Normal control of cell growth and differentiation Flashcards

1
Q

Morphogenesis

A

Shape organism by embryological processes (differentiation and growth)

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2
Q

Undifferentiated cells can…

A

Differentiate, apoptosis, proliferate, grow

Most common in early development = proliferation + growth (usually coupled)

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3
Q

Cell growth requires…

A
  1. Increase cell mass and volume - macromolecule synthesis (polysaccharides, proteins, lipids)
  2. Relative movement at cell surface - change interactions/ connections w/ other cells and ECM
  3. Change shape
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4
Q

Why is cell growth important?

A
  1. Massive but consistent size increase during development
  2. Huge diff. animal sizes (even though same mechanisms regulate)
  3. Organs maintain in proportion to each other
  4. Cells in many organs cont. grow during adulthood
  5. Defective growth = disease (esp. cancer)
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5
Q

Cell growth and survival influenced by…

A
  1. Extracellular growth factors and inhibitors
  2. Contact w/ extracellular matrix
  3. Normal growth cond. = organs grow to fixed size (intrinsic control of growth)
  4. Regulate growth - reduce/ xs extrinsic growth factors
  5. Nutrition
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6
Q

When does cell growth occur?

A

Early development: Fertilised egg - embryo - fetus - adult
Huge increase in size
Adult: Hypertrophy (growth, no division) - e.g. skeletal muscle
Hyperplasia (coupled growth and proliferation) - renew tissues (stem cells)
Disease: Neoplasia - tumour growth (abnormal growth and division)

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7
Q

Hypoplasia

A

Cell/tissue loss
Development: Tissue patterning - digit formation, neural patterning (many neurons formed during development die)
Physiological atrophy (decrease size) : Pulmonary artery/ aorta at birth, thymus at puberty, epithelial cells
Developmental/ physiological disorders: Hypoplasia and atrophy - testes in Klinefelter’s syndrome, skeletal muscle degeneration after denervation,
neurodegenerative disease of ageing

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8
Q

Coupling of cell growth and proliferation

A

Current model = growth drives mitosis

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9
Q

Uncoupling of cell growth and proliferation

A

Proliferation w/ no growth - cleavage
Growth w/ no proliferation -skeletal muscle hypertrophy
Growth w/ DNA replication but no division = big cells ( e.g. myocardial cells - skeletal muscle fibres fuse)

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10
Q

How is normal tissue structure and function maintained?

A

Cell growth/division
Control - extracellular growth factors/ inhibitors
Balance by cell loss/death

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11
Q

Growth factors

A

Local factors - control growth of specific organs

Global factors - regulate coordinated growth of multiple organs (e.g. nutrient dependent)

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12
Q

How is organ size regulated?(experimental)

A

Autonomous control:
Transplantation experiments
Organ size usually determined autonomously
Transplant multiple fetal thymuses into developing mouse
Each grow to adult size
BUT transplant fetal spleens
Total mass of spleens = mass of normal spleen
NON-AUTONOMOUS control
Regeneration experiments
Hepatocytes regenerate ⅔ liver
Observe role of growth inhibitors

Non-autonomous control:
Defects in growth regulatory pathways
Reduced/ XS GH
Insulin receptor mutant (leprechaunism in humans)
Drosophila insulin receptor signalling - control body growth and affects lifespan

Link to nutrition (birth weight, health, lifespan) - Expression and activation of regulatory pathways
Signals from neighbouring structures - Sympathetic neurons and nerve growth factor

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13
Q

Renewing tissues: skin

A

Stratified squamous keratinised epithelium layer, basal layer contains proliferating SCs, cells move through layers, sloughed off at surface, move through states of gene expression towards terminal differentiation
Cells express series diff. keratin proteins during differentiation
30 day process - cell divide to slough off at surface
Basal layer contain few true SC (TSC) but many transit amplifying cells (TAC)
TSC not divide often - limit potent. mutations
TAC - potent. rapid repopulation when need (wound repair)
Move to skin surface

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14
Q

Renewing tissues: gut

A

Lining s.intestine renews faster than other tissues (1 week turnover)
Dividing multipotent stem cells in crypts, travel upwards to villus tip
Cells undergo apoptosis
Shed into gut lumen
Paneth cells migrate down
Regulate by cell-cell signalling
Produce 4 type differentiated cell

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15
Q

Resting tissues: liver

A

Survive surgical removal 75% total liver mass, original no. cells restored in 1 week, original tissue mass in 2-3 weeks
Hepatocytes
High capacity for cell division
Unipotent stem cell
Most tissue repair in liver
Also liver stem diff. from hepatocytes - respond to some forms x liver injury
Oval cells = hepatocyte precursors

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16
Q

Non-dividing tissues: neurons

A
Adult neurogenesis (stem cells in brain): 
Neurons = post-mitotic (don’t regenerate after birth) 
Neural stem cells (NSC) in human/mice throughout adulthood
17
Q

Apoptosis

A

Programmed cell death
Cells die in controlled way
Important physiological process in development
Interdigital cell death - correct limb development
Epiphyseal growth plate - apoptosis hypertrophic chondrocytes
Tail loss in metamorphosis tadpole to frog
Kill and remove cells w/ out spill bioactive contents
Molecular pathway involve: activate proteases and caspases (cascade), nucleus condensation and fragmentation, membrane blebbing, DNA fragmentation (visible as laddering x DNA)
Apoptotic cell fragments in pieces = apoptotic bodies
Engulf by phagocytic cells
Before bioactive contents spill out and cause damage

18
Q

Necrosis

A

Accidental cell death
Result x acute insult
Trauma
Lack blood supply

19
Q

Diseases of cell death: Ischaemic stroke (clinical)

A

Pathological condition
Restrict blood supply
Lack Ox = tissue hypoxia
Cells die by necrosis

Reperfusion injury
Restore blood flow and reOx
Contribute to tissue injury
Inflammatory and autoimmune response
Cells in penumbra die later by apoptosis
Caspase inhibitors may be beneficial drugs (prevent cell death after stroke)

20
Q

Diseases of cell death: neurodegeneration (clinical)

A
Loss spec. neurons
Accumulate protein aggregates (cause death or protection?) 
Route x cell death unknown 
Alzheimer’s - death cortical neurons 
Parkinson’s - death dopaminergic "
Huntington’s - death spiny "
Motor neuron - death motor "
21
Q

Diseases of cell death: Cancer (clinical)

A

Too much division/ not enough cell death
Cancer SC drive tumour form
SC required target for therapy (even though small proportion of tumour)
Therapy remove bulk tumour but leave SC = ineffective (tumour will reform)

22
Q

Stem cells

A

Undifferentiated
Capacity for self-renewal through cell division (limited)
Generate specialised cells through differentiation
Progressive restriction of developmental potential = lose potency

23
Q

Embryonic stem cells

A

Totipotent (early embryonic cell division - cleavage) -V. early mammalian embryo, can form entire blastocyst (embryo + fetal placenta)
Pluripotent (8 cell stage)
Can form embryo, not surrounding tissue, form 3 germ layers (ectoderm, endoderm, mesoderm)

24
Q

Development potential of cells

A

Totipotent: Inner cell mass of fertilised egg, can become any cell type, produce whole organism
Pluripotent: Can become some cell types, specialised gene expression programmes, often can still proliferate
Multipotent: Can become many cell types
Unipotent: Can become 1 cell type, fully committed to terminal differentiation
Committed SC - give rise to small subpopulation of cells

25
Q

Adult stem cells

A

Maintain cell populations last for a long time and need renewing
Repair/ regeneration x adult SC within tissue types:
Epithelium, Blood, Muscle, Liver, Brain

26
Q

Haematopoietic tissue

A

All blood cells (RBC, WBC, platelets) derived from haematopoietic SC in bone marrow

27
Q

Whole bone marrow transplant (experimental)

A

Resupply haematopoietic tissue
X-irradiation stop blood cell production in mouse - die if no further treatment
Inject bone marrow cells from healthy donor, injected SCs generate steady supply new blood cells - mouse survives
HSCs identified w/ cell surface antibodies (labelled)

28
Q

Bone marrow transplant (clinical)

A

Haematopoietic SC transplant
Autologous = from patient
Allogeneic = from matched donor
From bone marrow, peripheral blood or umbilical cord blood
Treat:
Severe aplastic anaemia (bone marrow failure)
Leukaemia (cancer x WBCs) - irradiation to kill cancer, followed by bone marrow and HSC transplant from healthy matched donor
Genetic blood and immune system disorders (e.g. sickle cell anaemia and thalassaemia)

29
Q

Induced pluripotent stem cells (IPSC)

A

Reprogramming cells to generate stem cells
Originate from fully differentiated cell
4 Reprogramming factors originally shown to convert primary cells (e.g fibroblast) to IPSC = Oct4, Sox2, Klf4, c-Myc
Other factors functional in combos = Lin28, Nanog
Put genetic info into cell w/:
Viral vectors, mRNA/protein transfection (deliberately intro to live cell)
Problems: lower proliferation rate, earlier senescence than embryonic SCs

30
Q

Disease in dish models (experimental)

A

IPSC generate from spec. individual (healthy or disease)
IPSC differentiate to desired cell type (e.g. neurons, cardiomyocytes)
Relative conc. spec. growth factors instruct stem cells to differentiate into spec. cell types = reprogramming factors
‘Disease in dish’ - study in vitro models of human disease
Valuable for model inaccessible cells/ tissues (e.g. neurons)

31
Q

IPSC-derived models for Parkinson’s (experimental)

A
Generate (spec. growth factors) and compare PD
Control neurons (dopamine) 
Model early neuron dysfunction and death 
(Stain w/ neuronal markers)
Understand early psychological dysfunction which leads to disease
Potent. disease mechanisms: 
Synaptic failure, vesicle bio. calcium signalling, mitochondrial dysfunction, electrophysiology
Use patient IPS-derived dopaminergic neurons to screen for new drugs (correct function of cells in dish)
32
Q

Terminally differentiated cells

A

Express cell-type specific proteins (not expressed in non-differentiated cells)
Specialise function
Specialised structures
Diff. cell types characterised by differential protein expression
Growth factors may cause to re-enter cell cycle

33
Q

How is cell type-specific transcription achieved?

A

Cells instruct other cells -become committed and differentiate = induction/ regulative development
Cell-cell signalling mechanisms (induction):
1. Diffusible ligand bind to cell surface/ intracellular receptor (juxtacrine and paracrine = nearby signalling)
2. Cell surface ligand and receptor (juxtacrine)
3. Gap junctions (juxtacrine = contact-dependent signal)

34
Q

What factors produce and maintain the differentiated stat?

A

Cell type-specific TFs - Drive differentiation and block cell cycle
Inactive genes in mammals:
Promoters of inactive genes methylated, associated histones deacylated, chromatin stably inactivated = heterochromatin
Active genes in mammals;
Activate by opp mechanisms
Euchromatic - can express
Somatic cloning requires reversing stable activation/inactivation of genes
Spec. TFs maintain terminally differentiated state in
E.g. Pax5 (B cell)
Gene expression also regulated via alternative splicing and RNA editing
Genomic rearrangements produce diff. antibodies in B cells

35
Q

Pax5 Transcription factor (experimental)

A

Genetic removal Pax5 TF in mature B cells
= Uncommitted progenitor cells
Can differentiate into other immune cell types

36
Q

Transplantation therapy of self cells: spinal cord injury (clinical/experimental)

A
Stem cells to generate: 
Neurons, astrocytes, oligodendrocytes 
Replace neurons died at injury 
Re-form myelin
Stimulate regrowth x damaged axons
Protect cells from further damage (release growth factors, remove free radicals) 
Suppress damaging local inflammation
37
Q

Transplantation therapy of self cells: Parkinson’s disease (clinical/experimental)

A

Transplant dopaminergic neurons
ESC derived/ iPSC derived
Transplant into site of cells loss (nigra)/site of dopamine loss (striatum)
Successful experimental work in rats and monkeys
Humans - anecdotal success but mixed results

38
Q

Transplantation therapy of self cells: muscular dystrophy (clinical/experimental)

A

Muscle SC/ muscle precursor cells to regenerate diseased muscles
Successful treat muscular dystrophy in mouse
Unsuccessful so far in humans
Challenges:
Transplant myogenic cells by intramuscular injection gives limited spread
Massive death x injected cells
Immune response to cell grafts
Immunosuppression may allow survival non-self cells
Lifelong immunosuppression creates other difficulties
Alt. = GM (mutation corrected) patient cells