Cell Differentiation Flashcards

1
Q

how cell development occurs

A
  • all cells contain the same genes
  • “genes are not gained or lost in the normal course of development”
  • rather their expression is controlled
  • Different cell types express different sets of proteins (differentiation)
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2
Q

development

A
  • In multi-cellular organisms, life begins as a single cell.
  • With few exceptions, somatic cells contain the same genetic information as the zygote.
  • In development, cells commit to specific fates & differentially express subsets of genes.
  • Cells identify and respond to their position in developmental fields.
  • Daughter cells may differ with respect to regulatory instructions and developmental fate.
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3
Q

cell differentiation –> specialisation

A
  • A cell changes or differentiates to carry out specialised functions
  • Often marked by a change in cell appearance – morphology
  • Differentiated cells produce specific proteins
  • Differentiation is usually preceded by rapid proliferation
  • Differentiation is a DNA-orchestrated set of cellular changes that normally occurs without error*
  • Differential gene expression from the same nuclear repertoire
  • Accomplished by regulation of gene expression at several levels
    (phenotype: physical appearance of the cell)
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4
Q

cells, tissues & organs

A
  • Cell fate and differentiation are patterned in space (special)
  • Also involves the intricate patterning & timing (temporal) of cell proliferation (temporal)
  • Activation of cell division in some regions
  • Imposition of cell cycle arrest in others ∴ controlled in a spatio-temporal manner
  • The cell cycle, its control & checkpoints are of major importance in differentiation & development
  • Cells not only have to proliferate & differentiate
  • Sort into different tissues
  • Segregate within tissues to form compartment boundaries
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5
Q

cell asymmetry

A

Early Mammalian Development

  • Symmetric division yields identical daughter cells that may have different fates if exposed to different external signals.
  • Asymmetric cell division yields two different types of daughter cells with different fates.
  • Mammalian embryo initial divisions yield equivalent totipotent cells;
  • subsequent divisions give rise to the blastocyst inner cell mass and surrounding trophectoderm as the first differentiation event.
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6
Q

building the embryo

A

Developmental decisions:
o made at specific times during development
o many are binary (yes/no), e.g., male or female
o most are irreversible
o many involve groups of cells rather than single cells
In animals decisions are made to:
o establish anterior-posterior and dorsal-ventral axes
o subdivide anterior-posterior axis into segments
o subdivide dorsal-ventral axis into germ layers
o produce various tissues and organs
- Most decisions involve changes in transcription

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7
Q

developmental strategy

A
  • Mother deposits material (mRNA and protein) that creates asymmetries - set up gradients that broadly define areas (basic body plan map!)
  • Gene interaction subdivides these areas (cells differentiate)
  • These identities are remembered
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8
Q

features of cell polarity and asymmetric cell division (Common hierarchy of steps in generating a polarized cell before cell division)

A
  1. Cells exposed to a spatial cue – soluble signals from other cells/ECM
  2. Closest cell receptors bind extracellular signaling molecules
  3. Cell receptors locally activate an intracellular signaling pathway.
  4. Signaling pathway directs organization/orientation of the cytoskeleton (microtubules and/or microfilaments, depending on the system).
  5. Polarized cytoskeleton transports membrane-trafficking organelles and macromolecular complexes including fate and polarity determinants to one end of cell.
  6. Polarity –
    o Reinforced by return of polarity determinants that have moved away from the site of concentration
    o May involve endocytosis of membrane proteins and transport back to polarity site
    (b) Cell polarity determinants – mRNAs, proteins, and lipids:
    o Asymmetrically localized in mother cell
    o Mitotic spindle – positioned so that polarity determinants are segregated differentially into daughter cells during cell division
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9
Q

role of cytoskeleton in development

A
  • Consists of highly organized rods and fibers
    o microfilaments (actin)
    o intermediate filaments
    o microtubules
  • Such structures are polar, with distinct “+” and “–” ends
  • Serve as highway system for intracellular transport
  • Asymmetry of cytoskeletal elements plays fundamental roles
    o directed transport of molecules
  • Cytoskeletal components give directional information - through orientation of filaments
  • Multiple independent trafficking system … different cell components moved
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10
Q

tissue identity

A
  • Gradients of differentiation factors define a coordinated system for the entire embryonic body, then axial subunits such as limb buds
    o Axial orientation (head /tail & anterior/posterior)
    o Homeo-box genes (patterning)
    o Dorso-ventral identity
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11
Q

differentiation

A

The development of specialised cells/tissues recognised morphologically

  • differentiated cells produce specific proteins
  • all genes of the genome are present in every cell BUT only a small specific number are expressed (switched on) in each cell type
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12
Q

the body plan

A
  • The spatial pattern of tissues and body parts is influenced by:
    o program of gene expression that specifies the pattern of the body
    o local cell interactions that induce different parts of the program
  • The basic body plan of all animals is very similar
    o preserves commonalities of molecular and cellular mechanisms controlling development
  • Structures during embryonic development very similar across species
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13
Q

patterning genes

A
  • Encode proteins that:
    o Control expression of other genes (transcription factors bind to DNA)
    o Cell adhesions molecules
    o Signalling molecules, morphogens & more protein kinases
  • All expressed in a spatio-temporal manner that permits the integration and coordination of events in the developing embryo
  • The precise timing of events is maintained by one group of cells inducing differentiation in a second group
  • Mediated by:
    o Direct cell-cell contact
    o Soluble factors released by cells (morphogens)
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14
Q

regulation of gene patterning

A

morphogen = a chemical agent able to cause or determine morphogenesis

  • “genes are not gained or lost in the normal course of development”
  • Therefore: Developmentally regulated and tissue specific gene expression must be very well regulated to enable differential gene expression in the right place at the right time.
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15
Q

differentiation, division and new cell types

A
  • Different cells have varying abilities to divide or differentiate.
  • Cells in the embryo proliferate rapidly before differentiating
  • Some adult tissues contain cells with a similar capacity to proliferate and regenerate tissue. These are called somatic stem cells.
  • Most adult cells have a limited capacity to divide because they lack telomerase activity.
  • Telomeres shorten with cell division
  • Embryonic (& tumour cells) express telomerase
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16
Q

adult tissues

A
  • Adult tissues require maintenance and repair/regeneration
  • Generally, differentiated cells are post-mitotic and cannot contribute to tissue repair
  • Cells in these tissues are replaced from a source of tissue stem cells* ((*Cells that have the capacity to divide, produce a limited range of differentiated cells, and (probably) self renew))
  • Cell division and differentiation in adult tissues must also be tightly regulated
17
Q

stem cells

A
  • Undifferentiated cells that may or may not be committed to a particular fate
  • Have the unique capacity to: give rise to more stem cells (self renewal), generate differentiated progeny
  • Probably exist (as a function if not an entity) in all multicellular organisms
  • Are present at all stages of development in many tissues (adult stem cells)
18
Q

stem cell niches

A
  • Most animal stem cells are multipotent and can undergo symmetric or asymmetric self-renewal divisions.
  • Stem cells are formed in niches that provide signals to maintain a population of undifferentiated stem cells but prevent excess proliferation.
  • Stem cells regenerate differentiated tissue cells that are damaged, sloughed, or aged.
19
Q

ESC vs iPS

A
  • Embryonic blastocyst inner mass cells are pluripotent
    o give rise to all differentiated cell types of the organism.
  • ES cells pluripotency is controlled by multiple factors,
    o including the state of DNA methylation, chromatin regulators, certain micro-RNAs, and the transcription factors Oct4, Sox2, and Nanog.
  • Induced pluripotent stem (iPS) cells can be formed from somatic cells by expression of combinations of key transcription factors.
20
Q

inner cell mass (ICM)

A
  • ICM can probably form all the cells of the body
    o but cannot form an organism
    o it is unable to give rise to the placenta & supporting tissues
  • These cells are pluripotent (remain developmentally plastic until 8 days)
21
Q

ESC in culture to form differentiated cell types

A
  • Embryonic stem cells can be isolated from the inner cell mass of early mammalian embryos and grown indefinitely in culture.
    (a) ES cell acquisition and culture: form ICM
    (b) ESC in suspension culture form multicellular embryos bodies
    ((C) embryoid body contains derivatives of all 3 germ layers formed from ICM during embryogenesis (endo,meso & ectoderm)
22
Q

expression of proteins determines SC behaviour via regulation of pluripotent

A

3 master transcription factors – Oct4, Sox2, and Nanog:
- Bind to own promoter as well as to promoters of the other two
o Positive autoregulatory loop – activates transcription of each of these genes
Bind to the transcription-control regions of many genes
o Activate genes encoding proteins and micro-RNAs important for the proliferation and self-renewal of ES cells
o Repress genes that are silenced in undifferentiated ES cells and that encode proteins and micro-RNAs essential for the formation of many differentiated cell types

23
Q

pathway from SC to lineage-restricted progenitors to final differentiated cells

A

Multipotent somatic stem cells give rise to both stem cells and multiple types of differentiated cells.
- Multipotent somatic stem cell self-renewal divisions:
o At least one daughter usually becomes a stem cell like the parent cell.
o Stem cell number – stays constant or increases during the organism’s lifetime
- Transient amplifying cells:
o Divide rapidly and undergo limited self-renewal divisions
o Produce lineage-restricted progenitor cells
• Divide and produce specific differentiated cells, cannot undergo self-renewal divisions

24
Q

SC patterns of cell division

A

Stem cells exhibit several patterns of cell division – must meet three objectives:
1. Maintain the stem-cell population
2. Sometimes increase stem cell number
3. Produce cells that differentiate
(a) Asymmetric divisions:
- Produce one stem cell and one differentiating cell
- Maintains constant stem cell number
(b, c) Symmetric divisions:
- Increase stem cell number – during normal development or injury recovery

  • Symmetric and asymmetric divisions may occur simultaneously in stem cell population to:
    (b) Increase stem cell number
    (c) Increase differentiated cell number
25
Q

cytokines control differentiation

A
  • Hematopoietic stem cells (HSCs) form all blood cells.
  • Multipotent hematopoietic stem cells:
    o Divide symmetrically – increase stem cell number
    o Divide asymmetrically:
    • One daughter cell – remains multipotent like the parent stem cell
    • One daughter – generates either lymphoid progenitors or myeloid progenitors (capable of limited self-renewal but committed to one of the two major hematopoietic lineages)
  • Cytokine types and amounts – regulate HSC self-renewal divisions and proliferation and differentiation of the precursor cells for various blood-cell lineages
    o Progenitors – either multipotent or unipotent
26
Q

adult (somatic) stem cell division

A
  • Most adult cells have a limited capacity to divide (ie people age-our tissues have a use-by date)
  • Some adult (non-embryonic) tissues do contain stem cells – bone marrow, muscle (somatic)
  • Somatic stem cells behave somewhat like Embryonic Stem cells because they:
    o Have the capacity divide extensively (indefinitely?)
    o Give rise to other cell types (-trans differentiate?)
    o Bone marrow mesenchymal cells can differentiate into: neuronal cells, liver, endothelial, pancreas, but not cardiac muscle
  • Ethical alternative to embryonic stem cells.
27
Q

uses of iPS

A
  • Medical uses of patient-specific iPS cells – e.g., patient with a neurodegenerative disorder caused by abnormalities in certain nerve cells (neurons):
  • Patient-specific iPS cells derived by recombinant expression of transcription factors in cells isolated from a skin biopsy – two uses (known disease and unknown)
28
Q

iPS with known disease

A

Known disease-causing mutation, e.g., familial Parkinson’s disease –
o Gene targeting – used to repair the DNA sequence
o Gene-corrected in patient-specific iPS cells – directed differentiation into the affected neuronal subtype (e.g., midbrain dopaminergic neurons)
o iPS cells transplanted into the patient’s brain – replenish cells destroyed by disease

29
Q

iPS directed differentiation

A

Directed differentiation of the patient-specific iPS cells into the affected neuronal subtype carrying mutation –
o Used to model patient’s disease for drug screening/testing novel therapies