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Neural Stem Cell Differentiation and Migration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neural stem cells are the precursors of neurons, astrocytes and oligodendrocytes. During neural development, the division of stem cells takes place close to the lumen of the neural tube, after which they migrate to their final positions within the central nervous system (CNS). Soluble factors, including growth factors, regulate neural stem cell proliferation, survival, migration and differentiation towards specific cell lineages.

This thesis describes the function of platelet-derived growth factor (PDGF) and stem cell factor (SCF) in neural stem cell regulation. PDGF was previously suggested to stimulate neuronal differentiation, but the mechanisms were not defined. This study shows that PDGF is a mitogen and a survival factor that expands a pool of immature cells from neural stem cells. The PDGF-treated cells can be stained by neuronal markers, but need further stimuli to continue their maturation. They can become either neurons or glia depending on the secondary instructive cues. Moreover, neural stem cells produce PDGF. Inhibition of this endogenous PDGF negatively affects the cell number in stem cell cultures. We find that SCF stimulates migration and supports the survival of neural stem cells, but that it has no effect on their proliferation or differentiation into neurons and glia. Intracellular signaling downstream from the receptors for PDGF and SCF includes activation of extracellular signal-regulated kinase (ERK). This investigation shows that active ERK is not needed for the differentiation of stem cells into neurons, at least not during early stages.

Neural stem cells have a future potential in the treatment of CNS disorders. To be able to use neural stem cells clinically we need to understand how their proliferation, differentiation, survival and migration are controlled. The results presented in this thesis increase our knowledge of how neural stem cells are regulated by growth factors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 73
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1281
Keywords [en]
Medicine, CNS, stem cells, neuron, PDGF, SCF, differentiation, migration, ERK
Keywords [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Research subject
Medical Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-3546ISBN: 91-554-5714-2 (print)OAI: oai:DiVA.org:uu-3546DiVA, id: diva2:163224
Public defence
2003-10-03, B21, BMC, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2016-04-29Bibliographically approved
List of papers
1. Immature neurons from CNS stem cells proliferate in response toplatelet-derived growth factor
Open this publication in new window or tab >>Immature neurons from CNS stem cells proliferate in response toplatelet-derived growth factor
2001 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 10, p. 3483-3491Article in journal (Refereed) Published
Abstract [en]

Identifying external signals involved in the regulation of neural stem cell proliferation and differentiation is fundamental to the understanding of CNS development. In this study we show that platelet-derived growth factor (PDGF) can act as a mitogen for neural precursor cells. Multipotent stem cells from developing CNS can be maintained in a proliferative state under serum-free conditions in the presence of fibroblast growth factor-2 (FGF2) and induced to differentiate into neurons, astrocytes, and oligodendrocytes on withdrawal of the mitogen. PDGF has been suggested to play a role during the differentiation into neurons. We have investigated the effect of PDGF on cultured stem cells from embryonic rat cortex. The PDGF alpha-receptor is constantly expressed during differentiation of neural stem cells but is phosphorylated only after PDGF-AA treatment. In contrast, the PDGF beta-receptor is hardly detectable in uncommitted cells, but its expression increases during differentiation. We show that PDGF stimulation leads to c-fos induction, 5'-bromo-2'deoxyuridine incorporation, and an increase in the number of immature cells stained with antibodies to neuronal markers. Our findings suggest that PDGF acts as a mitogen in the early phase of stem cell differentiation to expand the pool of immature neurons.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-51636 (URN)11331377 (PubMedID)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2018-01-11Bibliographically approved
2. Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons
Open this publication in new window or tab >>Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons
2002 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 1, no 2, p. 147-154Article in journal (Refereed) Published
Abstract [en]

Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90758 (URN)000181772500007 ()12496361 (PubMedID)
Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2017-12-14Bibliographically approved
3. Regulation of neural stem cells by exogenous and endogenous PDGF.
Open this publication in new window or tab >>Regulation of neural stem cells by exogenous and endogenous PDGF.
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-90759 (URN)
Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2010-01-13Bibliographically approved
4. Stem cell factor is a chemoattractant and a survival factor for CNS stem cells
Open this publication in new window or tab >>Stem cell factor is a chemoattractant and a survival factor for CNS stem cells
2004 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 301, no 2, p. 201-210Article in journal (Refereed) Published
Abstract [en]

Migration of neural cells to their final positions is crucial for the correct formation of the central nervous system. Several extrinsic factors are known to be involved in the regulation of neural migration. We asked if stem cell factor (SCF), well known as a chemoattractant and survival factor in the hematopoietic lineage, could elicit similar responses in neural stem cells. For that purpose, a microchemotaxis assay was used to study the effect of SCF on migration of neural stem cells from the embryonic rat cortex. Our results show that SCF-induced chemotaxis and that specific antibodies to SCF or tyrosine kinase inhibitors abolished the migratory response. The SCF-receptor, Kit, was expressed in neural stem cells and in their differentiated progeny. We also show that SCF is a survival factor, but not a mitogen or a differentiation factor for neural stem cells. These data suggest a role for SCF in cell migration and survival in the developing cortex.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90760 (URN)10.1016/j.yexcr.2004.08.009 (DOI)15530856 (PubMedID)
Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2017-12-14Bibliographically approved

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