3.6 Cellular Differentiation

Cellular differentiation is the process that transforms unspecialized cells into specialized ones with specific functions. It's crucial for embryonic development and maintaining homeostasis in adult tissues. Stem cells, capable of self-renewal and differentiation, play a key role in this process.

Changes in gene expression drive differentiation, turning specific genes on or off. This leads to the production of cell-type-specific proteins that determine cellular structure and function. Extracellular signals, like growth factors and hormones, influence this process by activating or inhibiting transcription factors.

Cellular Differentiation

Cell specialization during development

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• Cellular differentiation transforms unspecialized cells into specialized cells with specific functions (neurons, muscle cells, blood cells)
• Occurs throughout embryonic development and continues in adult tissues to maintain homeostasis
• Stem cells, unspecialized cells capable of self-renewal and differentiation, give rise to specialized cells
  • Stem cells undergo asymmetric division, producing one daughter cell that remains a stem cell and another that differentiates
• Changes in gene expression drive differentiation by turning specific genes on or off
  • Differential gene expression leads to the production of cell-type-specific proteins that determine cellular structure and function
• Extracellular signals, including growth factors (FGF) and hormones (testosterone), influence differentiation by activating or inhibiting transcription factors
• Differentiating cells undergo morphological and functional changes to suit their specialized roles
  • Cytoskeleton and organelles adapt to support the cell's specific function (extensive endoplasmic reticulum in secretory cells)
  • Cell surface receptors and adhesion molecules change to reflect the cell's role in the tissue (integrins in epithelial cells)

Potency levels of stem cells

• Stem cell potency refers to the ability to differentiate into various cell types
• Totipotent stem cells can give rise to all cell types, including embryonic and extraembryonic tissues (zygote, early blastomeres up to the 8-cell stage)
• Pluripotent stem cells differentiate into all cell types of the three germ layers (endoderm, mesoderm, ectoderm) but not extraembryonic tissues
  • Examples include embryonic stem cells and induced pluripotent stem cells (iPSCs)
• Multipotent stem cells differentiate into multiple cell types within a specific lineage or germ layer
  • Hematopoietic stem cells give rise to blood cells
  • Neural stem cells produce neurons and glial cells
  • Mesenchymal stem cells differentiate into bone, cartilage, and fat cells
• Oligopotent stem cells differentiate into a few closely related cell types (lymphoid progenitor cells produce B and T lymphocytes)
• Unipotent stem cells differentiate into only one specific cell type (spermatogonial stem cells give rise to sperm cells)

Transcription factors in differentiation

• Transcription factors are proteins that bind to specific DNA sequences and regulate gene expression by activating or repressing target gene transcription
• Specific sets of transcription factors are expressed in a coordinated manner during differentiation, determining the cell's identity and function
• Master regulatory transcription factors initiate and maintain cell-type-specific gene expression programs
  • MyoD directs muscle cell differentiation
  • Oct4 maintains pluripotency in embryonic stem cells
• Transcription factors form regulatory networks that control the expression of downstream genes involved in differentiation
  • Cross-regulation and feedback loops within these networks stabilize cell fate decisions
• Epigenetic modifications (DNA methylation, histone modifications) affect transcription factor binding by changing chromatin accessibility and influencing gene expression during differentiation
• External signals modulate transcription factor activity through signal transduction pathways
  • Post-translational modifications (phosphorylation, acetylation) affect transcription factor stability, localization, or DNA-binding ability, regulating differentiation

Molecular mechanisms of cellular differentiation

• Epigenetics plays a crucial role in cellular differentiation by modifying gene expression without changing the DNA sequence
  • DNA methylation and histone modifications regulate gene accessibility and expression patterns
• Cell fate determination involves the integration of multiple signals and factors that guide a cell towards a specific lineage
  • Intrinsic factors (transcription factors) and extrinsic factors (growth factors, cell-cell interactions) influence cell fate decisions
• Morphogens are signaling molecules that form concentration gradients and provide positional information to cells during development
  • Different concentrations of morphogens can induce distinct cell fates in responding cells
• Cell signaling pathways, such as Wnt, Notch, and BMP, play essential roles in coordinating cellular differentiation
  • These pathways transmit external signals to the nucleus, affecting gene expression and cell fate
• Chromatin remodeling complexes alter the structure of chromatin, making specific genes more or less accessible to transcription factors
  • This process is crucial for establishing and maintaining cell-type-specific gene expression patterns during differentiation