scholarly journals Regulation of Stem Cell Properties of Müller Glia by JAK/STAT and MAPK Signaling in the Mammalian Retina

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Krista M. Beach ◽  
Jianbo Wang ◽  
Deborah C. Otteson
Keyword(s):  
Stem Cells ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Muller Glia ◽  
Müller Glia ◽  
Cellular Mechanisms ◽  
Blood Retinal Barrier ◽  
Extrinsic Factors ◽  
Radial Glial Cells ◽  
Mammalian Retina

In humans and other mammals, the neural retina does not spontaneously regenerate, and damage to the retina that kills retinal neurons results in permanent blindness. In contrast to embryonic stem cells, induced pluripotent stem cells, and embryonic/fetal retinal stem cells, Müller glia offer an intrinsic cellular source for regenerative strategies in the retina. Müller glia are radial glial cells within the retina that maintain retinal homeostasis, buffer ion flux associated with phototransduction, and form the blood/retinal barrier within the retina proper. In injured or degenerating retinas, Müller glia contribute to gliotic responses and scar formation but also show regenerative capabilities that vary across species. In the mammalian retina, regenerative responses achieved to date remain insufficient for potential clinical applications. Activation of JAK/STAT and MAPK signaling by CNTF, EGF, and FGFs can promote proliferation and modulate the glial/neurogenic switch. However, to achieve clinical relevance, additional intrinsic and extrinsic factors that restrict or promote regenerative responses of Müller glia in the mammalian retina must be identified. This review focuses on Müller glia and Müller glial-derived stem cells in the retina and phylogenetic differences among model vertebrate species and highlights some of the current progress towards understanding the cellular mechanisms regulating their regenerative response.

scholarly journals Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 663
Author(s):  
Kwang-Hyun Baek ◽  
Jihye Choi ◽  
Chang-Zhu Pei
Keyword(s):  
Stem Cells ◽  
Cellular Proliferation ◽  
Critical Role ◽  
Embryonic Stem ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Specific Cell ◽  
Cellular Mechanisms ◽  
Proliferating Cells ◽  
Proliferation And Differentiation

Octamer-binding transcription factor 3/4 (OCT-3/4), which is involved in the tumorigenesis of somatic cancers, has diverse functions during cancer development. Overexpression of OCT-3/4 has been detected in various human somatic tumors, indicating that OCT-3/4 activation may contribute to the development and progression of cancers. Stem cells can undergo self-renewal, pluripotency, and reprogramming with the help of at least four transcription factors, OCT-3/4, SRY box-containing gene 2 (SOX2), Krüppel-like factor 4 (KLF4), and c-MYC. Of these, OCT-3/4 plays a critical role in maintenance of undifferentiated state of embryonic stem cells (ESCs) and in production of induced pluripotent stem cells (iPSCs). Stem cells can undergo partitioning through mitosis and separate into specific cell types, three embryonic germ layers: the endoderm, the mesoderm, and the trophectoderm. It has been demonstrated that the stability of OCT-3/4 is mediated by the ubiquitin-proteasome system (UPS), which is one of the key cellular mechanisms for cellular homeostasis. The framework of the mechanism is simple, but the proteolytic machinery is complicated. Ubiquitination promotes protein degradation, and ubiquitination of OCT-3/4 leads to regulation of cellular proliferation and differentiation. Therefore, it is expected that OCT-3/4 may play a key role in proliferation and differentiation of proliferating cells.

scholarly journals A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia

2020 ◽  
Author(s):  
William N Grimes ◽  
Didem Göz Aytürk ◽  
Mrinalini Hoon ◽  
Takeshi Yoshimatsu ◽  
Clare Gamlin ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Glial Cells ◽  
Amacrine Cell ◽  
Electrical Coupling ◽  
Amacrine Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Cell Type ◽  
Mammalian Retina ◽  
Ganglion Neurons

AbstractAmacrine cells are interneurons comprising the most diverse cell type in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, neurovascular control and metabolic regulation. Here, we report that a previously poorly characterized, but relatively abundant, inhibitory amacrine cell type in the mouse retina is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed extensive associations with Müller glia, whose processes often completely ensheathe the neurites of this amacrine cell type. Microinjections of small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Müller glia, leading us to suggest the name “Müller glia-coupled amacrine cell” or MAC. Our electrophysiological data also indicate that MACs release glycine at conventional chemical synapses with amacrine, bipolar and retinal ganglion cells (RGCs), and viral transsynaptic tracing showed connections to several known RGC types. Visually-evoked responses revealed a strong preference for light increments; these “ON” responses were primarily mediated by excitatory chemical synaptic input and direct electrical coupling to other cells. This initial characterization of the MAC provides the first evidence for neuron-glia coupling in the mammalian retina and identifies the MAC as a potential link between inhibitory processing and glial function.Significance StatementGap junctions between pairs of neurons or glial cells are commonly found throughout the nervous system, and play a myriad of roles including electrical coupling and metabolic exchange. In contrast, gap junctions between neurons and glia cells are rare and poorly understood. Here we report the first evidence for neuron-glia coupling in the mammalian retina, specifically between an abundant (but previously unstudied) inhibitory interneuron and Müller glia.

Abstract 361: Neuregulin Transcriptional Programming of Embryonic Endothelial Progenitor Cells and Embryonic Stem Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Jijun Hao ◽  
Cristi L Galindo ◽  
Radwan N Safa ◽  
Truc-Linh Tran ◽  
Douglas B Sawyer
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Heart Development ◽  
Progenitor Cell ◽  
Critical Role ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
P Value ◽  
Type I ◽  
Endothelial Progenitor

Jijun Hao, Cristi L. Galindo, Radwan N. Safa, Truc-Linh Tran, Douglas B. Sawyer Neuregulin-1 (NRG-1) plays a critical role in heart development by signaling through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3 and erbB4). Mice with disrupted expression of NRG-1, ErbB2, ErbB3 or ErbB4 die in utero with failure of cardiac development. We have previously shown that NRG-1 has distinct effects on two embryonic progenitor cell populations that express ErbB2 and ErbB3 receptors. In an embryonic endothelial progenitor cell line (eEPCs) NRG-1 treatment induces phosphorylation of Akt, GSK-3β, and Erk1/2, and protects eEPCs against serum deprivation-induced apoptosis. In embryonic stem cells (ESCs) we find that NRG-1 treatment from day 0∼2 induces cardiomyocyte formation by day 8 in culture, and when ErbB3 is knocked down in the ESCs, NRG-1 fails to promote cardiomyogenesis. To understand early molecular events that might regulate these distinct effects, we analyzed global transcriptional changes induced by NRG-1 in both eEPCs and ESCs using microarrays. There were only 244 significantly differential (p value < 0.05, fold-change > 1.5) genes detected in NRG-1-treated ESCs, while NRG-1 induced differential expression of 1,547 transcripts in eEPCs. Based on functional analysis, the most significantly over-represented function (Fishers Exact Test, p value with FDR < 0.05) in ESCs was “cell morphogenesis during differentiation”. In eEPCs, genes regulated via Ras/MAPK signaling were altered, as were those downstream of the Akt-PI3K pathway and calcium signaling. For both cell lines, the most statistically significant transcription factor identified as a regulator of the genes altered in response to NRG-1 was SRF, consistent with a role for NRG-1 in heart development and regeneration. Based on the results of this study, we constructed a putative signaling pathway whereby NRG mediates cardiomyogenesis in pluripotent stem cells that correlates with phenotypic observations.

scholarly journals Neural stem cell properties of Müller glia in the mammalian retina: Regulation by Notch and Wnt signaling

2006 ◽  
Vol 299 (1) ◽  
pp. 283-302 ◽  
Author(s):  
Ani V. Das ◽  
Kavita B. Mallya ◽  
Xing Zhao ◽  
Faraz Ahmad ◽  
Sumitra Bhattacharya ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Neural Stem Cell ◽  
Muller Glia ◽  
Müller Glia ◽  
Mammalian Retina

scholarly journals Midkine-a is required for cell cycle progression of Müller glia during neuronal regeneration

2019 ◽  
Author(s):  
Mikiko Nagashima ◽  
Travis S. D’Cruz ◽  
Doneen Hesse ◽  
Christopher J. Sifuentes ◽  
Pamela A. Raymond ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Muller Glia ◽  
Neuronal Regeneration ◽  
Müller Glia ◽  
Cycle Progression ◽  
Neuronal Stem Cells ◽  
Cell Cycle Genes

SummaryIn zebrafish, Müller glia function as intrinsic retinal stem cells that can regenerate ablated neurons. Understanding the mechanisms governing neuronal stem cells may provide clues to regenerate neurons in mammals. We report that in Müller glia the cytokine/growth factor, Midkine-a, functions as a core autocrine regulator of the cell cycle. Utilizing midkine-a mutants, we determined that Midkine-a regulates elements of an Id2a-retinoblastoma network in reprogrammed Müller glia that controls the expression of cell cycle genes and is required for transition from G1 to S phases of the cell cycle. In mutants, Müller glia that fail to divide undergo reactive gliosis, a pathological hallmark of Müller glia in mammals. Finally, we show that activation of the Midkine-a receptor, ALK, is required for Müller glia proliferation. These data provide mechanistic insights into Müller glia stem cells in the vertebrate retina and suggest avenues for eliciting neuronal regeneration in mammals.

scholarly journals ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ju Young Kim ◽  
Dong Hun Lee ◽  
Joo Kyung Kim ◽  
Hong Seo Choi ◽  
Bhakti Dwivedi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Mouse Embryonic Stem Cells ◽  
Micro Rna ◽  
Mitogen Activated Protein Kinase ◽  
The Novel

AbstractPrevious studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)+ cell generation from the mouse embryonic stem cells (mESCs). By performing a series of experiments including miRNA sequencing and ChIP (chromatin immunoprecipitation)-PCR, we found that miR-126 is directly induced by ETV2. Further, we identified that miR-126 can positively regulate the generation of FLK1+ cells by activating the MAPK pathway through targeting SPRED1 (sprouty-related EVH1 domain containing 1). Further, we showed evidence that JUN/FOS activate the enhancer region of FLK1 through AP1 (activator protein 1) binding sequences. Our findings provide insight into the novel molecular mechanisms of ETV2 function in regulating cardiovascular lineage development from mESCs.

scholarly journals Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos

2008 ◽  
Vol 40 (7) ◽  
pp. 921-926 ◽  
Author(s):  
Chi-Wei Lu ◽  
Akiko Yabuuchi ◽  
Lingyi Chen ◽  
Srinivas Viswanathan ◽  
Kitai Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Mouse Embryos

scholarly journals Generation of Transgenic Rats through Induced Pluripotent Stem Cells

2013 ◽  
Vol 288 (38) ◽  
pp. 27150-27158 ◽  
Author(s):  
Ming-Gui Jiang ◽  
Tianda Li ◽  
Chunjing Feng ◽  
Rui Fu ◽  
Yan Yuan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Germ Line ◽  
Glycogen Synthase ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Transgenic Rats ◽  
Induced Pluripotent

The rat is an important animal model for human disease research. Using inhibitors of glycogen synthase kinase 3 and MAPK signaling pathways, rat embryonic stem cells and rat induced pluripotent stem cells (riPSCs) have been derived. However, unlike rat embryonic stem cells, germ line competent riPSCs have only been derived from Wistar rats at low efficiency. Here, we found that an optimized induction medium containing knock-out serum replacement and vitamin C improved the rate and efficiency of riPSCs generation from Dark Agouti rat fibroblasts and Sertoli cells. riPSCs maintained an undifferentiated status for >30 passages and could differentiate into various cells types including germ cells when injected into rat blastocysts. Moreover, transgenic riPSCs could be generated through the PiggyBac transposon, which could be used to generate transgenic rats through germ line transmission. riPSCs can be used as a novel tool in genetic and genomic studies of the rat.

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