Stem Cell Plasticity Controlling Neuronal Differentiation Prior to Cell Transplantation

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease and affects 2% of the population over 65 years of age. The disease is characterized by the progressive loss of dopaminergic neurons. Over time, symptoms increase and, in particular, lead to a dramatic slowness of movements. Unfortunately, when the fi rst symptoms are discovered, more than 50% of the dopaminergic neurons are already dead. Until now, endogenous neural precursors, derived from the patients? own brains, have not been found proliferate and differentiate into to dopamine neurons that can reverse the symptoms of the disease. Therefore it is necessary to transplant neurons in order to replace those lost due to the disease. The fi rst benefi cial effect of cell therapy in PD patients grafted with fetal nigral tissue was reported in 1990. To date, around 400 patients have been transplanted worldwide. However, due to post-surgery complications, lack of donor tissue and unpredictable variability in the outcome of the surgery, clinical trials were stopped in the late 90ies (Bjorklund et al., 2003). In the early 90?s, the concept of neural stem cells as source of cells for cell replacement therapies emerged. The culture of single neural stem cells, in vitro, could lead to the formation of an entire neural lineage (Reynolds and Weiss, 1992; Reynolds and Weiss, 1996). Rapidly, researchers investigated the potential of such cells to be used as cell replacement therapy for neurological disorders. Thus, all types of stem cells, including neural stem cells, embryonic stem cells and later bone marrow stem cells were subjected to extensive experimental work aiming to generate specifi ed neuronal subtypes for transplantation purposes. Most of the work was dedicated to the generation of dopaminergic neurons. The studies we have performed for this thesis aimed at improving and understanding differentiation of these different types of stem cells into neurons, especially dopaminergic neurons. Using different protocols we assessed the potential of the hematopoietic stem cells, which are non-neuronal committed stem cells, to cross lineage boundaries and transdifferentiate into neural cells. We investigated whether gene overexpression could override the intrinsic programs of regionalized and specifi ed neural stem cells and redirect their differentiation toward a dopaminergic fate. The studies we performed indicate that lineage commitment and regional identity are barriers to stem cell plasticity. We fi nally assessed the differentiation potential of human pluripotent embryonic stem cells and found that time-dependant predifferentiation is required for safe transplantation of human embryonic stem cells-derived cells into the brain. In general, we concluded that the current methods for generating midbrain dopaminergic neurons from hematopoietic, neural and embryonic stem cells are diffi cult and need further improvements to make these stem cells good candidates of cells to be successfully used in restorative therapy for neurodegenerative diseases. However, we present promising results for the future use of embryonic stem cells (ESC) for transplantation in neurodegenerative diseases. We speculate that ESC may become the most promising stem cells to be used in the future for neural replacement due to their unlimited capacity of differentiation.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Li, Jia-Yi, Supervisor
Award date2006 Sep 22
Publisher
Print ISBNs91-85559-29-6
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-09-22
Time: 09:15
Place: Grubbsalen, BMC, Lunds universitet, Lund

External reviewer(s)

Name: Ericson, Johan
Title: professor
Affiliation: Department of cell and molecular biology, Karolinska Institute, Stockholm, Sweden

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<div class="article_info">L Roybon, Z Ma, F Asztely, A Fosum, SE Jacobsesn, P Brundin and JY Li. <span class="article_issue_date">2006</span>. <span class="article_title">Failure of transdifferentiation of adult hematopoietic stem cells into neurons.</span> <span class="journal_series_title">Stem Cells</span>, <span class="journal_volume">vol 24</span> <span class="journal_pages">pp 1594-1604</span>.</div>
<div class="article_info">L Roybon, P Brundin and JY Li. <span class="article_issue_date">2005</span>. <span class="article_title">Stromal cell-derived inducing activity does not promote dopaminergic differentiation, but enhances differentiation and proliferation of neural stem cell-derived astrocytes.</span> <span class="journal_series_title">Experimental Neurology</span>, <span class="journal_volume">vol 196</span> <span class="journal_pages">pp 373-80</span>.</div>
<div class="article_info">L Roybon, T Hjalt, JY Li and P Brundin. <span class="article_issue_date"></span>. <span class="article_title">Retroviral-mediated transgene delivery of Neurogenin2, Pitx3, Lmx1a or Msx1 does not affect dopaminergic differentiation of mesencephalic committed rat embryonic neuronal precursors.</span> (submitted)</div>
<div class="article_info">L Roybon, T Hjalt, S Stott, D Ribeiro, P Brundin and JY Li. <span class="article_issue_date"></span>. <span class="article_title">Ectopic expression of Neurogenin2 terminates GABAergic phenotype and alters cell migration and cell fate of adult ganglionic eminence-derived neural progenitors.</span> (submitted)</div>
<div class="article_info">A Brederlau, AS Correia, SV Anisimov, M Elmi, G Paul, L Roybon, Anna Morizane, F Bergquist, I Riebe, U Nannmark, M Carta, E Hanse, J Takahashi, Y Sasai, K Funa, P Brundin, PS Eriksson and JY Li. <span class="article_issue_date">2006</span>. <span class="article_title">Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson's disease: effect of in vitro differentiation on graft survival and teratoma formation.</span> <span class="journal_series_title">Stem Cells</span>, <span class="journal_volume">vol 24</span> <span class="journal_pages">pp 1433-1440</span>.</div>

Subject classification (UKÄ)

  • Basic Medicine

Keywords

  • Differentiation
  • Stem cells
  • Immunology
  • serology
  • Immunologi
  • serologi
  • transplantation

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