplasmic determinants: Unequally distributed substances in the early embryo that influence cell fate.
  • Extracellular signals: Signals acting on receptors to induce a response in the cell.
• Cytoplasmic determinants:
  • Factors within early developing cells that are unequally distributed during cell division, leading to different developmental pathways.
• Extracellular signals signal effectors, the receptors and the intracellular signaling molecules:
  • Induction: Signals from one group of cells (inducing cells) influence the fate of another group of cells (responders).
  • Responders must be competent to receive the signals.
  • Inducing signals can act over long or short ranges.
  • Permissive induction: A signal allows a cell already specified to adopt its fate.
  • Instructive induction: A signal tells a cell what to become.

Morphogens

• Morphogens are molecules that induce different responses based on their concentration, forming a signaling gradient.
• Cells respond differently based on the concentration of the morphogen they receive.
• Also known as the gradient hypothesis or the French flag model.
• Example: Limb development, where a morphogen gradient patterns the digits.
  • Cells closest to the morphogen source form digit 4, those further away form digit 3, and the furthest form digit 2.

Lateral Inhibition

• Prevents cells from adopting the same fate through cell contact involving Notch signaling.
• Stochastic changes lead to one cell adopting a higher level of signaling.
• Feedback amplifies the difference, causing that cell to differentiate (e.g., into a neuron) while preventing its neighbors from doing the same (they become skin cells).
• Important for controlling the balance between proliferation and differentiation.

Reversibility of Differentiation

• Differentiation state is generally very stable.
• Differentiation can be reversed under certain conditions through:
  • Dedifferentiation: Loss of differentiation characteristics, associated with regeneration.
  • Transdifferentiation: Change of one differentiated cell into another, also associated with regeneration or pathological conditions like cancer.
• Induced Pluripotent Stem Cells (iPSCs):
  • Differentiated adult somatic cells can be reprogrammed back into a pluripotent state.
  • Expression of Yamanaka factors (four transcription factors) is sufficient to dedifferentiate cells into iPSCs.
  • Revolutionized tissue engineering and regenerative medicine.
  • Discovery led to the Nobel Prize in Medicine in 2012 to Boshino Yakimaka and Sir John Gordon.