Year: 2012
Type: dissertation
Abstract: Neural stem/progenitor cells (NPC) can be used for therapeutic purposes in several ways.Cultured NPCs offer a unique cell source to study the neural mechanisms in normal situations as well as in the pathogenesis of genetic diseases.In neurodegenerative disorders, potential therapies to recover the damaged neurons are NPC transplantation or activation of a patient's own NPCs.However, the mechanisms of NPC differentiation are still poorly known and before any clinical use, it is of utmost importantance to know how the differentiation of NPCs is regulated.These four studies provide new information about the differentiation of NPCs.Fragile X syndrome (FXS) is caused by the defiency of fragile X mental retardation protein (FMRP).We investigated how FMRP deficiency affects the differentiation of NPCs.We show that FMRP deficiency directs the NPC differentiation into neuronal phenotypes, but developing neurons have fewer and shorter neurites and smaller body volume.Furthermore, FMRP deficient NPCs have increased occurrence of intense oscillatory Ca 2+ responses to neurotransmitters (NT) compared to controls.In the second study, we used Ca 2+ imaging techniques to monitor the neurotransmitter responsiveness in an early state of NPC differentiation.We found that during the early stage of differentiation, cells responded to various NTs and could be distinguished based on their NT responses.During development, cells progressively lose their metabotropic responses and gain ionotropic responses while they simultaneously develop into neuronal cells.Next, we studied the effect of Alzheimer's disease (AD) -linked mutation and environment on NPC differentiation.We treated NPCs with synthetic amyloid-(A ) in vitro and also transplanted NPCs into AD-linked mutant mouse brain.We show that both AD-linked mutation in NPCs and AD-brain environment have effects on NPC differentiation.Transplanted NPCs survived and migrated better when transplanted into AD mouse brain.In addition, transplanted NPCs stimulated brain neurogenesis even in highly A -burdened brain.Oxidative stress (OS) is one of main characteristics in AD brain.Activation of a transcription factor nuclear factor erythroid 2-related factor (Nrf2) during the OS leads to activation of cellular defense mechanisms.We also show that the activation of Nrf2 protects NPCs against A -induced toxicity by enhancing their survival, proliferation and neuronal differentiation.Furthermore, we discovered another important function for Nrf2: the ability to regulate injury-induced neurogenesis.
Author: Virve Kärkkäinen
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2186320079