Neural Transplants & Rewiring

Question 0

Repairing brain damage : 3 ways that transplants can help

Answer 0

1. Release neurotransmitters to substitute lost ones
2. Release factors that promote recovery
3. Integrate neurons into cell-loss, re-establish connections

Question 1

Gatrulation

Answer 1

Day 21 when the cells develop into specific cells

Before then , are considered pluripotent

Question 2

Neural stem cells

Answer 2

Ability to replicate indefinitely
In tissues - internal repair system
Stem cell division - remain/become specialised
Replicate!

Question 3

Adult neurogenesis:
Sub ventricular zone
Subgrannular zone

Answer 3

Lining of ventricles, migrate to olfactory bulb

Hippocampus to other areas of the hippocampus

Question 4

Rewiring & transplants

Alzheimer’s - what is it?

Answer 4

Degeneration of cholinergic system
Multiple pathologies including several brain regions
Tropic factors (BDNF) can reduce ageing in Alzheimer’s
Promotes neurogenesis and protects the neurons

Question 5

Rewiring & transplants
Alzheimer’s disease
Blurton-Jones et al (10)

Answer 5

Transgenic mice with AD and cognitive deficits
Implanted 100,000 neural stem cells in each hippocampus&glow
Hippocampal memory test - Morris water maze
Improved performance, increased hippocampal synaptic density
Increased BDNF

Question 6

Rewiring & transplants
Alzheimer’s
Gaillard et al (07)

Answer 6

Grafts
Motor cortex damage = motor impairment
Transplantation of embryonic cortical neurons induced in partial recovery (mice tissue develops faster)
Watched with fluorescent protein
Graft grew - extended connections to appropriate areas, 
New synapses between grafted and host
Functional improvements in motor control
Neurons travelled

Question 7

Rewiring & transplants
Stroke
Andre et al (11)

Answer 7

Transplanted human foetal cell
Infarct caused through MCAO 
Transplanted human neural precursor cells
Survived in isechemic host brain
Reduced white matter atrophy
Enhanced functional recovery
Induced plastic and axonal rewiring

Question 8

Rewiring & transplants
Stroke
Modo et al (02)

Answer 8

Used rat MCAO mol to test transplant effects on recovery and behaviour of transplanted material
Transplant into ventricles 2/3w after stroke,
Behv tests over 14w
Histological investigation of cell distribution

Cells migrated out of ventricles into brain
Occupied homologous region
Intact and lesions hemispheres attracted graft stem cells
Repair and emphasis

Question 9

Rewiring & transplants
Stroke
NPC

Answer 9

Neural progenitor cells
Grafted to surrounding tissue lesion
Survive, differentiate, enhance functional recovery
Cells spontaneously migrate to lesion

Question 10

Rewiring & transplants
Stroke
hNT neurons - immature

Answer 10

Derived from human teratocarcinoma
Genetically modified to replicate without cancer
Maintains properties in vitro/vivo for up to 1yr without reverting to cancerous state
Improves functional recovery if in isechemia (rat striatum)
Behv improvement after 6m if cells survived

Question 11

Rewiring & transplants
Stroke
Non human NPCs

Answer 11

In experimental stroke
All recover from ischemia (adult/foetal)
Robust migration to ischemic area
Potential hazard of tumour formation

Question 12

Rewiring & transplants
Stroke
Clinical trials of cell transplantation

Answer 12

hNT used in clinical trials - no cell related adverse effects for 5yrs after transplant.
High levels of activity in graft area for long time
6 of 12 SS improved on EU stroke scale
Phase 11: 8w of constraint therapy: 6 of 14 SS improved

Question 18

Rewiring & transplants
Qiang et al (11)
Future

Answer 18

Human induced neuronal cells from adult skin cells

Question 27

Rewiring & transplants
Parkinson’s Disease
Bjorkland et al (02)

Answer 27

Grafted mouse ES cell suspensions into rat striatum
Examined 14/16w later
Behaviour after graft decreased
ES cells differentiated into dopamine neurons
Integrated with host circuitry
Mediating functional recovery

Question 28

Rewiring & transplants
Parkinson’s Disease
Gaillard & Jaber (11)

Answer 28

Ingram grafts can grow axons through to the striatum = full functional recovery
Use of foetal cells and solid blocks of fetal brain tissue
Grafted neurons without limitations
Didn’t work in PD SS - too old? Poor grafting?

Question 29

Rewiring & transplants
Parkinson’s Disease
Winder et al (92)

Answer 29

MPTP: took 2yrs, then could almost move normally.

Drastic improvements.

Question 30

Rewiring & transplants
Parkinson’s Disease: do nigral grafts increase dopamine release in SS?
Piccini et al (99)

Answer 30

PET scans to measure dopamine receptor occupancy
Received r.putamen transplant 10yrs earlier
Sig clinical benefit, graft restored basal ganglia and normalised dopamine storage in grafted putamen.
Continued to store & release dopamine for 10yrs
Sig symptom relief

Question 31

Rewiring & transplants
Parkinson’s Disease
Striatal vs nigral grafts
Brudin et al (10)

Answer 31

Grafted cells survive for up to 20yrs
Sig functional recovery
Mixed results, not universal recovery, serious side effects
Patient selection? Graft preparation? Immunosuppression? Graft induced dyskenisia?