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Stem Cell Plasticity Controlling Neuronal Differentiation Prior to Cell Transplantation

Roybon, Laurent LU (2006) In Doctoral dissertation series 2006:105.
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... (More)
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. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Parkinsons sjukdom är den näst mest vanliga neurodegenerativa sjukdomen och den drabbar 2% av befolkningen över 65 år. Sjukdomen kännetecknas av en gradvis ökad förlust av dopaminproducerande nervceller. Symtomen tilltar successivt och leder framförallt till allvarliga fördröjningar i rörelsemönstret. Dessvärre, när de första symptomen väl upptäcks, så har redan 50% av de dopaminproducerande nervcellerna dött och hittills så har man inte kunnat påvisa att stamceller i patienternas egna hjärnor skulle kunna motverka händelseförloppet. 1990 rapporterades det för första gången att transplantat av celler från substantia nigra-området (en del av hjärnan) i ett foster kan minska symtomen hos patienter... (More)
Popular Abstract in Swedish

Parkinsons sjukdom är den näst mest vanliga neurodegenerativa sjukdomen och den drabbar 2% av befolkningen över 65 år. Sjukdomen kännetecknas av en gradvis ökad förlust av dopaminproducerande nervceller. Symtomen tilltar successivt och leder framförallt till allvarliga fördröjningar i rörelsemönstret. Dessvärre, när de första symptomen väl upptäcks, så har redan 50% av de dopaminproducerande nervcellerna dött och hittills så har man inte kunnat påvisa att stamceller i patienternas egna hjärnor skulle kunna motverka händelseförloppet. 1990 rapporterades det för första gången att transplantat av celler från substantia nigra-området (en del av hjärnan) i ett foster kan minska symtomen hos patienter med Parkinsons sjukdom. Idag har ca 400 patienter genomgått transplantationer världen över. På grund av komplikationer efter transplantationerna, samt en brist på vävnad och osäkerheten på utfallet av operationerna, så avbröts de kliniska prövningarna i slutet av 90-talet. I början av 90-talet växte idén fram att man kunde använda stamceller från nervsystemet (neurala stamceller) inom cellterapin. Genom att experimentellt odla en enda neural stamcell, skulle denna i sin tur kunna generera alla typer av nervceller. Omedelbart undersökte forskare de olika möjligheterna att använda stamceller för cellterapi inom neurodegenerativa sjukdomar. Således, påbörjades omfattande experiment på alla typer av stamceller, inkluderande neurala stamceller, embryonala stamceller och något senare även stamceller från benmärgen, med syftet att få fram dopaminproducerande nervceller. De studier som vi har utfört i denna avhandling avsåg att förbättra och öka förståelsen för utvecklingen av dessa olika typer av stamceller till nervceller, mer specifikt dopaminproducerande nervceller. Genom att använda olika metoder, undersökte vi möjligheten att blodbildande stamceller, som normalt inte bildar nervceller, skulle kunna frångå sina egenskaper och istället utvecklas till nervceller. Vi undersökte även om man genom genteknik kan ändra de program som finns i omogna nervcellers arvsmassa, och som normalt styrs av vilken hjärnregion de tillhör. På så sätt hoppades vi få cellerna att ändra sin funktion och bli dopaminproducerade nervceller ? den celltyp som dör vid Parkinsons sjukdom. Vi kunde påvisa genom våra studier att (1) blodbildande stamceller inte kan bilda nervceller, (2) neurala stamceller kan inte ändras och skapa andra typer av celler och (3) embryonala stamceller måste differentieras (omvandlas) innan man transplanterar dem i hjärnan för att minska symtomen vid Parkinsons sjukdom. Sammanfattningsvis, kunde vi dra slutsatsen att de metoder som används idag för att generera dopaminproducerande celler från stamceller, är komplicerade. Det kommer att krävas fortsatta förbättringar för att i framtiden kunna använda stamceller framgångsrikt inom restorativ terapi för neurodegenerativa sjukdomar. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Ericson, Johan, Department of cell and molecular biology, Karolinska Institute, Stockholm, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Differentiation, Stem cells, Immunology, serology, Immunologi, serologi, transplantation
in
Doctoral dissertation series
volume
2006:105
pages
164 pages
publisher
Department of Experimental Medical Science, Lund Univeristy
defense location
Grubbsalen, BMC, Lunds universitet, Lund
defense date
2006-09-22 09:15:00
ISSN
1652-8220
ISBN
91-85559-29-6
language
English
LU publication?
yes
additional info
id
ec9b8ec2-579e-4876-a3b3-f5e03a7ac89b (old id 547209)
date added to LUP
2016-04-01 16:38:03
date last changed
2019-05-21 13:15:46
@phdthesis{ec9b8ec2-579e-4876-a3b3-f5e03a7ac89b,
  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.},
  author       = {Roybon, Laurent},
  isbn         = {91-85559-29-6},
  issn         = {1652-8220},
  language     = {eng},
  publisher    = {Department of Experimental Medical Science, Lund Univeristy},
  school       = {Lund University},
  series       = {Doctoral dissertation series},
  title        = {Stem Cell Plasticity Controlling Neuronal Differentiation Prior to Cell Transplantation},
  volume       = {2006:105},
  year         = {2006},
}