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L13 - Stem Cells II
Outline the factors governing adult stem cell…
L13 - Stem Cells II
- Outline the factors governing adult stem cell plasticity
- Name and list the functions of common cell signaling pathways in stem cell function
- Discuss the role of the stem cell niche in regulating stem cell activation and quiescence
- Describe tissue-specific examples of stem cell homeostasis; skeletal muscle, gut and blood, and liver (from last lecture!).
Stem Cell Niche
Provides the SC with all it needs
- Growth factors
- Shields them from damage
(Cartliage-forming SC and muscle SC have been pulled from bodies post mortem)
Plasticity
- Bipotential = lows plasticity
- Multipotenital = high plasticity
A stem cell's plasticity is largely influenced by where it is located in the body
- Unlike embryonic SC's, somatic/adult SC's are located in specific tissues
- They have determined fates (e.g. muscle SC => muscle cell)
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Composition and Bio-Processes within the Niche
There are common principles that apply to all SC Niche's
- Extracellular mechanisms activate Intracellular processes which regulate behaviour [EC => IC]
- These signals maintains the quiescent stem cell or drive activation and progenitor differentiation
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Activation => Transit Amplification => Mature Cells
Activation of SC
- Stimuli (Environemental Signals/Niche disruption/damage)
- Exit G0 quiescience & re-enter cell cycle
- Undergo Asymmetric Division - self renewal and differentiation (1st/2nd round of mitosis)
- Progeny of SC are transit-amplifying cells
Transit Amplifying Cells
Proliferate rapidly
- Controlled by signalling
- Contact with other cells regulates this
Induced Differentiation
- Involves fate specification decisions
- Withdrawal from cell-cycle once response is adequate
- Maturation
SC Deactivation
- Original SC regain quiescience, after recieving;
- *Contact Signals (From the SC NICHE*)
- Short range sgnals
- Undergo asymmetric division
Notch Singalling facilitates this
Notch's primary function is to inhibit differentiation
- Numb inhibits Notch
During SC mitoses Numb protein is assymetrically distributed
- Numb protein is trasnferred to progeny, and is not retained in original SC
- Notch is activated in absence of Numb
- SC's do not dfferentiate => re-enter G0
Numb inhibits activity of Notch
and allows proliferation & differentiation-
- Numb protein is trasnferred to progeny, and is not retained in original SC
- Notch is activated in absence of Numb
- 1 more item...
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Adult Stem Cell Examples
- Proliferate
- Differentiate
- Self-regenerate
Some stem cells are tissue specific (i.e. muscles SC & neuroepithelial SC's)Others are simply multi potent
(i.e. HSC or Embryonic SC's )
Skeletal Muscle
Satellite Cells
- In adults they are largely quiescent, with low turnover
- Regenerate rapidly during muscle damage
-
Injury and Proliferation
Migration, Adhesion and Fusion
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TF's involved in Satellite Cell Regeneration
- Pax7 (Activate Stem Cells)
- MyoD (TA cells)
- Myogenin (differentiating cells)
- Notch is also involved with suppressing differentiation ??
GUT - Crypt Base Columnar Cells
- Primary cells which allow regeneration in the gut
Differentiate into many cell types
- Enterocytes (Absorption)
- Goblet Cells (Secretion)
- Endocrine Cells (Hormone Signal)
- Paneth Cells (Anti-Bacterial peptides)
- GI stem cell differentiate in the crypt of the gut, first orginating in e GI tract (vontinual process0
CBC Stem Cells
- Multipotent
- Marked by LGR5 (Notch member pathway)
- Also differentiate into a class of Reserve Stem Cells
CBC's => Transit Amplifying Cells
- Divide every 12-16h ~ 300 cells per crypt/day
- Sequential Diffeenatiation
CBC's proliferate and differentiate from the base of the crypt up the villi - displacing senescent cells
Haematopoietic Stem Cells
- Niche located in the Bone Marrow
- Multipotent => forms all blood cells
- Marrow produces 30mL (100 x 10^9 cells) each day
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HSC Niche
Endosteal Niche
- Quiescient
Perivascular niche
- Less quiescent and more active
Erythropoiesis
- Reduction in cell size
- Loss of nucleus & organelles
- Increase in Haemoglobin content
- HSC => Reticulocyte ~15 days, + 2 days in bloodstream before mature RBC
Erytropoietin
Typically responds to
- TISSUE HYPOXIA (low RBCs)
- High Blood Viscosity (too cellularised)
Renal Control
Kidney stimulates EPO in response to hypoxia
- Speeds HSC => Proerythroblast
- Speeds maturation of proerythroblast
- Increased RBC count in ~ 5 days