scholarly journals Midkine is neuroprotective and influences glial reactivity and the formation of Müller glia‐derived progenitor cells in chick and mouse retinas

Glia ◽  
2021 ◽  
Author(s):  
Warren A. Campbell ◽  
Amanda Fritsch‐Kelleher ◽  
Isabella Palazzo ◽  
Thanh Hoang ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Glial Reactivity

scholarly journals Cannabinoid signaling promotes the reprogramming of Muller glia into proliferating progenitor cells.

2021 ◽  
Author(s):  
Warren Campbell ◽  
Sydney Blum ◽  
Alana Reske ◽  
Thanh Hoang ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Expression Patterns ◽  
Synaptic Function ◽  
Muller Glia ◽  
Müller Glia ◽  
Rna Seq ◽  
Retinal Neurons ◽  
Pharmacological Agents ◽  
Retinal Microglia ◽  
Glial Reactivity

Endocannabinoids (eCB) are lipid-based neurotransmitters that are known to influence synaptic function in the visual system. eCBs are also known to suppress neuroinflammation in different pathological states. However, nothing is known about the roles of the eCB system during reprogramming of Müller glia (MG) into proliferating progenitor-like cells in the retina. Accordingly, we used the chick and mouse model to characterize expression patterns of eCB-related genes and applied pharmacological agents to examine how the eCB system impacts glial reactivity and the capacity of MG to become Müller glia-derived progenitor cells (MGPCs). We probed single cell RNA-seq libraries to identify eCB-related genes and identify cells with dynamic patterns of expression in damaged retinas. MG and inner retinal neurons expressed the eCB receptor CNR1, as well as enzymes involved in eCB metabolism. In the chick, intraocular injections of 2-Arachidonoylglycerol (2-AG) and Anandamide (AEA) potentiated the formation of MGPCs. Consistent with these findings, CNR1-agonists and MGLL-inhibitor promoted reprogramming, whereas CNR1-antagonist and inhibitors of eCB synthesis suppressed reprogramming. Surprisingly, retinal microglia were largely unaffected by increases or decreases in eCB signaling in both chick and mouse models. However, eCB-signaling suppressed the activation of NFkB-reporter in MG in damaged mouse retinas. We conclude that the eCB system in the retina influences the reactivity of MG and is important for regulating glial reactivity and the reprogramming of MG into proliferating MGPCs, but not for regulating the reactivity of immune cells in the retina.

Muller glia induce retinal progenitor cells to differentiate into retinal ganglion cells

Neuroreport ◽  
2006 ◽  
Vol 17 (12) ◽  
pp. 1263-1267 ◽  
Author(s):  
Jing Yao ◽  
Xinghuai Sun ◽  
Yang Wang ◽  
Ling Wang
Keyword(s):  
Progenitor Cells ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor

scholarly journals NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina

Development ◽  
2020 ◽  
Vol 147 (10) ◽  
pp. dev183418 ◽  
Author(s):  
Isabella Palazzo ◽  
Kyle Deistler ◽  
Thanh V. Hoang ◽  
Seth Blackshaw ◽  
Andy J. Fischer
Keyword(s):  
Progenitor Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Avian Retina

scholarly journals NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina

2019 ◽  
Author(s):  
Isabella Palazzo ◽  
Kyle Deistler ◽  
Thanh V. Hoang ◽  
Seth Blackshaw ◽  
Andy J. Fischer
Keyword(s):  
Progenitor Cells ◽  
Nuclear Factor Kappa B ◽  
Neuronal Damage ◽  
Muller Glia ◽  
Müller Glia ◽  
Reactive Microglia ◽  
Chick Retina ◽  
Cell Signaling Pathways

AbstractNeuronal regeneration in the retina is a robust, effective process in some cold-blooded vertebrates, but this process is ineffective in warm-blooded vertebrates. Understanding the mechanisms and cell-signaling pathways that restrict the reprogramming of Müller glia into proliferating neurogenic progenitors is key to harnessing the regenerative potential of the retina. Inflammation and reactive microglia are known to influence the formation of Müller glia-derived progenitor cells (MGPCs), but the mechanisms underlying this response are unknown. Using the chick retina in vivo as a model system, we investigate the role of the Nuclear Factor kappa B (NF-κB) signaling, a critical regulator of inflammation. We find that components of the NF-κB pathway are expressed by Müller glia and are dynamically regulated after neuronal damage or treatment with growth factors. Inhibition of NF-κB enhances, whereas activation suppresses the formation of proliferating MGPCs. Additionally, activation of NF-κB promotes glial differentiation from MGPCs in damaged retinas. With microglia ablated, the effects of NF-κB-agonists/antagonists on MGPC formation are reversed, suggesting that the context and timing of signals provided by reactive microglia influence how NF-κB-signaling impacts the reprogramming of Müller glia. We propose that NF-κB-signaling is an important signaling “hub” that suppresses the reprogramming of Müller glia into proliferating MGPCs and this “hub” coordinates signals provided by reactive microglia.

scholarly journals Heparin-binding EGF-like growth factor (HB-EGF) stimulates the proliferation of Müller glia-derived progenitor cells in avian and murine retinas

2015 ◽  
Vol 69 ◽  
pp. 54-64 ◽  
Author(s):  
Levi Todd ◽  
Leo I. Volkov ◽  
Chris Zelinka ◽  
Natalie Squires ◽  
Andy J. Fischer
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Muller Glia ◽  
Heparin Binding ◽  
Müller Glia

scholarly journals BMP- and TGFβ-signaling regulate the formation of Müller glia-derived progenitor cells in the avian retina

Glia ◽  
2017 ◽  
Vol 65 (10) ◽  
pp. 1640-1655 ◽  
Author(s):  
Levi Todd ◽  
Isabella Palazzo ◽  
Natalie Squires ◽  
Ninoshka Mendonca ◽  
Andy J. Fischer
Keyword(s):  
Progenitor Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Tgfβ Signaling ◽  
Avian Retina

scholarly journals Potential of Müller glia to become neurogenic retinal progenitor cells

Glia ◽  
2003 ◽  
Vol 43 (1) ◽  
pp. 70-76 ◽  
Author(s):  
Andy J. Fischer ◽  
Thomas A. Reh
Keyword(s):  
Progenitor Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor

scholarly journals Dynamic miRNA expression patterns during retinal regeneration in zebrafish: Reduced dicer or miRNA expression suppresses proliferation of Müller Glia‐derived neuronal progenitor cells

2014 ◽  
Vol 243 (12) ◽  
pp. 1591-1605 ◽  
Author(s):  
Kamya Rajaram ◽  
Rachel L. Harding ◽  
Travis Bailey ◽  
James G. Patton ◽  
David R. Hyde
Keyword(s):  
Progenitor Cells ◽  
Mirna Expression ◽  
Expression Patterns ◽  
Muller Glia ◽  
Müller Glia ◽  
Retinal Regeneration ◽  
Neuronal Progenitor Cells ◽  
Neuronal Progenitor

scholarly journals Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells

2020 ◽  
Author(s):  
Warren A. Campbell ◽  
Amanda Fritsch-Kelleher ◽  
Isabella Palazzo ◽  
Thanh Hoang ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Neuronal Survival ◽  
Expression Patterns ◽  
Model Systems ◽  
Muller Glia ◽  
Heparin Binding ◽  
Müller Glia ◽  
Related Factors ◽  
Neuroprotective Effects ◽  
Dying Cells

AbstractRecent studies have shown that midkine (MDK), a basic heparin-binding growth factor, is involved in the development and regeneration of the zebrafish retina. However, very little is known about MDK in the retinas of warm-blooded vertebrates. We investigate the expression patterns of MDK and related factors, roles in neuronal survival, and influence upon the formation of Müller glia-derived progenitor cells (MGPCs) in chick and mouse model systems. By using single-cell RNA-sequencing, we find that MDK is upregulated during Müller glia (MG) maturation in chick development and when stimulated to reprogram into MGPCs after NMDA damage or FGF2/Insulin treatment. Interestingly, MDK is significantly up-regulated by MG in damaged chick retinas, but down-regulated by MG in damaged mouse retinas. In both chick and mouse retinas, exogenous MDK selectively up-regulates cFOS and pS6 (a readout of mTOR-signaling) in MG. In the chick, intraocular injections of MDK before injury is neuroprotective with an observed decrease in dying neurons and microglial reactivity, inducing fewer proliferating MGPCs. Blocking MDK signaling with Na3VO4 following blocks neuroprotective effects with an increase the number of dying cells and negates the pro-proliferative effects on MGPCs. Inhibitors of PP2A and Pak1 associated with MDK integrin β1 signaling had MG specific inhibitory effects on MGPC formation. In mice, MDK administration with NMDA damage drives a small but significant increase in MGPCs. We conclude that MDK expression is dynamically regulated in reactive Müller glia and during reprogramming into MGPCs. MDK acts to coordinate glial activity, neuronal survival, and may act in an autocrine manner to influence the re-programming of Müller glia into proliferating MGPCs.

scholarly journals NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina

2021 ◽  
Author(s):  
Isabella Palazzo ◽  
Levi J. Todd ◽  
Thanh V. Hoang ◽  
Thomas A. Reh ◽  
Seth Blackshaw ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Immune Cells ◽  
Muller Glia ◽  
Müller Glia ◽  
Dynamic Expression ◽  
Lower Vertebrates ◽  
Mammalian Retina ◽  
Neuron Regeneration ◽  
Glial Reactivity

AbstractMüller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however NFkB activity is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFβ2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.

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