Generation of cells for cell-replacement therapy: Specification of neural precursors in vivo and in neural stem cell cultures
type: CreativeWork
description: Cell replacement therapy of neurodegenerative disorders aims to substitute the degenerating cells with new functional neurons. Clinical trails with patients suffering from Parkinson’s or Huntington’s disease have generated proof-of-principle results that neural precursors taken from the developing human brain can survive upon grafting to the diseased brain and provide long-lasting symptomatic relief. However, further development of this type of therapy critically depends on the generation of an unlimited and standardized source of neural precursors that after transplantation differentiate into the proper neuronal subtypes. This requires knowledge on the molecular mechanisms responsible for the specification of neurons during development, and how cells with the potential for regional specific neuronal differentiation can be expanded in culture. The work of this thesis has focused on the role of the proneural gene Neurogenin2 in specification of the midbrain dopaminergic (mesDA) neurons, the cell population that degenerate in Parkinson’s disease. Additionally, we have studied to what extent neural stem cells isolated from the developing brain and expanded under growth-factor stimulation in culture maintain their regional specification. We show that Neurogenin2 is required in vivo for proper development of the mesDA neuron system, more specifically for the immature mesDA neuron precursors to adopt a neuronal fate. Furthermore, we successfully applied a new culture system for expansion of neural stem cells, the neural stem cell (NS cell) cultures, to neural precursors from different regions of the developing brain. We showed that even after extensive expansion cells in the NS cell cultures retain their capacity to form neurons. Furthermore, the expanded cells harbor regional differences in their growth properties and to some extend in their gene expression profile. This show that the NS cell culture is an attractive alternative to the traditionally and more commonly use…
abstract: Cell replacement therapy of neurodegenerative disorders aims to substitute the degenerating cells with new functional neurons. Clinical trails with patients suffering from Parkinson’s or Huntington’s disease have generated proof-of-principle results that neural precursors taken from the developing human brain can survive upon grafting to the diseased brain and provide long-lasting symptomatic relief. However, further development of this type of therapy critically depends on the generation of an unlimited and standardized source of neural precursors that after transplantation differentiate into the proper neuronal subtypes. This requires knowledge on the molecular mechanisms responsible for the specification of neurons during development, and how cells with the potential for regional specific neuronal differentiation can be expanded in culture. The work of this thesis has focused on the role of the proneural gene Neurogenin2 in specification of the midbrain dopaminergic (mesDA) neurons, the cell population that degenerate in Parkinson’s disease. Additionally, we have studied to what extent neural stem cells isolated from the developing brain and expanded under growth-factor stimulation in culture maintain their regional specification. We show that Neurogenin2 is required in vivo for proper development of the mesDA neuron system, more specifically for the immature mesDA neuron precursors to adopt a neuronal fate. Furthermore, we successfully applied a new culture system for expansion of neural stem cells, the neural stem cell (NS cell) cultures, to neural precursors from different regions of the developing brain. We showed that even after extensive expansion cells in the NS cell cultures retain their capacity to form neurons. Furthermore, the expanded cells harbor regional differences in their growth properties and to some extend in their gene expression profile. This show that the NS cell culture is an attractive alternative to the traditionally and more commonly use…
author: Hebsgaard, Josephine
language: eng
keywords: Neurosciences, Neurospheres, Dopaminergic neurons, Parkinson's disease, Neurogenin2
date published: 2008
date modified: 2026-07-24T03:00:02Z
provider: University of Lund
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Josephine Hebsgaard