Neuronal vs. Glial Fate of Embryonic Stem Cell-Derived Neural Progenitors (ES-NPs) is Determined by FGF2/EGF During Proliferation

Sanalkumar, Rajendran; Sasidharan, Vidyanand; Indulekha, Chandrasekharan Lalitha; James, Jackson

doi:10.1007/s12031-010-9335-z

Cited by 23 publications

(21 citation statements)

References 45 publications

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“…NPCs were cultured in suspension as neurospheres in medium containing epidermal growth factor (EGF) and leukemia inhibitory factor (LIF) for 4-6 wk. In the absence of fibroblast growth factor 2 (FGF2), coapplication of EGF and LIF in prolonged culture promoted astroglial specification of NPCs (13,14) and efficiently selected for neurospheres with a high content of astroglial progenitors. After this enrichment phase, neurospheres were expanded in EGF-and FGF2-containing medium before enzymatic dissociation to single cells.…”

Section: Resultsmentioning

confidence: 99%

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Serio

Bilican

Barmada

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

304

331

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Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy in transactive response DNAbinding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALScausing TDP-43 mutation and show that mutant astrocytes exhibit increased levels of TDP-43, subcellular mislocalization of TDP-43, and decreased cell survival. We then performed coculture experiments to evaluate the effects of M337V astrocytes on the survival of wild-type and M337V TDP-43 motor neurons, showing that mutant TDP-43 astrocytes do not adversely affect survival of cocultured neurons. These observations reveal a significant and previously unrecognized glial cell-autonomous pathological phenotype associated with a pathogenic mutation in TDP-43 and show that TDP-43 proteinopathies do not display an astrocyte non-cell-autonomous component in cell culture, as previously described for SOD1 ALS. This study highlights the utility of induced pluripotent stem cell-based in vitro disease models to investigate mechanisms of disease in ALS and other TDP-43 proteinopathies.glia | motor neuron disease | disease modeling T ransactive response DNA-binding protein (TDP-43) is the major component of ubiquitinated cytoplasmic and nuclear inclusions in neurons and astroglia in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP) (1-3). These pathological hallmarks provide a unifying description of a range of conditions defined as TDP-43 proteinopathies (4). At present, >30 mutations in the TDP-43 gene (TARDBP) have been linked to familial ALS (fALS) (5), strongly suggesting a causative role for TDP-43 in the pathogenesis of ALS.Accumulating evidence from experimental systems implicating non-cell-autonomous mechanisms in ALS has highlighted the importance of the glial cellular environment to motor neuron (MN) degeneration (1,3,(6)(7)(8)(9). In vivo rodent models of ALS with lineage-specific SOD1 expression have particularly influenced our understanding of the nonneuronal contribution to disease progression. Glial expression of mutant SOD1 cannot initiate MN disease on its own, but is necessary for disease progression (6, 7). Furthermore, astrogliosis precedes MN degeneration in some animal models and is a dominant feature of all human ALS pathology (4, 6, 10). Collectively, these observations highlight the need to better understand the nature of astroglial pathology in ALS. Combining developmental neurobiological principles of cell fate determination with human induced pluripotent stem cell (iPSC) lines derived from patients carrying ALS disease-causing mutations may provide important insights into astroglia pathology.We recently generated human MNs from iPSC lines derived from a fALS patient and demonstrated that the M337V TDP-43 mutation confers cell-autonomous toxicity to MNs (11). More...

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Section: Resultsmentioning

confidence: 99%

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Serio

Bilican

Barmada

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

304

331

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Section: Fgf2 Promotes Cell Proliferation and Inhibits Adipogenesismentioning

confidence: 99%

“…20,21 FGF2 is critical for stimulating embryonic development when undifferentiated stem cells and progenitor cells are abundant. 20,21 During the postnatal stage, however, FGF2 are critical for wound healing and angiogenesis, where extensive proliferation of fibroblasts and progenitor cells are needed. 22,23 FGF2 stimulates cell proliferation through enhancing both ERK1/2 and AKT signaling pathways, which are critical for cell proliferation and protein synthesis respectively.…”

Section: Fgf2 Promotes Cell Proliferation and Inhibits Adipogenesismentioning

confidence: 99%

Lysyl oxidase propeptide promotes adipogenesis through inhibition of FGF-2 signaling

et al. 2016

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Lysyl oxidase (LOX) catalyzes the oxidative deamination of lysine residues in collagen and elastin, key components of connective tissue. LOX is synthesized as an inactive 50 kD pre-proenzyme, and secreted to the extracellular matrix where it is cleaved into an active 32 kD LOX, and an 18kD free propeptide (LOX-PP), purportedly an inhibitor of fibroblast growth factor-2 (FGF-2) signaling. Given that adipocytes are distributed inside the connective tissue, it is likely that LOX-PP has an important regulatory role in adipogenesis, which has not been studied. Using NIH 3T3-L1 cells, we observed that FGF-2 inhibited adipogenesis, and LOX-PP promoted adipogenesis of 3T3-L1 cells in the presence of FGF-2; the expression of peroxisome proliferator-activated receptor (PPAR) g and CCAAT-enhancer binding protein (C/EBP) a, two markers of adipogenesis, were enhanced in the presence of LOX-PP. We further observed that LOX-PP down-regulated AKT and ERK1/2, two proliferative signaling proteins down-stream of FGF-2 signaling. Similarly, inhibition of FGF-2 receptor signaling by canofin, a competitive inhibitor of FGF-2 receptor, promoted adipogenesis albeit less effective compared to LOX-PP. To further explore whether LOX-PP promoted adipogenesis through inhibition of FGF-2 signaling, site directed mutagenesis of LOX-PP, resulting in an Arg158 to Gln158 mutation which abolishes the inhibitory activity of LOX-PP to FGF-2 receptor, attenuated the adipogenic promoting properties of LOX-PP. In summary, for the first time, our data show that LOX-PP enhances adipogenesis at least partially through inhibition of FGF-2 receptor signaling. Our data suggest that LOX-PP may serve as a bona fide therapeutic target for regulating adipogenesis and adipose tissue development.

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“…After extended periods in culture, neurogenic cultures undergo a gliogenic switch, producing primarily astrocytes rather than neurons [24]. Treatment with mitogens, such as FGF, and patterning molecules, such as BMP and LIF, leads to increasingly enriched astrocyte cultures [25].…”

Section: Introductionmentioning

confidence: 99%

“…One challenge is the neuronal versus glia bias due to the later stage gliogenic switch [24]. As a consequence, in vitro cultures are not representative of brain due to a reduced proportion of astrocytes [138].…”

Section: Introductionmentioning

confidence: 99%

Stem cell models of Alzheimer’s disease: progress and challenges

Arber¹,

Lovejoy²,

Wray³

2017

Alz Res Therapy

116

126

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A major challenge to our understanding of the molecular mechanisms of Alzheimer’s disease (AD) has been the lack of physiologically relevant in vitro models which capture the precise patient genome, in the cell type of interest, with physiological expression levels of the gene(s) of interest. Induced pluripotent stem cell (iPSC) technology, together with advances in 2D and 3D neuronal differentiation, offers a unique opportunity to overcome this challenge and generate a limitless supply of human neurons for in vitro studies. iPSC-neuron models have been widely employed to model AD and we discuss in this review the progress that has been made to date using patient-derived neurons to recapitulate key aspects of AD pathology and how these models have contributed to a deeper understanding of AD molecular mechanisms, as well as addressing the key challenges posed by using this technology and what progress is being made to overcome these. Finally, we highlight future directions for the use of iPSC-neurons in AD research and highlight the potential value of this technology to neurodegenerative research in the coming years.

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Neuronal vs. Glial Fate of Embryonic Stem Cell-Derived Neural Progenitors (ES-NPs) is Determined by FGF2/EGF During Proliferation

Cited by 23 publications

References 45 publications

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

Lysyl oxidase propeptide promotes adipogenesis through inhibition of FGF-2 signaling

Stem cell models of Alzheimer’s disease: progress and challenges

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