Differentiation Chapter 17

Differentiation Differentiation is the process leading to the expression of phenotypic properties characteristic of functionally mature cell in vivo Can be irreversible and reversible

Differentiation Combination of constitutive (stably expressed without induction) and adaptive (subject to positive and negative regulation of expression) properties Commitment is an irreversible transition from stem cell to a particular defined lineage endowing the cell potential to express a limited repertoire of properties, either constitutively or when induced to do so

Terminal differentiation Cell has progressed down a particular lineage -Phenotype is fully expressed and beyond which cell cannot progress -Neurons, skeletal muscle, or keratinized squames - irreversible

Dedifferentiation Describes loss of differentiated properties of a tissue when it becomes malignant or when it is grown in culture Contributing factors – cell death, selective outgrowth and adaptive responses Differentiated phenotype may be regained – right inducers (adaptive process)

Lineage selection Wrong lineage selection – no amount of induction can bring back required phenotype

Two pathways of differentiation Undifferentiated stem cells – progenitor cells that will proliferate and progress towards terminal differentiation -Reach terminal stages - gives rise to mature differentiated cells that will not further divide

Two pathways of differentiation In trauma – cells show less proliferation – lose differentiation property - undergo cell division - Tissue is regained -Differentiation is reinduced -Renewal is rapid Problem – cells reentering cell cycle may/not give phenotypically identical cells as differentiated cells - can give rise to subset of reversibly differentiated cells

Proliferation and Differentiation Differentiation progresses – cell division reduces and ceases Cell proliferation – incompatible – with expression of differentiated properties Tumor cells break this restriction – continuously synthesizes – while cells are proliferating

Commitment and Lineage Progression from stem cell to particular differentiation – commitment A hematopoietic stem cell – commits to form lymphocytes -Will not change later stage and adopt myeloid or erythrocytic form -Point between stem cell and particular progenitor stage where a cell or its progeny can no longer transfer to a separate lineage

Home work Explain the proliferation and differentiation conditions of an organ culture. Explain how tumor cells will behave in their commitment and lineage activities

Status of a cell in making a commitment to a lineage Stem cells or early progenitor cells may differentiate in one or more directions Late progenitor cells may stay true to lineage Differentiated cells – fibrocytes may dedifferentiate and proliferate but retain lineage fidelity

Stem cell plasticity Stem cell theory: More primitive a stem cell – the greater its potency Unipotent stem cell gives rise to only one lineage Bipotent – gives rise to only two lineages – a lymphoid stem cell gives rise to T- or B- lymphocytes Multipotent- gives rise to more than two lineages

Stem cell plasticity Totipotency: stem cell gives rise to all known cell types – embryonal stem cell

Stem cell plasticity Greater the degree of commitment, the greater the likelihood of stem cell being located in a specific tissue -Ex: Hematopoietic stem cells are located in bone marrow -With commitment and histological localization comes a reduction in potency – questioned?

Stem cell plasticity Tissues that are non-regenerative such as neurons in brain have stem cells Tissue localization – does not mean lineage commitment and reduced potency -Liver cells can generate neurons -Bone marrow stem cells can generate cardiac cells

Markers of Differentiation Lineage markers – expressed early and retained throughout subsequent maturation stages Are specific cell products or enzymes involved in synthesis of those products -Hemoglobin in an erythrocyte -Serum albumin in a hepatocyte Measured by RT-PCR and Microarray analysis

Induction of differentiation Five parameters that control differentiation Cell-cell interaction Cell-matrix interaction Cell shape and polarity Oxygen tension Soluble systemic factors

Cell-cell interaction Homotypic: Homologous cell interaction Involves metabolites, second messengers such as AMP, diacylglcerol (DAG), Ca or electrical charge communicated between cells Harmonizes expression of differentiation within a population of similar cells

Cell-cell interaction Heterotypic: Heterologous cell interaction Between mesodermally and endodermally or ectodermally derived cells Initiating and promoting differentiation Positively and negatively acting growth factors

Cell-Matrix Interactions Mixture of glycoproteins and proteoglycans is highly specific for each tissue Construction of artificial matrices from different constituents can regulate gene expression Collagen – expression of epithelial cells

Systemic or Exogenous factors Systemic physiological regulators – Hormones, Vitamins, Inorganic ions (role of calcium) Nonphysiological regulators – DMSO, N- methyl acetamide etc

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