Brain Defects and Regeneration Flashcards
What are some sources that can be used for tissue regeneration from injury? (3)
- Endogenous adult stem/precursor cells -> oligodendrocyte
- De-differentiation of somatic cells into stem/precursor cells -> newt limb re-formation
- Trans-differentiation of somatic cells into stem/precursor cells of a different lineage -> hair cells in ear following an injury
Explain the spontaneous regeneration of myelin after injury from endogenous progenitors (3)
1) Oligodendrocyte precursor cell(OPC) - existing in myelin sheath
2) injury takes place = all myelin is destroyed in this tissue
3) oligodendrocytes become activated = start restoring axon with fresh myelin
Limb regeneration in newts is achieved by … (3)
Limb regeneration in newts is achieved by de-differentiation of somatic cells in limb and muscle
The bone regrows and muscles reform, nerves grow out and innervated appropriately = new fully functioning limb
Based on the idea that these tissues (w/ loss or amputation) will dedifferentiate into pluripotent/ multi potent stem cells => which then have the ability to form all different types of tissues necessary for limb regeneration
Explain trans-differentiation of supporting cells in the ear (3)
After damage occurs in the supporting cells surrounding the hair cells = the hair cells are lost and that’s how deafness comes about.
The supporting cells have the ability to trans-differentiate into hair cells. This is using the Wnt/ beta-catenin, increased Atoh1 and mitosis.
Atoh1 is a specific tissue TF upregulator that drives these supporting cells to develop into hair cells
Why is tissue regeneration limited in most mammals including humans? (3)
Because of the inability of cells to de-differentiate, trans-differentiate
Because of the absence of suitable tissue specific stem cell reservoirs
Other systemic factors
Explain the development of the understanding of adult neurogenesis (4)
Until recently, ppl thought no new neurons are added to the brain during childhood
Endogenous neural stem cells!!!!!
1960 - evidence for neurogenesis in dentists gyrus and subventricular zone of lateral forebrain ventricles in adult brains discovered
1990s - existence of neural stem cells in these regions were demonstrated
Neurogenesis declines dramatically with age = relevance/ importance of adult neurogenesis on human brain health + function = controversial/ heavily disputed topic
Explain neurogenic niches in the adult brain (2)
The olfactory bulb contains neurogenic niches that can generate new neurons
- subventricular zone
- Subgranular zone in dentate gyrus contains neural stem cells
Explain the rostral migratory pathway (5)
1) neuroblasts are formed
2) these neuroblasts migrate across towards the front of the brain
3) this is along the rostral migratory stream
4) towards the olfactory bulb
5) then integrate into olfactory circuitry
Explain the composition of the subventricular zone (4)
It is made up of:
-B cells – self-renewing neural stem cells (astroglial cells – GFAP+, Nestin+) (symmetric)
- C cells – transit amplifying neuroblasts (asymmetric)
- A cells – migrating neuroblasts to olfactory bulb
- order also is B -> C -> A
very tightly regulated with blood vessels => suggesting that some mediators of neurogenesis might gain access + modulate neurogenesis via the bloodstream
What happens when the neuroblasts complete migration to the olfactory bulb? (3)
They:
- switch to radial migration
- differentiate into interneurons
- and integrate into the existing OB circuitry
Explain the neural stem cells found in the dentate gyrus (3)
It is made up of:
- As (stem cell)
- D (progenitor)
- G (granule neuron)
the order is As -> D -> G
They don’t migrate BUT instead remain within the DG and integrate into the hippocampal circuitry
What is the purpose of adult neurogenesis? (3)
Unlike other stem cell populations, adult neurogenesis do not
appear to have a role in repairing damage, although the
possibility that they might be used for this purpose remains
OB neurogenesis is involved in olfactory learning (eg mouse)
DG neurogenesis is required for some forms of spatial
learning, especially where a temporal component is
involved. This is referred to as “pattern separation” and defects in DG neurogenesis might be involved in post-traumatic stress disorders
Explain the link between DG neurogenesis and exercise (2)
Exercise stimulates DG neurogenesis
seen in BrdU assays in which exercise increases the BrdU expression which acts as a marker for cell proliferation - interesting to see if this will have any benefits or not
Explain the pattern of DG neurogenesis overtime(3)
Neurogenesis decreases rapidly with age
- neurogenesis peaks very early in humans
- but it rapidly declines by the 10th of one’s lifespan (7-8yrs)
What is cytoprotective function prevents NSC depletion? (3)
-Increased quiescence with age protects adult NSCs from depletion
we don’t lose the stem cells with age but instead they become quiescent -> protects them from depletion
- Increased proliferation → NSC depletion if CHD7 is deleted
- also seen that CHD7 is important reg of quiescence -> supresses the cell cycle regulators needed for quiescence
Summary 1 (3)
Adult neurogenesis is functionally important and defects might underlie defective spatial memory and specific psychiatric conditions
The relevance to human brain function is heavily debated
Adult NSCs decline with age
How many types of adult stem cells are there that already regenerate + repair tissue? (1)
They are many types of adult stem cells but they display limited potency
eg
- haemopoietic system - bone marrow
- intestine -
- interfollicular epidermis - basal layer of epidermis
- hair follicle - bulge
Name 2 tissue types that have low or no turnover (2)
brain - subventricular zone + subgranular zone
skeletal muscle - b/w basement membrane + muscle fibres
Explain transplantation/clinical application of adult stem cells (3)
Some adult stem cells may be used for transplantation:
Skin cell transplantation: This can be for skin grafts as it may be useful to replace tissue
Bone marrow transplantation: Isolate bone marrow -> contains haematopoietic stem cells and they can be transplanted into the recipient
- recipient is irradiated = completely removes bone marrow = restores haematopoietic system
What are some alternative approaches to regeneration? (2)
Trans-differentiation (or de-differentiation) of other endogenous somatic cell types
In vitro cell differentiation and transplantation
explain the In vivo conversion parkinson’s eg (5+1)
a) mouse with PD
b) stereotaxic injection in striatum or in midbrain
c) induce astrocyte to neuron conversion
d) DAergic phenotype
e) functionality and motor recovery assessed
In vivo conversion of resident glia into neurons
Note: mechanisms still unclear: direct trans-differentiation or via dedifferentiation
Explain the ex vivo generation of cell types and transplantation debate (4)
Embryonic stem (ES) cells can give rise to multiple tissue cell types:
- ES cells may be used to generate specific cell types for transplantation into damaged tissue
- Non-autologous (immune rejection)
- Ethical concerns
How does one induce pluripotency: iPS cells (5)
by using Yamanaka factors = OKSM
1) adult fibroblast cell culture from adult skin biopsy
2) Add OKSM
3) reprogram cells
4) These create iPS cells
5) gives rise to all tissue types: Cardiomyocyte, adipocytes, dopaminergic neurons, neural cells, motoneurons, pancreatic b-cells, hematopoietic cells
iPSC debate (4 +1)
- Adult cells are reprogrammed into stem cells
- No ethical concern
- Can allow autologous transplantation (patient based therapy)
- Still in its infancy
- real eg: using the cells to replace eye tissue damaged by age-related macular degeneration (AMD) did not improve a
patient’s vision, but did halt disease progression
Explain iPSC-derived cortical organoids (5)
iPSC-derived cortical organoids can be implanted, and integrate into brain circuitry
a)hiPSC cell
b) cortical differentiation
c) hCO
d) Cortical transplantation
e) hCO in S1
(tested for mice whiskers successfuly = suggesting that we really have the ability to generate human neurons in culture that then has the ability to be transplanted into the brain, integrate into the normal circuitry and for all intensive purposes function appropriately)
Explain an eg of direct in vivo
reprogramming (2)
Yamanaka factors to rejuvenate mice
Transient expression of Yamnaka factors can rejuvenate the epigenome
Gill et al. Reik lab – found ageing clock (30-40% of DNAme changes) are re-set fairy early in reprogramming of fibroblasts with OKSM – transient reprogramming until maturation phase: initiation, maturation, stabilization
Transient/partial reprogramming (3)
Substantial resetting of DNAme epigenetic clock early during
reprogramming
-Horvath skin and blood clock -> the cells don’t fully reprogram + become pluripotent stem cells but their epigenome seems rejuvenated
-No induction of pluripotency markers in transiently reprogrammed cells, but significant reduction in transcriptional age
What is the link b/w OSK and vision? (3)
Restores vision in old mice
Restores transcriptional patterns
Normalises age-associated DNAme
Summary 2 (2)
Somatic cells can be reprogrammed to iPSCs which can then be used to differentiate into any cell type
Transient expression of Yamanaka factors in vivo can reprogramme the aged epigenome without full reprogramming
Explain how Spiny mouse are an emerging model system (2)
- Complete regeneration of tissues
- Spinal cord
