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

Campbell, Warren A.; Fritsch-Kelleher, Amanda; Palazzo, Isabella; Hoang, Thanh; Blackshaw, Seth; Fischer, Andy J.

doi:10.1002/glia.23976

Cited by 43 publications

(83 citation statements)

References 103 publications

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“…This antibody was raised to full length recombinant human AP2-alpha. Patterns of immunolabeling for Nkx2.2 have been wellestablished in in chick retina (Fischer et al, 2007;Campbell et al, 2021) and precisely match patterns of expression of TFAP2A in scRNA-seq databases of chick, pig and monkey retinas (Supplemental Fig. 1).…”

Section: Fixation Sectioning and Immunocytochemistrysupporting

confidence: 53%

“…This antibody was raised to Nkx2.2-GST fusion protein expressed in E. coli. Patterns of immunolabeling for Nkx2.2 have been well-established in in chick retina (Fischer et al, 2010b;a) and precisely match patterns of expression of NKX2-2 in scRNA-seq databases of chick retina (Campbell et al, 2019(Campbell et al, , 2021.…”

Section: Fixation Sectioning and Immunocytochemistrymentioning

confidence: 57%

“…We re-probed scRNA-seq databases that have previously been used to compare MG and MGPCs across fish, chick and mouse model systems (Hoang et al, 2020) and characterize expression patterns of genes related to NFkB-signaling (Palazzo et al, 2020), midkine-signaling (Campbell et al, 2021) and matrix metalloproteases (Campbell et al, 2019). scRNA-seq libraries were established for retinas from chick embryos at E5, E8, E12, and E15.…”

Section: Nfis In Embryonic Retinamentioning

confidence: 99%

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Nuclear Factor I in neurons, glia and during the formation of Müller glia-derived progenitor cells in avian, porcine and primate retinas

El‐Hodiri

Campbell

Kelly

et al. 2021

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The regenerative potential of Müller glia (MG) is extraordinary in fish, poor in chick and terrible in mammals. In the chick model, MG readily reprogram into proliferating Müller glia-derived progenitor cells (MGPCs), but neuronal differentiation is very limited. The factors that suppress the neurogenic potential of MGPCs in the chick are slowly being revealed. Isoforms of Nuclear Factor I (NFI) are cell-intrinsic factors that limit neurogenic potential; these factors are required for the formation of MG in the developing mouse retina (Clark et al., 2019) and deletion of these factors reprograms MG into neuron-like cells in mature mouse retina (Hoang et al., 2020). Accordingly, we sought to characterize the patterns of expression NFIs in the developing, mature and damaged chick retina. In addition, we characterized patterns of expression of NFIs in the retinas of large mammals, pigs and monkeys. Using a combination of single cell RNA-sequencing (scRNA-seq) and immunolabeling we probed for patterns of expression. In embryonic chick, levels of NFIs are very low in early E5 (embryonic day 5) retinal progenitor cells (RPCs), up-regulated in E8 RPCs, further up-regulated in differentiating MG at E12 and E15. NFIs are maintained in mature resting MG, microglia and neurons. Levels of NFIs are reduced in activated MG in retinas treated with NMDA and/or insulin+FGF2, and further down-regulated in proliferating MGPCs. However, levels of NFIs in MGPCs were significantly higher than those seen in RPCs. Immunolabeling for NFIA and NFIB closely matched patterns of expression revealed in different types of retinal neurons and glia, consistent with findings from scRNA-seq. In addition, we find expression of NFIA and NFIB through progenitors in the circumferential marginal zone at the far periphery of the retina. We find similar patterns of expression for NFIs in scRNA-seq databases for pig and monkey retinas. Patterns of expression of NFIA and NFIB were validated with immunofluorescence in pig and monkey retinas wherein these factors were predominantly detected in MG and a few types of inner retinal neurons. In summary, NFIA and NFIB are prominently expressed in developing chick retina and by mature neurons and glia in the retinas of chicks, pigs and monkeys. Although levels of NFIs are decreased in chick, in MGPCs these levels remain higher than those seen in neurogenic RPCs. We propose that the neurogenic potential of MGPCs in the chick retina is suppressed by NFIs.

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Section: Fixation Sectioning and Immunocytochemistrysupporting

confidence: 53%

Section: Fixation Sectioning and Immunocytochemistrymentioning

confidence: 57%

Section: Nfis In Embryonic Retinamentioning

confidence: 99%

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Nuclear Factor I in neurons, glia and during the formation of Müller glia-derived progenitor cells in avian, porcine and primate retinas

El‐Hodiri

Campbell

Kelly

et al. 2021

Preprint

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“…8q). MDK and FGF are known to active mTor-signaling and up-regulated pS6 in MG in the chick retina (Campbell et al, 2021a;Zelinka et al, 2016). Consistent with these findings, we observed reduced levels of pStat3 in MG nuclei in damaged retinas treated with BMS (Fig.…”

Section: Inhibition Of Fabps In Resting Mgmentioning

confidence: 99%

Fatty acid-binding proteins and fatty acid synthase influence glial reactivity and promote the formation of Müller glia-derived progenitor cells in the avian retina

Campbell

Tangeman

El‐Hodiri

et al. 2021

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The capacity for retinal regeneration varies greatly across vertebrates species. A recent comparative epigenetic and transcriptomic investigation of Muller glial (MG) in the retinas of fish, birds and mice revealed that Fatty Acid Binding Proteins (FABPs) are among the most highly up-regulated genes in activated chick MG (Hoang et al., 2020). Herein we provide an in-depth follow-up investigation to describe patterns of expression and how FABPs and fatty acid synthase (FASN) influence glial cells in the chick retina. During development, FABP7 is highly expressed by embryonic retinal progenitor cells (eRPCs) and maturing MG, whereas FABP5 is gradually up-regulated in maturing MG and remains elevated in mature glial cells. PMP2 (FABP8) is expressed by oligodendrocytes and FABP5 is expressed by non-astrocytic inner retinal glial cells, and both of these FABPs are significantly up-regulated in activated MG in damaged or growth factor-treated retinas. In addition to suppressing the formation of MGPCs, we find that FABP-inhibition suppressed the accumulation of proliferating microglia, although the microglia appeared highly reactive. scRNA-seq analyses of cells treated with FABP-inhibitor revealed distinct changes in patterns of expression suggesting that FABPs are involved in the transitions of MG from a resting state to a reactive state and conversion from reactive MG to MGPCs. Inhibition of FABPs in undamaged retinas had a significant impact upon the transcriptomic profiles of MG, with up-regulation of genes associated with gliogenesis, decreases in genes associated with neurogenesis, and suppression of the ability of MG to become MGPCs. scRNA-seq analyses of microglia indicated that FABP inhibition enhances gene modules related to reactivity, proliferation and cytokine signaling. We find that the proliferation of retinal progenitors in the circumferential marginal zone (CMZ) is unaffected by FABP-inhibitor. Upstream of FABP activity, we inhibited FASN in damaged retinas, which reduced numbers of dying cells, increased the proliferation of microglia, and potently suppressed the formation MGPCs in damaged retinas. We conclude that the activity of FASN and FABPs are required early during the formation of proliferating MGPCs. Fatty acid metabolism and cell signaling involving fatty acids are important in regulating glial homeostasis in the retina, and the dedifferentiation and proliferation of microglia and MGPCs.

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“…Animal models are critical to understand the mechanisms of retinal disease and potential treatments. A damage model that has been commonly used in chicks and other species is the NMDA (N-methyl-D-aspartate) excitotoxic damage model [ 1 – 3 ], which mimics glutamate excitotoxic damage in the retina. Glutamate excitotoxicity occurs when a surplus of glutamate, a neurotransmitter, forms in the retina due to either excessive release or inadequate clearance by glutamine synthetase [ 4 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Multimodal imaging and functional analysis of the chick NMDA retinal damage model

et al. 2021

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Objectives The chick is rapidly becoming a standardized preclinical model in vision research to study mechanisms of ocular disease. We seek to comprehensively evaluate the N-methyl-D-aspartate (NMDA) model of excitotoxic retinal damage using multimodal imaging, functional, and histologic approaches in NMDA-damaged, vehicle-treated, and undamaged chicks. Methods Chicks were either left undamaged in both eyes or were injected with NMDA in the left eye and saline (vehicle) in the right eye. TUNEL assay was performed on chicks to assess levels of retinal cell death one day post-injection of NMDA or saline and on age-matched untreated chicks. Spectral domain optical coherence tomography (SD-OCT) was performed weekly on chicks and age-matched controls day 1 (D1) up to D28 post-injection. Light adapted electroretinograms (ERG) were performed alongside SD-OCT measurements on post-injection chicks along with age-matched untreated controls. Results Untreated and vehicle-treated eyes had no TUNEL positive cells while NMDA-treated eyes accumulated large numbers of TUNEL positive cells in the Inner Nuclear Layer (INL), but not other layers, at D1 post injection. Significant inner retina swelling or edema was found on SD-OCT imaging at D1 post-injection which resolved at subsequent timepoints. Both the INL and the inner plexiform layer significantly thinned by one-week post-injection and did not recover for the duration of the measurements. On ERG, NMDA-treated eyes had significantly reduced amplitudes of all parameters at D1 with all metrics improving over time. The b-wave, oscillatory potentials, and ON/OFF bipolar responses were the most affected with at least 70% reduction immediately after damage compared to the fellow eye control. Conclusion This study establishes a normative baseline on the retinal health and gross functional ability as well as intraocular pressures of undamaged, vehicle-treated, and NMDA-damaged chicks to provide a standard for comparing therapeutic treatment studies in this important animal model.

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

Cited by 43 publications

References 103 publications

Nuclear Factor I in neurons, glia and during the formation of Müller glia-derived progenitor cells in avian, porcine and primate retinas

Nuclear Factor I in neurons, glia and during the formation of Müller glia-derived progenitor cells in avian, porcine and primate retinas

Fatty acid-binding proteins and fatty acid synthase influence glial reactivity and promote the formation of Müller glia-derived progenitor cells in the avian retina

Multimodal imaging and functional analysis of the chick NMDA retinal damage model

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