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

Research output: ThesisDoctoral Thesis (compilation)

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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 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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Neurology, Lund
Supervisors/Advisors
  • Kokaia, Zaal, Supervisor
  • Lindvall, Olle, Supervisor
Award date2015 May 21
Publisher
ISBN (Print)978-91-7619-130-9
Publication statusPublished - 2015

Bibliographical note

Defence details

Date: 2015-05-21
Time: 09:15
Place: Segerfalksalen, BMC A10, Wallenberg Neurocentrum, Sölvegatan 17 Lund

External reviewer(s)

Name: Pekna, Marcela
Title: Associate Professor
Affiliation: Laboratory of Regenerative Immunology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

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Subject classification (UKÄ)

  • Neurology

Free keywords

  • Neural stem cells
  • human
  • fetus
  • cortex
  • striatum
  • stroke
  • transplantation
  • inflammation
  • fusion
  • reprogramming
  • chimera
  • heterokaryon

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