Regenerative therapies Flashcards
LO
- Analyse the strategies to promote axonal regeneration in the PNS and CNS
- Compare and contrast the factors responsible for regeneration failure in the CNS
- Evaluate the potential as well as the limitations of cell replacement strategies in the CNS
- Discuss epidural stimulation as a ‘therapy’ to enhance motor function…. walking after SCI
Tell me the contribution of the glial cells with the glial scar in normal CNS?
Tell me the following about each glial cell…
- Major markers/ cell-surface molecules/ cytokines produced
- Main functions and behaviours
- CS-PGs expressed
Scar that forms from reactive astrocytes after injury
Not mature OG shown
Microglia are immune surveillance cells, secrete enzymes, no contribute to expression or secretion
Astrocytes: provide neuronal support, could be structural support, secrete growth factors which help axons and neurons survive, secrete the enzymes shown above
Oligodendrocyte precursor cells: cells give rise to OG, before mature state… provide population of cells, cycling around, if myelin is needed, they can help, express, have own complement of CS-PGs
Support or surveillance under normal circumstances
Tell me the contribution of the glial cells with the glial scar in injured CNS?
Tell me the following about each glial cell…
- Major markers/ cell-surface molecules/ cytokines produced
- Main functions and behaviours
- CS-PGs expressed
Cells are all ready to respond to injury
Hypertrophic with injury, growing in size
Secrete lots of different things when injury. OG not as much. Microglia and astrocytes secrete lot more of first molecules but also others like cytokines involved in immune response
Roles slightly different
A future treatment is combatting the glial scar with Chondroitinase ABC tell me about this
Chondroitinase ABC (cABC) is an enzyme that digests glycosaminoglycan side chains of CSPGs.
Following rodent spinal cord injury and digestion of glycosaminoglycan side chains with cABC, no CSPG immunoreactivity detected (left) and fibres regrew around lesion site better than untreated (above).
What are some potential limitations of cABCs?
Potential limitations of cABC: regrowth following treatment follows to areas where there is digestion of CSPGs. She has induced plasticity rather than regeneration in study by Bradbury et al., 2002, nature
Tell me how cABC enhances current treatment (rehabilitation)
specific forelimb reaching rehabilitation combined with cABC leads to dramatic recovery of skilled forelimb function, even with a chronic injury (tested on hungry rats which want to eat so therefore reach for the sugar pellets that are in the ‘staircase’). Another reaching task carried out, Whishaw, similar outcome to staircase task. Trying to mimic what a human would undergo
What does the combined treatment of anti-NOGO-A and cABC show?
Combined treatment shows promise for repair
Axonal growth up to 5mm caudal to lesion site
Improved forepaw reaching
Same test as rehabilitation activities
Not amazing amount of regenerative growth seen so more work to seen
If anti-NOGO-A given too late, then it’s not effective
If animal were not rehabilitated specifically on task they were going to do, there was a poor outcome i.e., running wheel against reaching. Have to do the task to recover the ability
Whats the importance of the glial scare for repair?
“Despite acting as a physical barrier to axonal regrowth, the glial scar modulates the inflammatory response after injury and that without the glial scar present, this inflammatory response can be an equivalent barrier to regrowth.” (Quraishe et al 2018 Neural Plast)
Presence of “transitional” astrocytes with potential neuroprotective and immune-regulatory roles…
Glial scar inhibits spread of lesion so if removed then this would spread
What may cell transplants provide with regeneration and repair?
Bridge over/through scar
Permissive substrate
Cell replacement
Growth factors
Remyelination
What are some common cell transport types in humans?
1. Schwann cells
2. Olfactory ensheathing cells
3. Stem cells
Induced pluripotent- ethically good, taken from adult i.e., skin cell
Embryonic- embryo required (aborted fetus)
Multipotent progenitors- more differentiated, from bone marrow, encompass huge area of stem cell
Tell me about Olfactory ensheathing cells (OECs)
Olfactory ensheathing cells (OECs) are a unique class of vertebrate glial cells that envelop bundles of olfactory axons, both peripherally in the olfactory nerve and within the olfactory nerve layer (ONL) of the olfactory bulb
Cells taken from nostrils
OECs are glial cells?
Ensheathed: insulation provided by glial cells which also provide growth factors, neurons regenerate throughout life
Tell me about regeneration and repair with OECs
They provide trophic support (i.e., neurotrophins); they can phagocytose debris, and they allow cells and axons to integrate through glial scar-rich regions
Functional recovery and/or CNS axon regeneration has been reported when OB-derived cells where transplanted.
OECs integrated with glial scar and provided channels for CNS?
How are stem cells used for regeneration and repair?
Stem Cells
- Embryonic
- Induced Pluripotent (iPSC)
- Mesenchymal stem cells
- As well as many others
Human Neural stem cells (NSCs) transplanted into immune-deficient mouse after T3 transection injury (cut injury). Assessed for regeneration and axon growth, 7-12 weeks post-injury- good growth and recovery function seen
There are at least 38 ‘clinical trials’ going on around the world using stem cells in SCI patients.
Has cell transplantation been useful in PD for regeneration?
Embryonic stem cells tissue and transplanted into areas affected by PDs
Repair of areas affected by PDs seen
These studies have been done in humans
Not a widespread therapy, L-DOPA is most common, but in some instances, this is done
What biomaterials can be used for regeneration and repair?
Hydrogels that mimic the ECM- good chance of growth across those areas
Provide physical or topographical cues for axonal growth
Substrate for cell delivery and survival
Important part of combined therapies (growth factors, cells, etc.)
Electrical stimulation and rehabilitation can also be used for regeneration and repair, tell me about this
Epidural stimulation uses electrical stimulation with propriospinal input derived from muscles, bones, and skin that project to the lower spinal cord (to serve as a source of neural control)
Electrode array implanted into spinal cord along with electronic and battery for stimulation
also works on Central Pattern Generators (CPGs) (A neural circuit that can produce a rhythmic motor pattern in the absence of descending control; potentially without sensory input)- acts on propriospinal input, controversial in humans as don’t know as much about this as you do in other mammals
Tell me about CPGs and mammalian locomotion
Walking, swimming, etc. all depend on cycles of muscle activity
For most quadruped mammals, it is assumed that the neural control of locomotion is based on CPGs within the spinal cord. This network generates the rhythm and shapes the pattern of bursts of motor neurons.
Specialized neural circuits located in the caudal spinal cord (the CPG) organize hindlimb locomotor activity, while those in the rostral spinal cord control forelimb movement
The coordination of both circuits is mediated by propriospinal neurons with long axons, which couple the cervical and lumbar enlargements of the spinal cord.
Tell me about Propriospinal (interneuron) neurons
Contained entirely within the spinal cord.
May have short segmental or multi-segment projections.
May convey supraspinal descending commands and aid in the integration of these commands with sensory feedback from the body.
Mediate and coordinate rhythmic motor output involving multiple joints and neurons across several spinal segments.
They provide a large proportion of the excitatory and inhibitory inputs that the motor neurons receive.
Proven in 4 legged animals like cats
