Week 7 Flashcards
(46 cards)
What must stem cells do?
Be proliferative
Self-renew (not necessarily indefinitely)
Undergo differentiation into multiple cell types
What must adult CNS stem cells do?
must make neurones, astrocytes, and oligodendrocytes
Where are stem cells in the rodent brain?
Subventricular zone of lateral ventricle of forebrain
Subgranular zone (SGZ) of the hippocampal dentate gyrus
These become granule cells in the dendate gyrus
What do stem cells in the rodent brain produce?
Precursors that migrate into olfactory bulb via rostral migratory stream (RMS)
Produce interneurons
What do the stem cells in the subgranular zone of the hippocampal dentate gyrus become in the rodent brain?
These become granule cells in the dendate gyrus
Where are the stem cells in the human brain?
SVZ of the lateral ventricle
Controversial if there is an RMS
Arguments whether there is neurogenesis in adult human olfactory bulb as we don’t use it as much as rodents!
Some evidence that instead these cells end up as interneurons in the stratum
Some evidence that the hippocampus/dendate gyrus also has stem cells, in the subgranular zone (SGZ)
Lots of cell proliferation in this region
What is some experimental evidence that CNS stem cells act as stem cells in adult rodents?
- Triated thymidine incorporation shows proliferation in SVZ+SGZ
- BrdU given to adults. Antibody labelling indicates that cells that label (which must have divided in adults) also express neuronal or glial differentiation markers
- Cell number in the adult dendate gyrus increase with exercise and learning and decrease with stress
- Cell culture of neurospheres show stem cell features (mainly SVZ, some arguments rage about SGZ)
What are markers of neuroepithelial stem cells?
Nestin
Sox2
Do CNS stem cells produce neurons in the human?
Radioactive isotopes (C14) incorporate into DNA. Those born at thetime of nuclear testing (1950s/60s) should have high levels in “old” neurons and then much lower levels in newer neurons (like a “birth date stamp”).
Suggests that 700 hippocampal neurons are born each day in adulthood!
Nobody can agree if this technique supports or refutes adult neurogenesis!
Olfactory Bulb - no evidence from C14 to suggest there are new neurons here (but do humans use this much and do they need new neurons here?).
However C14 dating points to different ages in adult striatal interneurons (derived from SVZ).
BrdU like compounds are used in cancer diagnosis. PM tissue analysis indicates cell division in differentiated striatal and dendate gyrus neurons
In vitro analysis indicates there are self renewing multipotent cells in the SVZ and hippocampus region (neurospheres)
Can adult CNS neurons be therapeutic?
Many different contexts to consider
Would it be useful to increase the endogenous production of neurons in the striatum and/or the hippocampus/dendate gyrus in the absence of disease?
These areas are associated with movement control, learning and memory. The target for ‘SMART’ drug therapies that could help memory loss in old age
Do endogenous adult stem cells contribute to the repair of the brain after damage such as in ischameic stroke?
In induced rodent models of stroke, cells from SVZ (labelled with GFP using various transgenic mice) migrate into damaged areas at quite a distance and differentiate into neurons. Did not fully repair the damage
Thought that they are not as effective in repair in humans
Work ongoing to see if drugs can enhance the function of these cells in vivo after stroke
What are the problems with using endogenous stem cells?
Can they be reliably reactivated?
Are there different responses in different people/animals to reactivation?
Can they repair a large number of neurons in a wide number of brain regions or only a select few along a specific lineage?
Can brain derived stem cells be harvested for use?
Mainly taken from foetuses rather than adults
Clinical trials are using these for various diseases inclusing ALS and AMD
Generally safe if partially differentiated before use
Tumours did form in one case when not partially differentiated
What do you know about putting non-endogenous stem cells into the brain?
Embryonic stem cells - currently in clinical trials for AMD
IPSCs - these are reprogrammed adult somatic cells that think they are embryonic stem cells
Significant advantage is you can derive them from own tissue (such as skin)
Recently been shown to incorporate and function in primate model of parkinsons disease without rejection
Summarise the key points of brain stem cells:
The adult brain contains stem cells that have remained from embryonic stages
They do appear to have a role in normal physiological brain processes
In damage or disease, they may make a small contribution to repair
It will be difficult to reliably activate them to function better in repair
Other stem cells therapies may prove more useful, particularly in the short term
What do we know about neuronal injury and repair?
Repair of neuronal injury is very often limited and does not always result in re-establishment of function
What do we know about neurogenesis?
Adult neurogenesis is possible but that it is limited to specific regions of the nervous system
In mammals it is the olfactory bulb and hippocampus
What stem cells are in the ventricular-subventricular zone contains stem cells?
Astroglial cells
Activated astroglial cells
Transit amplifying cells
Migrating neuroblasts
What do the cells from different regions of the V-SV zone give rise to?
Different populations of olfactory bulb cells
Is it just that not all regions of the nervous system contain stem cells and this limits neurogenesis?
Not true. Many regions of the nervous system contain stem cells, including parts that do not repair well e.g. spinal cord
So what are the factors that determine whether nervous tissue will repair or not?
What can stem cells from many neurogenic tissues do?
Can be activated and differentiated in vitro
The environment, or cell niche, the stem cell resides in therefore instructs the cell on how to behave
What factors may limit neuronal regeneration?
Do we have neuronal cells?
Are the neuronal cells behaving appropriately (axonal extension/pathfinding)
Are some neuronal tissues better at regenerating?
YES!
Some neuronal tissues are better
e.g. the peripheral nervous system regenerates better than the central nervous system
Why does the peripheral nervous system regenerate better than the central nervous system?
The Schwann cells dedifferentiate and then produce appropriate extracellular matrix
Fibronectin, Laminin, Tenascin, and some proteoglycans and trophic factors
NGF, BDNF, NT4, GDNF and IGF-1
What are the 2 Schwann Cell phenotypes?
Mature Phenotype
- Myelinating or non-myelinating
Reactive phenotype:
- Immature/reactive
