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Neural Stem Cells - interaction with the brain and prospects for cell replacement therapy for Stroke

Monni, Emanuela LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:51.
Abstract (Swedish)
Popular Abstract in Swedish

Stroke är ett akut neurologiskt tillstånd och den främsta anledningen till funktionsnedsättning hos vuxna. Det finns ingen behandling för effektiv återhämtning. Den vanligaste formen av stroke orsakas av att mellersta storhjärnsartären blockeras vilket gör att man förlorar hjärnceller, till exempel neuroner.

Neurala stamceller (NSCs) skulle kunna användas för att återställa hjärnfunktionen efter stroke. Vi har därför skapat en neural stamcellslinje av celler från striatum, en del av hjärnan, hos mänskliga foster och beskrivit dessa cellers potential in vitro och in vivo. De är mycket stabila när man odlar dem och bildar effektivt neuroner in vitro och in vivo om de transplanteras in i... (More)
Popular Abstract in Swedish

Stroke är ett akut neurologiskt tillstånd och den främsta anledningen till funktionsnedsättning hos vuxna. Det finns ingen behandling för effektiv återhämtning. Den vanligaste formen av stroke orsakas av att mellersta storhjärnsartären blockeras vilket gör att man förlorar hjärnceller, till exempel neuroner.

Neurala stamceller (NSCs) skulle kunna användas för att återställa hjärnfunktionen efter stroke. Vi har därför skapat en neural stamcellslinje av celler från striatum, en del av hjärnan, hos mänskliga foster och beskrivit dessa cellers potential in vitro och in vivo. De är mycket stabila när man odlar dem och bildar effektivt neuroner in vitro och in vivo om de transplanteras in i hjärnan på nyfödda råttor. För att skapa en fungerande NSC-baserad behandling spelar också andra faktorer, som antalet transplanterade celler och tidpunkten för transplantationen, en avgörande roll.

I denna avhandling har vi undersökt hur de olika stadierna av neurogenesen, nybildandet av neuroner, påverkas av att mänskliga NSCs transplanteras in i striatum efter en stroke. Vi upptäckte att NSCs som transplanteras som neurosfärer överlevde i ett strokeskadat striatum, migrerade från transplantationsstället och bildade neuroner. NSCs som transplanterades in 48 timmar efter en stroke överlevde bättre än NSCs som transplanterades sex veckor efter stroke. Senarelagd transplantation påverkade inte migrationens omfattning, bildandet av neuroner eller celldelningen i transplantationsstället. Intressant nog upptäckte vi att man inte kunde öka antalet överlevande celler eller antalet bildade neuroner genom att transplantera fler NSCs.

Vi ville också undersöka den miljö som de neurala stamcellerna transplanterats till. Vi upptäckte en ansenlig mängd aktiverade mikroglia, de naturliga immuncellerna i hjärnan, 48 timmar efter skadan i striatum. Antalet mikroglia var dock som störst efter en till sex veckor, vilket visar att en senarelagd transplantation eventuellt hade exponerat cellerna för en skadlig miljö.

Dessa resultat är av stor klinisk relevans då antalet transplanterade celler och den optimala tidpunkten för transplantation kommer att bli viktiga parametrar när NSC-transplantation ska testas på strokepatienter i kliniken.

I denna avhandling har vi också rapporterat förekomsten av fusion mellan neuroner och mikroglia in vitro och in vivo efter transplantation av NSCs till rått- och mushjärnor. Fusion kan vara intressant inom regenerativ medicin på grund av omprogrammeringen av cellkärnan, men kräver omfattande utredning innan den kan bli aktuell i kliniken. Vi upptäckte att mikroglia är en viktig del I fusionsprocessen, men det behövs ytterligare studier för att förstå dynamiken och den fysiologiska betydelsen av fenomenet. (Less)
Abstract
Stroke is an acute neurological condition and the leading cause of disability in adult humans. Treatments for efficient recovery are not available. The most common form of stroke results from the occlusion of the middle cerebral artery, which causes loss of brain parenchyma and many types of neurons as well as astrocytes and oligodendrocytes. Neural stem cells (NSCs) could potentially be used to develop novel therapies to restore loss of function after stroke.

We generated a NSC line derived as monolayer cultures from the human fetal striatum, termed NS, and described the in vitro and in vivo potential of these cells. The derived hNS are very stable during expansion and efficiently generate neurons in vitro and in vivo upon... (More)
Stroke is an acute neurological condition and the leading cause of disability in adult humans. Treatments for efficient recovery are not available. The most common form of stroke results from the occlusion of the middle cerebral artery, which causes loss of brain parenchyma and many types of neurons as well as astrocytes and oligodendrocytes. Neural stem cells (NSCs) could potentially be used to develop novel therapies to restore loss of function after stroke.

We generated a NSC line derived as monolayer cultures from the human fetal striatum, termed NS, and described the in vitro and in vivo potential of these cells. The derived hNS are very stable during expansion and efficiently generate neurons in vitro and in vivo upon transplantation into the rat neonatal brain.

In order to establish successful NSCs-based therapies, factors such as the number of cells and the appropriate time of transplantation play an important role. We found that when transplantation of NSCs into the stroke-damaged striatum was performed at 48 hours after stroke, it resulted in better cell survival than did transplantation at 6 weeks. Increasing the number of grafted NSCs beyond a certain number did not result in a greater number of surviving cells or increased neuronal differentiation. Transplantation at 48 hours exposed the cells to a less hostile environment compared to 6 weeks following stroke.

In the present thesis we reported that ES-derived NS cells fuse with microglia and cortical neurons both in vitro and in vivo. We found that microglia, the resident immune cells of the brain are important players in the fusion process. However further investigation is needed to understand the dynamics and the physiological relevance of this phenomenon.

In summary, we have reported here previously undescribed characteristics of NS cells, which are relevant to better understanding of NSCs and their interaction with the brain environment after transplantation. Fusion could be of potential interest in the regenerative medicine due to the nuclear reprogramming implications but needs extensive investigation before it can be considered in the clinical setting. A relevant aspect of the cell-based therapy approach is that it could extend the therapeutic time window of intervention for ischemic stroke, which is now limited, thus benefiting a larger number of stroke-patients. Therefore, the findings described in this thesis have direct clinical implications. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Pekna, Marcela, Laboratory of Regenerative Immunology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Neural stem cells, human, fetus, cortex, striatum, stroke, transplantation, inflammation, fusion, reprogramming, chimera, heterokaryon
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:51
pages
88 pages
publisher
Neural stem cell biology and therapy
defense location
Segerfalksalen, BMC A10, Wallenberg Neurocentrum, Sölvegatan 17 Lund
defense date
2015-05-21 09:15
ISSN
1652-8220
ISBN
978-91-7619-130-9
language
English
LU publication?
yes
id
3e082d13-6333-419b-b3dc-192d82fa7155 (old id 5366179)
date added to LUP
2015-05-08 12:36:54
date last changed
2016-09-19 08:44:51
@phdthesis{3e082d13-6333-419b-b3dc-192d82fa7155,
  abstract     = {Stroke is an acute neurological condition and the leading cause of disability in adult humans. Treatments for efficient recovery are not available. The most common form of stroke results from the occlusion of the middle cerebral artery, which causes loss of brain parenchyma and many types of neurons as well as astrocytes and oligodendrocytes. Neural stem cells (NSCs) could potentially be used to develop novel therapies to restore loss of function after stroke.<br/><br>
We generated a NSC line derived as monolayer cultures from the human fetal striatum, termed NS, and described the in vitro and in vivo potential of these cells. The derived hNS are very stable during expansion and efficiently generate neurons in vitro and in vivo upon transplantation into the rat neonatal brain.<br/><br>
In order to establish successful NSCs-based therapies, factors such as the number of cells and the appropriate time of transplantation play an important role. We found that when transplantation of NSCs into the stroke-damaged striatum was performed at 48 hours after stroke, it resulted in better cell survival than did transplantation at 6 weeks. Increasing the number of grafted NSCs beyond a certain number did not result in a greater number of surviving cells or increased neuronal differentiation. Transplantation at 48 hours exposed the cells to a less hostile environment compared to 6 weeks following stroke.<br/><br>
In the present thesis we reported that ES-derived NS cells fuse with microglia and cortical neurons both in vitro and in vivo. We found that microglia, the resident immune cells of the brain are important players in the fusion process. However further investigation is needed to understand the dynamics and the physiological relevance of this phenomenon.<br/><br>
In summary, we have reported here previously undescribed characteristics of NS cells, which are relevant to better understanding of NSCs and their interaction with the brain environment after transplantation. Fusion could be of potential interest in the regenerative medicine due to the nuclear reprogramming implications but needs extensive investigation before it can be considered in the clinical setting. A relevant aspect of the cell-based therapy approach is that it could extend the therapeutic time window of intervention for ischemic stroke, which is now limited, thus benefiting a larger number of stroke-patients. Therefore, the findings described in this thesis have direct clinical implications.},
  author       = {Monni, Emanuela},
  isbn         = {978-91-7619-130-9},
  issn         = {1652-8220},
  keyword      = {Neural stem cells,human,fetus,cortex,striatum,stroke,transplantation,inflammation,fusion,reprogramming,chimera,heterokaryon},
  language     = {eng},
  pages        = {88},
  publisher    = {Neural stem cell biology and therapy},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Neural Stem Cells - interaction with the brain and prospects for cell replacement therapy for Stroke},
  volume       = {2015:51},
  year         = {2015},
}