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Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation.

ABSTRACT: Multipotent neural stem/progenitor cells (NSPCs) can be isolated from many regions of the adult central nervous system (CNS), yet neurogenesis is restricted to the hippocampus and subventricular zone in vivo. Identification of the molecular cues that modulate NSPC fate choice is a prerequisite for their therapeutic applications. Previously, we demonstrated that primary astrocytes isolated from regions with higher neuroplasticity, such as newborn and adult hippocampus and newborn spinal cord, promoted neuronal differentiation of adult NSPCs, whereas astrocytes isolated from the nonneurogenic region of the adult spinal cord inhibited neural differentiation. To identify the factors expressed by these astrocytes that could modulate NSPC differentiation, we performed gene expression profiling analysis using Affymetrix rat genome arrays. Our results demonstrated that these astrocytes had distinct gene expression profiles. We further tested the functional effects of candidate factors that were differentially expressed in neurogenesis-promoting and -inhibiting astrocytes using in vitro NSPC differentiation assays. Our results indicated that two interleukins, IL-1beta and IL-6, and a combination of factors that included these two interleukins could promote NSPC neuronal differentiation, whereas insulin-like growth factor binding protein 6 (IGFBP6) and decorin inhibited neuronal differentiation of adult NSPCs. Our results have provided further evidence to support the ongoing hypothesis that, in adult mammalian brains, astrocytes play critical roles in modulating NSPC differentiation. The finding that cytokines and chemokines expressed by astrocytes could promote NSPC neuronal differentiation may help us to understand how injuries induce neurogenesis in adult brains.

SUBMITTER: Barkho BZ

PROVIDER: S-EPMC2777811 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation.

Barkho Basam Z BZ Song Hongjun H Aimone James B JB Smrt Richard D RD Kuwabara Tomoko T Nakashima Kinichi K Gage Fred H FH Zhao Xinyu X

Stem cells and development 20060601 3

Multipotent neural stem/progenitor cells (NSPCs) can be isolated from many regions of the adult central nervous system (CNS), yet neurogenesis is restricted to the hippocampus and subventricular zone in vivo. Identification of the molecular cues that modulate NSPC fate choice is a prerequisite for their therapeutic applications. Previously, we demonstrated that primary astrocytes isolated from regions with higher neuroplasticity, such as newborn and adult hippocampus and newborn spinal cord, pro ...[more]

PMID: 16846377

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Project description:Mucopolysaccharidosis type IIIA (MPS IIIA) is characterised by a progressive neurological decline leading to early death. It is caused by bi-allelic loss-of-function mutations in SGSH encoding sulphamidase, a lysosomal enzyme required for heparan sulphate glycosaminoglycan (HS GAG) degradation, that results in the progressive build-up of HS GAGs in multiple tissues most notably the central nervous system (CNS). Skin fibroblasts from two MPS IIIA patients who presented with an intermediate and a severe clinical phenotype, respectively, were reprogrammed into induced pluripotent stem cells (iPSCs). The intermediate MPS IIIA iPSCs were then differentiated into neural progenitor cells (NPCs) and subsequently neurons. The patient derived fibroblasts, iPSCs, NPCs and neurons all displayed hallmark biochemical characteristics of MPS IIIA including reduced sulphamidase activity and increased accumulation of an MPS IIIA HS GAG biomarker. Proliferation of MPS IIIA iPSC-derived NPCs was reduced compared to control, but could be partially rescued by reintroducing functional sulphamidase enzyme, or by doubling the concentration of the mitogen fibroblast growth factor 2 (FGF2). Whilst both control heparin, and MPS IIIA HS GAGs had a similar binding affinity for FGF2, only the latter inhibited FGF signalling, suggesting accumulated MPS IIIA HS GAGs disrupt the FGF2:FGF2 receptor:HS signalling complex. Neuronal differentiation of MPS IIIA iPSC-derived NPCs was associated with a reduction in the expression of neuronal cell marker genes βIII-TUBULIN, NF-H and NSE, revealing reduced neurogenesis compared to control. A similar result was achieved by adding MPS IIIA HS GAGs to the culture medium during neuronal differentiation of control iPSC-derived NPCs. This study demonstrates the generation of MPS IIIA iPSCs, and NPCs, the latter of which display reduced proliferation and neurogenic capacity. Reduced NPC proliferation can be explained by a model in which soluble MPS IIIA HS GAGs compete with cell surface HS for FGF2 binding. The mechanism driving reduced neurogenesis remains to be determined but appears downstream of MPS IIIA HS GAG accumulation. Highlights • Induced pluripotent stem cells (iPSCs) were generated from MPS IIIA skin fibroblasts.• MPS IIIA iPSCs were successfully differentiated into neural progenitor cells (NPCs).• MPS IIIA NPC proliferation was reduced due to interference with FGF2 signalling.• Neurogenesis from MPS IIIA iPSC-derived NPCs is reduced via an unknown mechanism.

Project description:IntroductionExercise therapies during rehabilitation significantly promote recovery from various deficits after cerebral infarction, which is mediated by neuronal plasticity with distinct inputs. Although adult neurogenesis can also be modulated by neuronal activity before synaptogenesis, how distinct exercises contribute to the neurological reorganization of the injured cerebral cortex remains unclear. In the present study, we aimed to elucidate the effects of different exercise therapies on motor recovery and neuronal reorganization after photochemically induced focal cerebral infarction.MethodsHere, we examined the effects of three different exercises-(a) forced lower-intensity and (b) higher-intensity treadmill exercises, and (c) voluntary exercise with wheel running-on motor recovery and adult neurogenesis in a rat model of focal cerebral infarction. Photochemically induced thrombosis (PIT) was used to generate focal infarction in rats that was mostly confined to their motor cortices.ResultsBeam walking tests showed that recovery after PIT-induced cortical infarction differed in acute and chronic stages and was influenced by the type of exercise. Furthermore, forced low-intensity training had more positive effects on functional recovery than other exercises or control. To evaluate the production of newly generated cells including de novo neurogenesis, we performed lineage analysis with BrdU labeling and immunofluorescence experiments. Lower-intensity treadmill exercise increased the number of BrdU/NeuN colabeled cells, but not total BrdU-retaining or BrdU/Sox2-colabeled cells, in the peri-infarct region of the ipsilateral cortex. In contrast, high-intensity treadmill or voluntary exercises had the opposite effects.ConclusionsThese results suggest that neuronal maturation can be differently modulated by distinct exercises and that low-intensity treadmill exercise could result in more potent generation of mature neurons. This also suggests the possibility that the generation of neural stem/progenitor cells and differentiation might be modulated by rehabilitation-mediated neural plasticity.

Dataset Information

Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation.

Publications

Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation.

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