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Adult Neural Stem Cells-Influence of Stroke, Inflammation and Aging

Ahlenius, Henrik LU (2009) In Lund University, Faculty of Medicine Doctoral Dissertations 2009:66.
Abstract
Neural stem cells (NSCs) in the embryo generate neurons, astrocytes and oligodendrocytes, the principal cells of the central nervous system (CNS), which contribute to the full diversity of the brain. Some NSCs persist in the adult brain and ensures neurogenesis throughout adult life in the subventricular zone (SVZ) and the subgranular zone (SGZ). NSCs in the SGZ generates neurons in the granule cell layer and NSCs in the SVZ generates neuroblasts that migrate trough the rostral migratory stream into the olfactory bulb where they develop into mature neurons. Neurogenesis in the adult brain continues into old age although with reduced capacity.

Neurogenesis in SVZ increases after insults to the brain such as stroke and status... (More)
Neural stem cells (NSCs) in the embryo generate neurons, astrocytes and oligodendrocytes, the principal cells of the central nervous system (CNS), which contribute to the full diversity of the brain. Some NSCs persist in the adult brain and ensures neurogenesis throughout adult life in the subventricular zone (SVZ) and the subgranular zone (SGZ). NSCs in the SGZ generates neurons in the granule cell layer and NSCs in the SVZ generates neuroblasts that migrate trough the rostral migratory stream into the olfactory bulb where they develop into mature neurons. Neurogenesis in the adult brain continues into old age although with reduced capacity.

Neurogenesis in SVZ increases after insults to the brain such as stroke and status epilepticus (SE). After stroke proliferation of NSCs increase and newly formed neurons migrate towards the damage where they mature into the same type of neurons that died as a result of the insult. This self-repair mechanism could potentially be of therapeutic value. However, existing neurogenesis as basis for functional recovery after stroke is most likely not sufficient. Therefore, it is extremely important to study regulation of basal and insult induced neurogenesis in order to find ways of optimizing the potential of endogenous NSCs for repair of neurodegenerative disease.

In this thesis we have addressed the regulation of adult NSCs and neurogenesis in response to aging, inflammation and stroke using in vivo and in vitro models as well as gene expression analysis.

In the first study we explored the influence of aging on intrinsic properties of NSCs and their progeny. We found severely decreased neurogenesis in old mice due to reduced proliferation and loss of NSCs in SVZ. However, when we cultured aged NSC in vitro they could proliferate, differentiate along all three lineages and produce functional neurons similar to their adult counterparts albeit with reduced capacity.

In the second study, we investigated the role of inflammation on stroke-induced neurogenesis. More specifically we identified tumor necrosis factor receptor 1 (TNF-R1) as a negative regulator of Stroke-induced NSC proliferation in SVZ. We found increased expression of TNF-α and TNF-R1 in SVZ after stroke. Furthermore we demonstrated a direct negative effect of TNF-α through TNF-R1 on proliferation of NSCs in vitro.

In the third study, we identified the adaptor protein Lnk as an insult specific negative regulator of NSC proliferation. Possibly acting by inhibiting growth factor and cytokine signaling. Deletion of Lnk increased the enhanced proliferation in SVZ after stroke but not under basal condition or after SE. We found increased expression of Lnk and growth factors in SVZ after stroke but decreased expression after SE. Furthermore elevated levels of Lnk decreased proliferation and survival while deletion of Lnk increased the proliferation of NSCs in vitro.

In summary, we have obtained evidence supporting that brain-repair from endogenous NSCs can work in old age. Furthermore, we have identified two potential therapeutic targets for enhancing neurogenesis after stroke. (Less)
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author
supervisor
opponent
  • PhD, Associate Professor Peterson, Daniel, A, Dept. of Neuroscience, Center for Stem Cell and Regenerative Mediciene,Rosalind Franklin University of Medicine and Science,Chicago, IL, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
inflammation, Neural stem cells, adult, neurogenesis, stroke, aging, TNF-R1, TNF-α
in
Lund University, Faculty of Medicine Doctoral Dissertations
volume
2009:66
pages
139 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Segerfalksalen, Wallenberg Neurocenter
defense date
2009-06-13 10:00
ISSN
1652-8220
ISBN
978-91-86253-54-7
language
English
LU publication?
yes
id
20001321-9f19-4fb5-a339-7b3dc6d5c72f (old id 1396739)
date added to LUP
2009-05-20 11:37:20
date last changed
2016-09-19 08:44:51
@phdthesis{20001321-9f19-4fb5-a339-7b3dc6d5c72f,
  abstract     = {Neural stem cells (NSCs) in the embryo generate neurons, astrocytes and oligodendrocytes, the principal cells of the central nervous system (CNS), which contribute to the full diversity of the brain. Some NSCs persist in the adult brain and ensures neurogenesis throughout adult life in the subventricular zone (SVZ) and the subgranular zone (SGZ). NSCs in the SGZ generates neurons in the granule cell layer and NSCs in the SVZ generates neuroblasts that migrate trough the rostral migratory stream into the olfactory bulb where they develop into mature neurons. Neurogenesis in the adult brain continues into old age although with reduced capacity.<br/><br>
Neurogenesis in SVZ increases after insults to the brain such as stroke and status epilepticus (SE). After stroke proliferation of NSCs increase and newly formed neurons migrate towards the damage where they mature into the same type of neurons that died as a result of the insult. This self-repair mechanism could potentially be of therapeutic value. However, existing neurogenesis as basis for functional recovery after stroke is most likely not sufficient. Therefore, it is extremely important to study regulation of basal and insult induced neurogenesis in order to find ways of optimizing the potential of endogenous NSCs for repair of neurodegenerative disease.<br/><br>
In this thesis we have addressed the regulation of adult NSCs and neurogenesis in response to aging, inflammation and stroke using in vivo and in vitro models as well as gene expression analysis.<br/><br>
In the first study we explored the influence of aging on intrinsic properties of NSCs and their progeny. We found severely decreased neurogenesis in old mice due to reduced proliferation and loss of NSCs in SVZ. However, when we cultured aged NSC in vitro they could proliferate, differentiate along all three lineages and produce functional neurons similar to their adult counterparts albeit with reduced capacity.<br/><br>
In the second study, we investigated the role of inflammation on stroke-induced neurogenesis. More specifically we identified tumor necrosis factor receptor 1 (TNF-R1) as a negative regulator of Stroke-induced NSC proliferation in SVZ. We found increased expression of TNF-α and TNF-R1 in SVZ after stroke. Furthermore we demonstrated a direct negative effect of TNF-α through TNF-R1 on proliferation of NSCs in vitro.<br/><br>
In the third study, we identified the adaptor protein Lnk as an insult specific negative regulator of NSC proliferation. Possibly acting by inhibiting growth factor and cytokine signaling. Deletion of Lnk increased the enhanced proliferation in SVZ after stroke but not under basal condition or after SE. We found increased expression of Lnk and growth factors in SVZ after stroke but decreased expression after SE. Furthermore elevated levels of Lnk decreased proliferation and survival while deletion of Lnk increased the proliferation of NSCs in vitro.<br/><br>
In summary, we have obtained evidence supporting that brain-repair from endogenous NSCs can work in old age. Furthermore, we have identified two potential therapeutic targets for enhancing neurogenesis after stroke.},
  author       = {Ahlenius, Henrik},
  isbn         = {978-91-86253-54-7},
  issn         = {1652-8220},
  keyword      = {inflammation,Neural stem cells,adult,neurogenesis,stroke,aging,TNF-R1,TNF-α},
  language     = {eng},
  pages        = {139},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertations},
  title        = {Adult Neural Stem Cells-Influence of Stroke, Inflammation and Aging},
  volume       = {2009:66},
  year         = {2009},
}