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Neuro Development and Disease > Neuronal Regeneration and Neural Stem Cells > Flashcards

Neuronal Regeneration and Neural Stem Cells Flashcards

1
Q

What is the ability to regenerate determined by?

A

the availability of neurotrophic factors and the presence of an intrinsic growth program

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2
Q

What is the ability to regenerate countered by?

A

the presence of growth inhibitors in the glial scar and myelin

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3
Q

What happens after SCI?

A

many cells die immediately as well as progressively

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4
Q

What happens after penetrating injury?

A

cells from the PNS often invade the injury site to form a connective tissue scar that incorporates astrocytes, progenitor cells and microglia

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5
Q

What happens during the early stages of injury?

A

myelin-associated inhibitors from intact oligodendrocytes and myelin debris can restrict axon regrowth

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6
Q

What does the recruitment of inflammatory cells and reactive astrocytes over time lead to?

A

the formation of a glial scar, often accompanied by a fluid-filled cyst

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7
Q

What is the scarring process associated with?

A

the increased release of chondroitin sulphate proteoglycans, which can further limit regeneration

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8
Q

What is Nogo-A?

A

a neurite growth inhibitor that plays a role both in the restriction of axonal regeneration after injury and in structural plasticity in the CNS of higher vertebrates

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9
Q

What are the 3 types of factor that regulate neurite outgrowth?

A
  • permissive e.g. ECM-associated, CAMs, neurotrophic factors
  • inhibitory e.g. Nogo
  • guiding e.g. ephrins, Slits
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10
Q

What are the 2 main molecular inhibitors of the adult CNS glial environment?

A
  • CSPGs associated with reactive astrocytes from the glial scar
  • myelin-associated inhibitors from intact oligodendrocytes and myelin debris
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11
Q

What does signalling from the Nogo-66 receptor do?

A

affect the actin cytoskeleton through activation of RhoA

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12
Q

What does a reduction of myelin-associated inhibitors do?

A

enhance regeneration

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13
Q

What does the end of severed nerve in the extracellular space between cells in a wounded spinal cord do?

A

form a growth cone which explores the territory by constantly forming and retracting filopodia

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14
Q

What does the extracellular space between cells in a wounded spinal cord contain?

A
  • CSPG molecules, which have a backbone and many side branches that block the way
  • special cell-membrane-anchored proteins that actively stop growing nerve fibres
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15
Q

What does the bacterial enzyme ChABC do?

A

prune the side chains of CSPGs, clearing the way for growing nerve fibres and promote regeneration of corticospinal tract axons

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16
Q

What does intrathecal treatment with ChABC degraded CS-GAG at the injury site do?

A
  • upregulate a regeneration-associated protein in injured neurons
  • promote regeneration of both ascending sensory projections and descending corticospinal tract axons
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17
Q

What do embryonic neurons have for regeneration?

A

a cell-intrinsic program leading to axonal elongation

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18
Q

What is the intrinsic growth capacity of adult CNS and PNS neurons respectively?

A
  • CNS = limited
  • PNS = high
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19
Q

What does a conditioning lesion do?

A

protect axons from degeneration after a second injury

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20
Q

What is the DRG neuron model for CNS axonal regeneration?

A
  • young DRG CNS axons could regenerate, but adult ones could not
  • regeneration of the CNS branch of the DRG neuron could be enhanced by a conditioning lesion to the PNS branch
  • cAMP could mimic the effects of a conditioning lesion, overcoming even the inhibitory effects of myelin-associated inhibitors
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21
Q

What is the relationship between cAMP levels and regenerative ability?

A

decreased cAMP levels = decreased ability

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22
Q

What does neurotrophin treatment do?

A

elevate cAMP levels

23
Q

What is PTEN?

A

a tumour suppressor phosphatase whose deletion enhances axonal regeneration

24
Q

What does PTEN act as?

A

a brake for the mTORC1 pathway, which promotes potent CNS axon regeneration

25
Q

What does mTOR activation do?

A

promote the synthesis of the raw materials for axon extension

26
Q

What do PI3K and GSK-3 do?

A

enhance axonal transport and cytoskeleton assembly in the axon terminal

27
Q

What does axotomy trigger?

A

the translation of importin β1 and vimentin mRNAs

28
Q

What is axotomy?

A

the cutting or severing of an axon

29
Q

What does vimentin do?

A

link pERK to the importin–dynein complex so that the injury signal is retrogradely transported to the cell body

30
Q

What is required for the axonal localisation of β-actin and GAP-43 mRNAs that are translated after injury?

A

zipcode binding protein 1 (ZBP1)

31
Q

What do intracellular signalling molecules do after CNS injury?

A

regulate the ability of the neuron to regenerate its damaged axon through the lesion environment

32
Q

What does C3 transferase do after CNS injury?

A

inhibit RhoA to promote axon extension and cell survival

33
Q

What does bpV do after CNS injury?

A

inhibit PTEN to promote neuroprotection

34
Q

What does rolipram do after CNS injury?

A

inhibit phosphodiesterase 4 (PDE4) to stabilise cAMP and promote axon extension

35
Q

What do MT stabilisers do after CNS injury?

A

reduce fibrotic scarring and promote axon extension

36
Q

What does ChABC do after CNS injury?

A

digest GAG chains, relieving CSPG-dependent growth inhibition

37
Q

What do Nogo extracellular peptides do after CNS injury?

A

compete for NgR binding to neutralise inhibitory signalling through NgR

38
Q

How can stem cells be used in CNS repair?

A
  • endogenous adult neurogenesis
  • transplantation-based therapy
39
Q

What is the source of stem cells for endogenous adult neurogenesis?

A

adult neurogenic regions e.g. SVZ and DG

40
Q

What is the source of stem cells for transplantation-based therapy?

A

allogenic autologous

41
Q

What must the neurons from neurogenic zones do during endogenous adult neurogenesis?

A

survive and differentiate/mature into site-specific functional neurons, and form appropriate axonal and dendritic connections

42
Q

Where can stem/progenitor cells be collected?

A
  • the inner cell mass layer of the mature blastocyst
  • the brain, spinal cord, olfactory system or umbilical cord of the foetus
  • the brain, spinal cord, olfactory system, bone marrow or blood of the adult
43
Q

Which cells can be used for autologous transplantation?

A
  • olfactory system cells
  • umbilical cord blood cells
  • haematopoietic stem cells
  • bone marrow stromal cells
44
Q

What is possible treatment for acute damage e.g. SCI?

A
  • peripheral nerve grafts
  • schwann cells
  • olfactory ensheathing cells
  • activated macrophages
  • embryonic/foetal spinal cord tissues
  • stem cells
45
Q

What is possible treatment for neurodegenerative diseases e.g. PD?

A
  • embryonic/foetal striatal tissues
  • stem cells
  • dopaminergic neurons derived from the above
46
Q

What are embryonic stem cells the best in terms of?

A

generating specific neuron subtypes

47
Q

Which neuron subtypes can embryonic stem cells generate?

A
  • motor neurons that can populate the embryonic spinal cord, extend axons and form synapses
  • grafted cells that become TH positive neurons
48
Q

What happens when human neural stem cells were used in CNS repair?

A

most transplanted cells assumed an astrocytic fate

49
Q

What may transplantation therapy require?

A

stringent checks for tumorigenic potential (even with the use of pre-differentiated cells)

50
Q

What are the advantages of bone marrow stromal mesenchymal cells in CNS repair?

A
  • autologous, patient specific source
  • little ethical concern
51
Q

What are the disadvantages of bone marrow stromal mesenchymal cells in CNS repair?

A

capacity for neuronal/glia differentiation not yet clearly defined

52
Q

What can BMSCs form?

A

neurospheres that can morphologically differentiate into neuron-like cells which expressed neuronal markers and some electrophysiological properties

53
Q

How do iPSCs facilitate research into brain disorders?

A

through the generation of brain organoids

54
Q

What are the 8 main strategies of CNS repair?

A
  • growth conduits
  • helper cells
  • endogenous adult neurogenesis
  • stem cell replacement therapy
  • reduced inflammation and environment hostility
  • reduce myelin-associated inhibition
  • enhanced intrinsic regenerative growth capacity
  • exogenous neurotrophic help

Neuro Development and Disease (9 decks)

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