| 1. |
- Åberg, Maria A I, 1972, et al.
(författare)
-
IGF-I has a direct proliferative effect in adult hippocampal progenitor cells.
- 2003
-
Ingår i: Molecular and cellular neurosciences. - 1044-7431. ; 24:1, s. 23-40
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate the potential direct effects of insulin-like growth factor-I (IGF-I) on adult rat hippocampal stem/progenitor cells (AHPs). IGF-I-treated cultures showed a dose-dependent increase in thymidine incorporation, total number of cells, and number of cells entering the mitosis phase. Pretreatment with fibroblast growth factor-2 (FGF-2) increased the IGF-I receptor (IGF-IR) expression, and both FGF-2 and IGF-I were required for maximal proliferation. Time-lapse recordings showed that IGF-I at 100 ng/ml decreased differentiation and increased proliferation of single AHPs. Specific inhibition of mitogen-activated protein kinase kinase (MAPKK), phosphatidylinositol 3-kinase (PI3-K), or the downstream effector of the PI3-K pathway, serine/threonine p70 S6 kinase (p70(S6K)), showed that both the MAPK and the PI3-K pathways participate in IGF-I-induced proliferation but that the MAPK activation is obligatory. These results were confirmed with dominant-negative constructs for these pathways. Stimulation of differentiation was found at a low dose (1 ng/ml) of IGF-I, clonal analysis indicating an instructive component of IGF-I signaling.
|
|
| 2. |
- Åberg, Maria A I, 1972, et al.
(författare)
-
Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus.
- 2000
-
Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 20:8, s. 2896-903
-
Tidskriftsartikel (refereegranskat)abstract
- In several species, including humans, the dentate granule cell layer (GCL) of the hippocampus exhibits neurogenesis throughout adult life. The ability to regulate adult neurogenesis pharmacologically may be of therapeutic value as a mechanism for replacing lost neurons. Insulin-like growth factor-I (IGF-I) is a growth-promoting peptide hormone that has been shown to have neurotrophic properties. The relationship between IGF-I and adult hippocampal neurogenesis is to date unknown. The aim of this study was to investigate the effect of the peripheral administration of IGF-I on cellular proliferation in the dentate subgranular proliferative zone, which contains neuronal progenitor cells, and on the subsequent migration and differentiation of progenitor cells within the GCL. Using bromodeoxyuridine (BrdU) labeling, we found a significant increase of BrdU-immunoreactive progenitors in the GCL after 6 d of peripheral IGF-I administration. To determine the cell fate in progenitor progeny, we characterized the colocalization of BrdU-immunolabeled cells with cell-specific markers. In animals treated with IGF-I for 20 d, BrdU-positive cells increased significantly. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the neuronal markers Calbindin D(28K), microtubule-associated protein-2, and NeuN. There was no difference in the fraction of newly generated astrocytes. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and selectively induces neurogenesis in the progeny of adult neural progenitor cells. This corresponds to a 78 +/- 17% (p < 0.001) increase in the number of new neurons in IGF-I-treated animals compared with controls.
|
|
| 3. |
- Åberg, Maria A I, 1972, et al.
(författare)
-
Selective introduction of antisense oligonucleotides into single adult CNS progenitor cells using electroporation demonstrates the requirement of STAT3 activation for CNTF-induced gliogenesis
- 2001
-
Ingår i: Mol Cell Neurosci. - : Elsevier BV. ; 17:3, s. 426-43
-
Tidskriftsartikel (refereegranskat)abstract
- We have developed a novel method in which antisense DNA is selectively electroporated into individual adult neural progenitor cells. By electroporation of antisense oligonucleotides against signal transducer and activator of transcription 3 (STAT3) we demonstrate that ciliary neurotrophic factor (CNTF) is an instructive signal for astroglial type 2 cell fate specifically mediated via activation of STAT3. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway induced only a transient increase in glial fibrillary acidic protein (GFAP) expression, and inhibition of this signaling pathway did not block the induction by CNTF of glial differentiation in progenitor cells. In addition we show that microelectroporation is a new powerful method for introducing antisense agents into single cells in complex cellular networks.
|
|
| 4. |
- Åberg, N David, 1970, et al.
(författare)
-
Insulin-like growth factor-I increases astrocyte intercellular gap junctional communication and connexin43 expression in vitro.
- 2003
-
Ingår i: Journal of neuroscience research. - : Wiley. - 0360-4012. ; 74:1, s. 12-22
-
Tidskriftsartikel (refereegranskat)abstract
- Connexin43 (cx43) forms gap junctions in astrocytes, and these gap junctions mediate intercellular communication by providing transport of low-molecular-weight metabolites and ions. We have recently shown that systemic growth hormone increases cx43 in the brain. One possibility was that local brain insulin-like growth factor-I (IGF-I) could mediate the effect by acting directly on astrocytes. In the present study, we examined the effects of direct application of recombinant human IGF-I (rhIGF-I) on astrocytes in primary culture concerning cx43 protein expression and gap junctional communication (GJC). After 24 hr of stimulation with rhIGF-I under serum-free conditions, the GJC and cx43 protein were analyzed. Administration of 30 ng/ml rhIGF-I increased the GJC and the abundance of cx43 protein. Cell proliferation of the astrocytes was not significantly increased by rhIGF-I at this concentration. However, a higher concentration of rhIGF-I (150 ng/ml) had no effect on GJC/cx43 but increased cell proliferation. Because of the important modulatory role of IGF binding proteins (IGFBPs) on IGF-I action, we analyzed IGFBPs in conditioned media. In cultures with a low abundance of IGFBPs (especially IGFBP-2), the GJC response to 30 ng/ml rhIGF-I was 81%, compared with the average of 25%. Finally, as a control, insulin was given in equimolar concentrations. However, GJC was not affected, which suggests that rhIGF-I acted via IGF-I receptors. In summary, the data show that rhIGF-I may increase GJC/cx43, whereas a higher concentration of rhIGF-I--at which stimulation of proliferation occurred--did not affect GJC/cx43. Furthermore, IGFBP-2 appeared to modulate the action of rhIGF-I on GJC in astrocytes by a paracrine mechanism.
|
|
| 5. |
|
|
| 6. |
- Johnson, Magnus S.C. 1969, et al.
(författare)
-
Interaction of scavenger receptor class B type I with peroxisomal targeting receptor Pex5p.
- 2003
-
Ingår i: Biochemical and biophysical research communications. - 0006-291X. ; 312:4, s. 1325-34
-
Tidskriftsartikel (refereegranskat)abstract
- Scavenger receptor class B type I (SR-BI) is an HDL receptor that mediates selective HDL lipid uptake. Peroxisomes play an important role in lipid metabolism and peroxisomal targeting signal type 1 (PTS1)-containing proteins are translocated to peroxisomes by the peroxisomal targeting import receptor, Pex5p. We have previously identified a PTS1 motif in the intracellular domain of rat SR-BI. Here, we examine the possible interaction between Pex5p and SR-BI. Expression of a Flag-tagged intracellular domain of SR-BI resulted in translocation to the peroxisome as demonstrated by double labeling with anti-Flag IgG and anti-catalase IgG analyzed by confocal microscopy. Immunoprecipitation experiments with anti-SR-BI antibody showed that Pex5p co-precipitated with SR-BI. However, when an antibody against Pex5p was used for immunoprecipitation, only the 57kDa, non-glycosylated form, of SR-BI co-precipitated. We conclude that the PTS1 domain of SR-BI is functional and can mediate peroxisomal interaction via Pex5p, in vitro.
|
|
| 7. |
- Åberg, Maria A I, 1972
(författare)
-
New neurons and astrocytes in the adult brain. Studies on adult rat neural progenitors in vivo and in vitro with special reference to the effects of IGF-I and CNTF regarding proliferation and lineage determination
- 2001
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The hippocampal dentate gyrus in several species, including man, continues to produce new neurons and glial cells in adulthood. The generation of new neurons and glial cells in the adult hippocampus is under strict regulation. Two major events of significance for cell genesis from progenitor cells are proliferation and lineage determination. In the present thesis, the importance of two endogenous proteins, namely ciliary neurotrophic factor (CNTF) and insulin-like growth factor I (IGF-I), in adult hippocampal progenitor cell regulation was investigated concerning proliferation and lineage determination. Recent studies suggest that CNTF may play a role in reactive gliosis, a hallmark of most CNS disorders. The CNTF receptor a-subunit (CNTFRa) was expressed in fibroblast growth factor-2 (FGF-2) expanded adult-derived rat hippocampal neural progenitors (AHPs). Binding of CNTF to CNTFRa resulted in activation of the Janus kinase - signal transducer and activator of transcription (Jak - STAT) pathway. It was demonstrated that CNTF is an instructive signal for astroglial type 2 cell fate in AHPs, and by electroporation of antisense oligonucleotides against STAT3 it was shown that the astroglial lineage determination is specifically mediated via activation of STAT3. However, inhibition of the mitogen-activated protein kinase (MAPK) signalling pathway did not block CNTF-induced gliogenesis in progenitor cells. These experiments demonstrated that microelectroporation is a novel powerful method for introducing agents into single cells in complex cellular networks. In vivo we investigated the effect of the peripheral administration of IGF-I on cellular proliferation in the adult rat dentate subgranular proliferative zone, and on the subsequent migration and differentiation of progenitor cells within the granule cell layer (GCL). Using bromodeoxyuridine (BrdU) labelling, we found a significant increase of BrdU-immunoreactive progenitors in the GCL after 6 days of peripheral IGF-I administration. BrdU-positive cells also increased significantly in animals treated with IGF-I for 20 days. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the co-localisation of neuronal markers and BrdU after 20 days of IGF-I treatment. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and induces neurogenesis in progeny of adult neural progenitor cells. This corresponds to a 78 + 17% (P < 0.001) increase in the number of new neurons in IGF-I-treated animals compared to controls. In vitro we found that the IGF-I receptor, IGF binding protein-2 and -4 (IGFBP-2 and IGFBP-4) are expressed in AHPs. IGF-I-treated cultures showed a dose-dependent increase in DNA synthesis and number of cells, well separated from the effects mediated by insulin, demonstrating a proliferative effect of IGF-I. The proliferative effect of IGF-I was additive to the proliferative effect of FGF-2. We also demonstrated by means of inhibitors and dominant negative constructs that the MAPK signalling pathway was required for IGF-I-stimulated proliferation in AHPs. Furthermore, an analysis of the phenotypic distribution showed that the fraction of newly generated neurons increased significantly. These findings demonstrate the importance of extracellular signals and indicate that proliferation and cell fate determination are regulated by complex interactions between AHPs and extracellular cues like the CNTF and IGF-I systems. As peripheral IGF-I has been shown to mediate an exercise-induced increase in hippocampal neurogenesis which in turn has been shown to improve memory in rodents, these results suggest that cognitive functions may be affected by peripheral IGF-I. Increased information about the regulation of progenitor cell proliferation and cell fate determination provides new insight into neurogenesis and its possible therapeutic potential.
|
|
