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Article ; Online: Single-cell approaches define two groups of mammalian oligodendrocyte precursor cells and their evolution over developmental time.

Dennis, Daniel J / Wang, Beatrix S / Karamboulas, Konstantina / Kaplan, David R / Miller, Freda D

2024 Volume 19, Issue 5, Page(s) 654–672

Abstract: Here, we used single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq), and single-cell spatial transcriptomics to characterize murine cortical OPCs throughout postnatal life. During development, we identified two groups of ... ...

Abstract	Here, we used single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq), and single-cell spatial transcriptomics to characterize murine cortical OPCs throughout postnatal life. During development, we identified two groups of differentially localized PDGFRα
MeSH term(s)	Animals ; Single-Cell Analysis ; Oligodendrocyte Precursor Cells/metabolism ; Oligodendrocyte Precursor Cells/cytology ; Mice ; Cell Differentiation/genetics ; Oligodendroglia/metabolism ; Oligodendroglia/cytology ; Epigenesis, Genetic ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; Receptor, Platelet-Derived Growth Factor alpha/genetics ; Transcriptome ; Gene Expression Regulation, Developmental ; Mice, Inbred C57BL ; White Matter/metabolism ; White Matter/cytology
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2024.03.002
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Article ; Online: (H)Elping nerve growth factor: Elp1 inhibits TrkA's phosphatase to maintain retrograde signaling.

Kaplan, David R / Mobley, William C

The Journal of clinical investigation

2020 Volume 130, Issue 5, Page(s) 2195–2198

Abstract: Nerve growth factor (NGF) regulates many aspects of neuronal biology by retrogradely propagating signals along axons to the targets of those axons. How this occurs when axons contain a plethora of proteins that can silence those signals has long ... ...

Abstract	Nerve growth factor (NGF) regulates many aspects of neuronal biology by retrogradely propagating signals along axons to the targets of those axons. How this occurs when axons contain a plethora of proteins that can silence those signals has long perplexed the neurotrophin field. In this issue of the JCI, Li et al. suggest an answer to this vexing problem, while exploring why the Elp1 gene that is mutated in familial dysautonomia (FD) causes peripheral neuropathy. They describe a distinctive function of Elp1 as a protein that is required to sustain NGF signaling by blocking the activity of its phosphatase that shuts off those signals. This finding helps explain the innervation deficits prominent in FD and reveals a unique role for Elp1 in the regulation of NGF-dependent TrkA activity.
MeSH term(s)	Dysautonomia, Familial ; Humans ; Nerve Growth Factor/genetics ; Neurogenesis ; Phosphoric Monoester Hydrolases ; Receptor, trkA/genetics ; Receptor, trkA/metabolism ; Signal Transduction
Chemical Substances	Nerve Growth Factor (9061-61-4) ; Receptor, trkA (EC 2.7.10.1) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2)
Language	English
Publishing date	2020-04-20
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI136162
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Article ; Online: Nail-associated mesenchymal cells contribute to and are essential for dorsal digit tip regeneration.

Mahmud, Neemat / Eisner, Christine / Purushothaman, Sruthi / Storer, Mekayla A / Kaplan, David R / Miller, Freda D

Cell reports

2022 Volume 41, Issue 12, Page(s) 111853

Abstract: Here, we ask why the nail base is essential for mammalian digit tip regeneration, focusing on the inductive nail mesenchyme. We identify a transcriptional signature for these cells that includes Lmx1b and show that the Lmx1b-expressing nail mesenchyme is ...

Abstract	Here, we ask why the nail base is essential for mammalian digit tip regeneration, focusing on the inductive nail mesenchyme. We identify a transcriptional signature for these cells that includes Lmx1b and show that the Lmx1b-expressing nail mesenchyme is essential for blastema formation. We use a combination of Lmx1bCreERT2-based lineage-tracing and single-cell transcriptional analyses to show that the nail mesenchyme contributes cells for two pro-regenerative mechanisms. One group of cells maintains their identity and regenerates the new nail mesenchyme. A second group contributes specifically to the dorsal blastema, loses their nail mesenchyme phenotype, acquires a blastema transcriptional state that is highly similar to blastema cells of other origins, and ultimately contributes to regeneration of the dorsal but not ventral dermis and bone. Thus, the regenerative necessity for an intact nail base is explained, at least in part, by a requirement for the inductive nail mesenchyme.
MeSH term(s)	Animals ; Mesenchymal Stem Cells ; Bone and Bones ; Cells, Cultured ; Extremities ; Mammals
Language	English
Publishing date	2022-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111853
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Article ; Online: The P-body protein 4E-T represses translation to regulate the balance between cell genesis and establishment of the postnatal NSC pool.

Kolaj, Adelaida / Zahr, Siraj K / Wang, Beatrix S / Krawec, Taylor / Kazan, Hilal / Yang, Guang / Kaplan, David R / Miller, Freda D

Cell reports

2023 Volume 42, Issue 3, Page(s) 112242

Abstract: Here, we ask how developing precursors maintain the balance between cell genesis for tissue growth and establishment of adult stem cell pools, focusing on postnatal forebrain neural precursor cells (NPCs). We show that these NPCs are transcriptionally ... ...

Abstract	Here, we ask how developing precursors maintain the balance between cell genesis for tissue growth and establishment of adult stem cell pools, focusing on postnatal forebrain neural precursor cells (NPCs). We show that these NPCs are transcriptionally primed to differentiate and that the primed mRNAs are associated with the translational repressor 4E-T. 4E-T also broadly associates with other NPC mRNAs encoding transcriptional regulators, and these are preferentially depleted from ribosomes, consistent with repression. By contrast, a second translational regulator, Cpeb4, associates with diverse target mRNAs that are largely ribosome associated. The 4E-T-dependent mRNA association is functionally important because 4E-T knockdown or conditional knockout derepresses proneurogenic mRNA translation and perturbs maintenance versus differentiation of early postnatal NPCs in culture and in vivo. Thus, early postnatal NPCs are primed to differentiate, and 4E-T regulates the balance between cell genesis and stem cell expansion by sequestering and repressing mRNAs encoding transcriptional regulators.
MeSH term(s)	Cell Differentiation/physiology ; Neural Stem Cells/metabolism ; Neurons/metabolism ; Processing Bodies ; Protein Biosynthesis ; Repressor Proteins/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Nucleocytoplasmic Transport Proteins/metabolism
Chemical Substances	Repressor Proteins ; RNA, Messenger ; Nucleocytoplasmic Transport Proteins
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112242
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Article ; Online: Schwann Cells Are Key Regulators of Corneal Epithelial Renewal.

Mirmoeini, Kaveh / Tajdaran, Kiana / Zhang, Jennifer / Gordon, Tessa / Ali, Asim / Kaplan, David R / Feinberg, Konstantin / Borschel, Gregory H

Investigative ophthalmology & visual science

2023 Volume 64, Issue 4, Page(s) 7

Abstract: Purpose: Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue- ... ...

Abstract	Purpose: Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue-innervating axon terminals mediate tissue regeneration. This study defines the critical role of the corneal axon-ensheathing SCs in homeostatic and regenerative corneal epithelial cell renewal. Methods: SC localization in the cornea was determined by in situ hybridization and immunohistochemistry with SC markers. In vivo SC visualization and/or ablation were performed in mice with inducible corneal SC-specific expression of tdTomato and/or Diphtheria toxin, respectively. The relative locations of SCs and LSCs were observed with immunohistochemical analysis of harvested genetically SC-prelabeled mouse corneas with LSC-specific antibodies. The correlation between cornea-innervating axons and the appearance of SCs was ascertained using corneal denervation in rats. To determine the limbal niche cellular composition and gene expression changes associated with innervation-dependent epithelial renewal, single-cell RNA sequencing (scRNA-seq) of dissociated healthy, de-epithelized, and denervated cornea limbi was performed. Results: We observed limbal enrichment of corneal axon-associated myelinating and non-myelinating SCs. Induced local genetic ablation of SCs, although leaving corneal sensory innervation intact, markedly inhibited corneal epithelial renewal. scRNA-seq analysis (1) highlighted the transcriptional heterogenicity of cells populating the limbal niche, and (2) identified transcriptional changes associated with corneal innervation and during wound healing that model potential regulatory paracrine interactions between SCs and LSCs. Conclusions: Limbal SCs are required for innervation-dependent corneal epithelial renewal.
MeSH term(s)	Animals ; Mice ; Rats ; Cornea/innervation ; Epithelial Cells ; Epithelium, Corneal/metabolism ; Limbus Corneae ; Schwann Cells ; Stem Cells/metabolism
Language	English
Publishing date	2023-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.64.4.7
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Article ; Online: Translating neural stem cells to neurons in the mammalian brain.

Zahr, Siraj K / Kaplan, David R / Miller, Freda D

Cell death and differentiation

2019 Volume 26, Issue 12, Page(s) 2495–2512

Abstract: The mammalian neocortex underlies our perception of sensory information, performance of motor activities, and higher-order cognition. During mammalian embryogenesis, radial glial precursor cells sequentially give rise to diverse populations of excitatory ...

Abstract	The mammalian neocortex underlies our perception of sensory information, performance of motor activities, and higher-order cognition. During mammalian embryogenesis, radial glial precursor cells sequentially give rise to diverse populations of excitatory cortical neurons, followed by astrocytes and oligodendrocytes. A subpopulation of these embryonic neural precursors persists into adulthood as neural stem cells, which give rise to inhibitory interneurons and glia. Although the intrinsic mechanisms instructing the genesis of these distinct progeny have been well-studied, most work to date has focused on transcriptional, epigenetic, and cell-cycle control. Recent studies, however, have shown that posttranscriptional mechanisms also regulate the cell fate choices of transcriptionally primed neural precursors during cortical development. These mechanisms are mediated primarily by RNA-binding proteins and microRNAs that coordinately regulate mRNA translation, stability, splicing, and localization. Together, these findings point to an extensive network of posttranscriptional control and provide insight into both normal cortical development and disease. They also add another layer of complexity to brain development and raise important biological questions for future investigation.
MeSH term(s)	Animals ; Brain/physiopathology ; Humans ; Mammals ; Neural Stem Cells/metabolism ; Neurons/metabolism
Language	English
Publishing date	2019-09-24
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-019-0411-9
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche.

Fatt, Michael P / Tran, Lina M / Vetere, Gisella / Storer, Mekayla A / Simonetta, Jaclin V / Miller, Freda D / Frankland, Paul W / Kaplan, David R

Stem cell reports

2022 Volume 17, Issue 2, Page(s) 259–275

Abstract: Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an ...

Abstract	Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs. This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.
MeSH term(s)	Aging ; Aniline Compounds/pharmacology ; Animals ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Cellular Senescence/physiology ; Dentate Gyrus/cytology ; Dentate Gyrus/metabolism ; Female ; Hippocampus/cytology ; Male ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Neurogenesis/drug effects ; Spatial Memory/drug effects ; Stem Cell Niche/physiology ; Sulfonamides/pharmacology
Chemical Substances	Aniline Compounds ; Sulfonamides ; navitoclax (XKJ5VVK2WD)
Language	English
Publishing date	2022-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2021.12.010
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Article ; Online: A Shared Transcriptional Identity for Forebrain and Dentate Gyrus Neural Stem Cells from Embryogenesis to Adulthood.

Borrett, Michael J / Innes, Brendan T / Tahmasian, Nareh / Bader, Gary D / Kaplan, David R / Miller, Freda D

eNeuro

2022 Volume 9, Issue 1

Abstract: Adult neural stem cells (NSCs) reside in two distinct niches in the mammalian brain, the ventricular-subventricular zone (V-SVZ) of the forebrain lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. They are thought to be ... ...

Abstract	Adult neural stem cells (NSCs) reside in two distinct niches in the mammalian brain, the ventricular-subventricular zone (V-SVZ) of the forebrain lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. They are thought to be molecularly distinct since V-SVZ NSCs produce inhibitory olfactory bulb (OB) interneurons and SGZ NSCs excitatory dentate granule neurons. Here, we have asked whether this is so by directly comparing V-SVZ and SGZ NSCs from embryogenesis to adulthood using single-cell transcriptional data. We show that the embryonic radial glial precursor (RP) parents of these two NSC populations are very similar, but differentially express a small cohort of genes involved in glutamatergic versus GABAergic neurogenesis. These different RPs then undergo a similar gradual transition to a dormant adult NSC state over the first three postnatal weeks. This dormancy state involves transcriptional shutdown of genes that maintain an active, proliferative, prodifferentiation state and induction of genes involved in sensing and regulating their niche environment. Moreover, when reactivated to generate adult-born progeny, both populations reacquire a development-like state and re-express proneurogenic genes. Thus, V-SVZ and SGZ NSCs share a common transcriptional state throughout their lifespans and transition into and out of dormancy via similar trajectories.
MeSH term(s)	Adult ; Animals ; Dentate Gyrus ; Embryonic Development ; Humans ; Lateral Ventricles ; Mammals ; Neural Stem Cells ; Neurogenesis/physiology ; Prosencephalon
Language	English
Publishing date	2022-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0271-21.2021
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Article ; Online: Mobilizing endogenous stem cells for repair and regeneration: are we there yet?

Miller, Freda D / Kaplan, David R

Cell stem cell

2012 Volume 10, Issue 6, Page(s) 650–652

Abstract: Harnessing endogenous repair mechanisms to promote tissue regeneration in situations in which it does not normally occur has long been a goal in biomedical science. Recent advances in tissue stem cells indicate that this goal may now be achievable. Here ... ...

Abstract	Harnessing endogenous repair mechanisms to promote tissue regeneration in situations in which it does not normally occur has long been a goal in biomedical science. Recent advances in tissue stem cells indicate that this goal may now be achievable. Here we consider both the promise and the hurdles we still have to overcome.
MeSH term(s)	Animals ; Humans ; Regenerative Medicine/methods ; Stem Cells/cytology ; Stem Cells/physiology ; Wound Healing
Language	English
Publishing date	2012-06-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2012.05.004
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Zs.A 6589: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The DEAD-box helicase DDX56 is a conserved stemness regulator in normal and cancer stem cells.

Pryszlak, Michael / Wiggans, Mallory / Chen, Xin / Jaramillo, Julia E / Burns, Sarah E / Richards, Laura M / Pugh, Trevor J / Kaplan, David R / Huang, Xi / Dirks, Peter B / Pearson, Bret J

Cell reports

2022 Volume 34, Issue 13, Page(s) 108903

Abstract: Across the animal kingdom, adult tissue homeostasis is regulated by adult stem cell activity, which is commonly dysregulated in human cancers. However, identifying key regulators of stem cells in the milieu of thousands of genes dysregulated in a given ... ...

Abstract	Across the animal kingdom, adult tissue homeostasis is regulated by adult stem cell activity, which is commonly dysregulated in human cancers. However, identifying key regulators of stem cells in the milieu of thousands of genes dysregulated in a given cancer is challenging. Here, using a comparative genomics approach between planarian adult stem cells and patient-derived glioblastoma stem cells (GSCs), we identify and demonstrate the role of DEAD-box helicase DDX56 in regulating aspects of stemness in four stem cell systems: planarians, mouse neural stem cells, human GSCs, and a fly model of glioblastoma. In a human GSC line, DDX56 localizes to the nucleolus, and using planarians, when DDX56 is lost, stem cells dysregulate expression of ribosomal RNAs and lose nucleolar integrity prior to stem cell death. Together, a comparative genomic approach can be used to uncover conserved stemness regulators that are functional in both normal and cancer stem cells.
MeSH term(s)	Adult Stem Cells/metabolism ; Animals ; Cell Line, Tumor ; Cell Lineage ; Cell Nucleolus/metabolism ; Cell Proliferation ; Cell Self Renewal ; Cell Survival ; Cerebral Cortex/cytology ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; Drosophila/metabolism ; Drosophila Proteins/metabolism ; Gene Expression Regulation, Neoplastic ; Genomics ; Glioblastoma/genetics ; Glioblastoma/pathology ; HEK293 Cells ; Humans ; Mice ; Models, Biological ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Neural Stem Cells/metabolism ; Planarians/cytology ; Planarians/metabolism ; RNA Interference ; Ribosome Subunits/metabolism ; Treatment Outcome ; Up-Regulation/genetics
Chemical Substances	Drosophila Proteins ; DDX56 protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.108903
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