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

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.

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

Neuroreport ◽

10.1097/01.wnr.0000227991.23046.b7 ◽

2006 ◽

Vol 17 (12) ◽

pp. 1263-1267 ◽

Cited By ~ 3

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

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Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

Neuron Glia Biology ◽

10.1017/s1740925x08000082 ◽

2007 ◽

Vol 3 (3) ◽

pp. 209-220 ◽

Cited By ~ 47

Author(s):

Adan Aguirre ◽

Vittorio Gallo

Keyword(s):

Growth Factor ◽

Progenitor Cells ◽

Subventricular Zone ◽

Transforming Growth Factor ◽

Mammalian Brain ◽

Heparin Binding ◽

Egfr Signaling ◽

Transforming Growth Factor Α ◽

Physiological Conditions ◽

Focal Demyelination

AbstractNeural progenitor cells that express the NG2 proteoglycan are present in different regions of the adult mammalian brain where they display distinct morphologies and proliferative rates. In the developing postnatal and adult mouse, NG2+ cells represent a major cell population of the subventricular zone (SVZ). NG2+ cells divide in the anterior and lateral region of the SVZ, and are stimulated to proliferate and migrate out of the SVZ by focal demyelination of the corpus callosum (CC). Many NG2+ cells are labeled by GFP-retrovirus injection into the adult SVZ, demonstrating that NG2+ cells actively proliferate under physiological conditions and after demyelination. Under normal physiological conditions and after focal demyelination, proliferation of NG2+ cells is significantly attenuated in wa2 mice, which are characterized by reduced signaling of the epidermal growth factor receptor (EGFR). This results in reduced SVZ-to-lesion migration of NG2+ cells and oligodendrogenesis in the lesion. Expression of vascular endothelial growth factor (VEGF) and EGFR ligands, such as heparin binding-EGF and transforming growth factor α, is upregulated in the SVZ after focal demyelination of the CC. EGF-induced oligodendrogenesis and myelin protein expression in wild-type SVZ cells in culture are significantly attenuated in wa2 SVZ cells. Our results demonstrate that the response of NG2+ cells in the SVZ and their subsequent differentiation in CC after focal demyelination depend on EGFR signaling.

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

Development ◽

10.1242/dev.183418 ◽

2020 ◽

Vol 147 (10) ◽

pp. dev183418 ◽

Cited By ~ 6

Author(s):

Isabella Palazzo ◽

Kyle Deistler ◽

Thanh V. Hoang ◽

Seth Blackshaw ◽

Andy J. Fischer

Keyword(s):

Progenitor Cells ◽

Muller Glia ◽

Müller Glia ◽

Avian Retina

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

10.1101/668210 ◽

2019 ◽

Cited By ~ 1

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.

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

10.1101/724260 ◽

2019 ◽

Cited By ~ 2

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.

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Different levels of epidermal growth factor signaling modifies the differentiation of specific cell types in mouse postnatal retina

Archives of Biological Sciences ◽

10.2298/abs190617054i ◽

2019 ◽

Vol 71 (4) ◽

pp. 711-719

Author(s):

Sanja Ivkovic ◽

Irena Jovanovic-Macura ◽

Tijana Antonijevic ◽

Selma Kanazir ◽

Domingos Henrique

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Horizontal Cells ◽

Muller Glia ◽

Müller Glia ◽

Rod Photoreceptors ◽

Infected Cells ◽

Epidermal Growth ◽

Egf Signaling ◽

Different Levels

Epidermal growth factor (EGF) signaling has been implicated in the regulation of the differentiation and proliferation of retinal progenitors. We assessed how different levels of EGF signaling, achieved either by increasing receptor expression or via addition of the exogenous ligand, or an increase in both, can affect the differentiation of progenitors in the first week of postnatal retinal development in the model system of retinal explants (REs). Proliferating progenitor cells in REs were infected with either the control CLV3/ESR-related peptide family (CLE)-green fluorescent protein (GFP)- or with EGF receptor (EGFR)-GFP-expressing retrovirus, and grown in the control medium or in the presence of exogenous EGF (10 ng/mL). The differentiation of infected cells into Muller glia (Sox9+), rod photoreceptors (rhodopsin+) and horizontal cells (calbindin+) was analyzed. In all the examined conditions, infected cells differentiated into Muller glia and rod photoreceptors that normally develop postnatally. Horizontal cells finished their development during the embryonic stages and progenitors infected with control-GFP virus did not differentiate into GFP+/calbindin- in either control or EGFsupplemented medium, however, cells infected with EGFR-GFP differentiated into horizontal cells (GFP+/calbindin+) in both culture conditions. These results imply that altering the levels of EGFR and/or the amount of the EGF ligand can overcome progenitor competence restriction.

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