Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

ABSTRACTSome animals can regenerate their central nervous system (CNS) after injury by inducing de novo neurogenesis: discovering the underlying mechanisms would help promote regeneration in the damaged human CNS. Glial cells could be the source of regenerative neurogenesis, but this is debated. The glia transmembrane protein Neuron-Glia antigen-2 (NG2) may have a key role in sensing injury-induced neuronal signals, however these have not been identified. Here, we used Drosophila genetics to search for functional neuronal partners of the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Alterations in Ia-2 function induced neural stem cell fate, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic epistasis analysis and lineage tracing, we demonstrate that Ia-2 functions with Kon to regulate Drosophila insulin-like peptide 6 (Dilp-6) which in turn generates both more glial cells and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia, and reprograms glia into neural stem cells for CNS regeneration.

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Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

eLife ◽

10.7554/elife.58756 ◽

2021 ◽

Vol 10 ◽

Author(s):

Neale J Harrison ◽

Elizabeth Connolly ◽

Alicia Gascón Gubieda ◽

Zidan Yang ◽

Benjamin Altenhein ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

De Novo ◽

Lineage Tracing ◽

Cell Gene Expression ◽

The Central Nervous System ◽

Induced Neural Stem Cell ◽

Islet Antigen ◽

Cell Gene ◽

Stem Cell Gene

Understanding how injury to the Central Nervous System (CNS) induces de novo neurogenesis in animals would help promote regeneration in humans. Regenerative neurogenesis could originate from glia and glial Neuron-Glia antigen-2 (NG2) may sense injury-induced neuronal signals, but these are unknown. Here, we used Drosophila to search for genes functionally related the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Alterations in Ia-2 function induced neural stem cell gene expression, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic analysis and lineage tracing, we demonstrate that Ia-2 and Kon regulate Drosophila insulin-like peptide 6 (Dilp-6), to induce glial proliferation and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia, and reprograms glia into neural stem cells for regeneration.

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Coordinated control of self-renewal and differentiation of neural stem cells by Myc and the p19ARF–p53 pathway

The Journal of Cell Biology ◽

10.1083/jcb.200807130 ◽

2008 ◽

Vol 183 (7) ◽

pp. 1243-1257 ◽

Cited By ~ 47

Author(s):

Motoshi Nagao ◽

Kenneth Campbell ◽

Kevin Burns ◽

Chia-Yi Kuan ◽

Andreas Trumpp ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Late Stage ◽

Early Stage ◽

Dependent Manner ◽

Self Renewal ◽

P53 Pathway ◽

Glial Fate ◽

Underlying Mechanisms

The modes of proliferation and differentiation of neural stem cells (NSCs) are coordinately controlled during development, but the underlying mechanisms remain largely unknown. In this study, we show that the protooncoprotein Myc and the tumor suppressor p19ARF regulate both NSC self-renewal and their neuronal and glial fate in a developmental stage–dependent manner. Early-stage NSCs have low p19ARF expression and retain a high self-renewal and neurogenic capacity, whereas late-stage NSCs with higher p19ARF expression possess a lower self-renewal capacity and predominantly generate glia. Overexpression of Myc or inactivation of p19ARF reverts the properties of late-stage NSCs to those of early-stage cells. Conversely, inactivation of Myc or forced p19ARF expression attenuates self-renewal and induces precocious gliogenesis through modulation of the responsiveness to gliogenic signals. These actions of p19ARF in NSCs are mainly mediated by p53. We propose that opposing actions of Myc and the p19ARF–p53 pathway have important functions in coordinated developmental control of self-renewal and cell fate choices in NSCs.

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Neural Stem Cells to Glial Cells an Important Factor for Brain Injury

Journal of Regenerative Biology and Medicine ◽

10.37191/mapsci-2582-385x-2(3)-025 ◽

2020 ◽

Author(s):

Prithiv K R Kumar

Keyword(s):

Stem Cells ◽

Central Nervous System ◽

Nervous System ◽

Neural Stem Cells ◽

Glial Cells ◽

Brain Injuries ◽

The Body ◽

The Central Nervous System ◽

Near Future

Stem cells have the capacity to differentiate into any type of cell or organ. Stems cell originate from any part of the body, including the brain. Brain cells or rather neural stem cells have the capacitive advantage of differentiating into the central nervous system leading to the formation of neurons and glial cells. Neural stem cells should have a source by editing DNA, or by mixings chemical enzymes of iPSCs. By this method, a limitless number of neuron stem cells can be obtained. Increase in supply of NSCs help in repairing glial cells which in-turn heal the central nervous system. Generally, brain injuries cause motor and sensory deficits leading to stroke. With all trials from novel therapeutic methods to enhanced rehabilitation time, the economy and quality of life is suppressed. Only PSCs have proven effective for grafting cells into NSCs. Neurons derived from stem cells is the only challenge that limits in-vitro usage in the near future.

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Human embryonic stem cells: challenges and opportunities

Reproduction Fertility and Development ◽

10.1071/rd06113 ◽

2006 ◽

Vol 18 (8) ◽

pp. 839 ◽

Cited By ~ 3

Author(s):

Steven L. Stice ◽

Nolan L. Boyd ◽

Sujoy K. Dhara ◽

Brian A. Gerwe ◽

David W. Machacek ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Line ◽

Cell Fate ◽

Neural Development ◽

Es Cells ◽

Embryonic Stem ◽

Normal Karyotype ◽

Es Cell ◽

Cell Therapies

Human and non-human primate embryonic stem (ES) cells are invaluable resources for developmental studies, pharmaceutical research and a better understanding of human disease and replacement therapies. In 1998, subsequent to the establishment of the first monkey ES cell line in 1995, the first human ES cell line was developed. Later, three of the National Institute of Health (NIH) lines (BG01, BG02 and BG03) were derived from embryos that would have been discarded because of their poor quality. A major challenge to research in this area is maintaining the unique characteristics and a normal karyotype in the NIH-registered human ES cell lines. A normal karyotype can be maintained under certain culture conditions. In addition, a major goal in stem cell research is to direct ES cells towards a limited cell fate, with research progressing towards the derivation of a variety of cell types. We and others have built on findings in vertebrate (frog, chicken and mouse) neural development and from mouse ES cell research to derive neural stem cells from human ES cells. We have directed these derived human neural stem cells to differentiate into motoneurons using a combination of developmental cues (growth factors) that are spatially and temporally defined. These and other human ES cell derivatives will be used to screen new compounds and develop innovative cell therapies for degenerative diseases.

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Dissecting Hes-centered transcriptional networks in neural stem cell maintenance and tumorigenesis in Drosophila

10.1101/2020.03.25.007187 ◽

2020 ◽

Cited By ~ 1

Author(s):

Srivathsa S. Magadi ◽

Chrysanthi Voutyraki ◽

Gerasimos Anagnostopoulos ◽

Evanthia Zacharioudaki ◽

Ioanna K. Poutakidou ◽

...

Keyword(s):

Stem Cells ◽

Nervous System ◽

Transcription Factor ◽

Stem Cell ◽

Neural Stem Cells ◽

Cell Fate ◽

Asymmetric Cell Division ◽

Transcriptional Networks ◽

Malignant Tumours ◽

Stem Cell Maintenance

ABSTRACTNeural stem cells divide during embryogenesis and post embryonic development to generate the entire complement of neurons and glia in the nervous system of vertebrates and invertebrates. Studies of the mechanisms controlling the fine balance between neural stem cells and more differentiated progenitors have shown that in every asymmetric cell division progenitors send a Delta-Notch signal back to their sibling stem cells. Here we show that excessive activation of Notch or overexpression of its direct targets of the Hes family causes stem-cell hyperplasias in the Drosophila larval central nervous system, which can progress to malignant tumours after allografting to adult hosts. We combined transcriptomic data from these hyperplasias with chromatin occupancy data for Dpn, a Hes transcription factor, to identify genes regulated by Hes factors in this process. We show that the Notch/Hes axis represses a cohort of transcription factor genes. These are excluded from the stem cells and promote early differentiation steps, most likely by preventing the reversion of immature progenitors to a stem-cell fate. Our results suggest that Notch signalling sets up a network of mutually repressing stemness and anti-stemness transcription factors, which include Hes proteins and Zfh1, respectively. This mutual repression ensures robust transition to neuronal and glial differentiation and its perturbation can lead to malignant transformation.

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SV40T reprograms Schwann cells into stem-like cells that can re-differentiate into terminal nerve cells

The International Journal of Developmental Biology ◽

10.1387/ijdb.210062zz ◽

2021 ◽

Author(s):

Rui-fang Li ◽

Guo-xin Nan ◽

Dan Wang ◽

Chang Gao ◽

Juan Yang ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Neural Stem Cells ◽

Neural Crest ◽

Schwann Cells ◽

Early Development ◽

Glial Cells ◽

Embryonic Stem ◽

Specific Effect ◽

Neural Crest Cells

Background: The specific effect of SV40T on neurocytes has been rarely investigated by the researchers. We transfected Schwann cells (SCs) that did not have differentiation ability with MPH 86 plasmid containing SV40T in order to explore the effects of SV40T on Schwann cells.Methods: SCs were transfected with MPH 86 plasmid carrying the SV40T gene and cultured in different media, as well as co-cultured with neural stem cells (NSCs). In our study, SCs overexpressing SV40T were defined as SV40T-SCs. The proliferation of these cells was detected by WST-1, and the expression of different biomarkers was analyzed by qPCR and immunohistochemistry. Results: SV40T induced the characteristics of NSCs, such as the ability to grow in suspension, form spheroid colonies and proliferate rapidly, in the SCs, which were reversed by knocking out SV40T by the Flip-adenovirus. In addition, SV40T upregulated the expressions of neural crest-associated markers Nestin, Pax3 and Slug, and down-regulated S100b as well as the markers of mature SCs MBP, GFAP and Olig1/2. These cells also expressed NSC markers like Nestin, Sox2, CD133 and SSEA-1, as well as early development markers of embryonic stem cells (ESCs) like BMP4, c-Myc, OCT4 and Gbx2. Co-culturing with NSCs induced differentiation of the SV40T-SCs into neuronal and glial cells. Conclusions: SV40T reprograms Schwann cells to stem-like cells at the stage of neural crest cells (NCCs) that can differentiate to neurocytes.

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Definitive Hematopoietic Stem Cells Minimally Contribute to Embryonic Hematopoiesis

10.1101/2021.05.02.442359 ◽

2021 ◽

Author(s):

Bianca A Ulloa ◽

Samima S Habbsa ◽

Kathryn S Potts ◽

Alana Lewis ◽

Mia McKinstry ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

De Novo ◽

Marker Gene ◽

Lineage Tracing ◽

Hematopoietic Stem ◽

Functional Potential ◽

Injury Model ◽

Rare Cells

Hematopoietic stem cells (HSCs) are rare cells that arise in the embryo and sustain adult hematopoiesis. Although the functional potential of nascent HSCs is detectable by transplantation, their native contribution during development is unknown, in part due to the overlapping genesis and marker gene expression with other embryonic blood progenitors. Using single cell transcriptomics, we defined gene signatures that distinguish nascent HSCs from embryonic blood progenitors. Applying a new lineage tracing approach, we selectively tracked HSC output in situ and discovered significantly delayed lymphomyeloid contribution. Using a novel inducible HSC injury model, we demonstrated a negligible impact on larval lymphomyelopoiesis following HSC depletion. HSCs are not merely dormant at this developmental stage as they showed robust regeneration after injury. Combined, our findings illuminate that nascent HSCs self-renew but display differentiation latency, while HSC-independent embryonic progenitors sustain developmental hematopoiesis. Understanding the differences among embryonic HSC and progenitor populations will guide improved de novo generation and expansion of functional HSCs.

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Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

International Journal of Molecular Sciences ◽

10.3390/ijms20020455 ◽

2019 ◽

Vol 20 (2) ◽

pp. 455 ◽

Cited By ~ 3

Author(s):

Felix Beyer ◽

Iria Samper Agrelo ◽

Patrick Küry

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Ex Vivo ◽

Meta Analysis ◽

Cell Types ◽

Adult Brain ◽

Repair Capacity ◽

Cell Fate Decisions ◽

Limiting Parameters

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

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