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Roles of PDGF for Neural Stem Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stem cells are endowed with unique qualities: they can both self-renew and give rise to new mature cell types. Central nervous system (CNS) stem cells can give rise to neurons and glia. What factors regulate stem cell fate decisions? Identifying signals that are involved in the regulation of CNS stem cell proliferation, survival, differentiation and migration is fundamental to the understanding of CNS development. In addition, this knowledge hopefully will contribute to more efficient therapies of CNS damages and diseases.

The focus of this thesis was to investigate mechanisms of CNS stem cell proliferation and differentiation. We have studied the role for platelet-derived growth factor (PDGF) in these cellular events both in vitro and in vivo. Previous reports have shown that PDGF are implicated in brain tumorigenesis and also supports neuronal differentiation of CNS stem cells. We have found that PDGF promotes survival and proliferation of immature neurons, thereby supporting neuronal differentiation. The intracellular Ras/ERK signaling pathway probably mediates the mitogenic activity of PDGF. In contrast, neuronal differentiation is not dependent on the Ras/ERK pathway. A genetic expression profile of stem cells during their differentiation was obtained. This microarray analysis suggests that PDGF-treated stem cells are at an intermediate stage between proliferation and differentiation. Furthermore, we generated transgenic mice that overexpress Pdgf-b in neural stem cells. Preliminary data indicate no signs of enhanced proliferation of immature neurons. Instead, increased apoptosis was detected in the developing striatum.

The results presented in this thesis show how CNS stem cells are regulated by PDGF. PDGFs are widely expressed in the developing CNS and also in some brain tumors, which are thought to arise from CNS stem cells. Thus, this knowledge may contribute to an increased understanding of brain tumorigenesis in addition to normal CNS development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 60
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1348
Keywords [en]
Developmental biology, CNS, stem cells, neuron, PDGF, proliferation, differentiation, ERK, microarray, transgenic mouse
Keywords [sv]
Utvecklingsbiologi
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-4245ISBN: 91-554-5956-0 (print)OAI: oai:DiVA.org:uu-4245DiVA, id: diva2:164525
Public defence
2004-05-19, B41, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-04-28 Created: 2004-04-28 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. Analysis of gene expression in neural stem cells during proliferation and differentiation
Open this publication in new window or tab >>Analysis of gene expression in neural stem cells during proliferation and differentiation
Show others...
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91703 (URN)
Available from: 2004-04-28 Created: 2004-04-28 Last updated: 2010-01-13Bibliographically approved
4. Overexpression of PDGF-B in neural stem cells leads to increased apoptosis in the developing striatum
Open this publication in new window or tab >>Overexpression of PDGF-B in neural stem cells leads to increased apoptosis in the developing striatum
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91704 (URN)
Available from: 2004-04-28 Created: 2004-04-28 Last updated: 2010-01-13Bibliographically approved

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