Notch Signaling Activates Stem Cell Properties of Müller Glia through Transcriptional Regulation and Skp2-mediated Degradation of p27Kip1

Over the past two decades, progress in our understanding of glial function has been revolutionary. Within the retina, a subset of glial cells termed the “Müller glia (MG),” have been demonstrated to play key roles in retinal homeostasis, structure and metabolism. Additionally, MG have also been shown to possess the regenerative capacity that varies across species. In teleost fish, MG respond to injury by reprogramming into stem-like cells capable of regenerating lost tissue. The expression of stem/progenitor cell markers has been demonstrated broadly in mammalian MG, including human MG, but their in vivo regenerative capacity appears evolutionarily limited. Advances in stem cell therapy have progressively elucidated critical mechanisms underlying innate MG reprogramming in teleost fish, which have shown promising results when applied to rodents. Furthermore, when cultured ex vivo, MG from mammals can differentiate into several retina cell types. In this review, we will explore the reparative and regenerative potential of MG in cellular therapy approaches, and outline our current understanding of embryonic retinal development, the stem-cell potential of MG in adult vertebrate retina (including human), and microenvironmental cues that guide MG reprogramming.

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Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

The Journal of Cell Biology ◽

10.1083/jcb.2043oia18 ◽

2014 ◽

Vol 204 (3) ◽

pp. 2043OIA18

Author(s):

Jiong Hu ◽

Rüdiger Popp ◽

Timo Frömel ◽

Manuel Ehling ◽

Khader Awwad ◽

...

Keyword(s):

Notch Signaling ◽

Muller Glia ◽

Müller Glia ◽

Glia Cells ◽

Retinal Angiogenesis

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Tgfb3 collaborates with PP2A and notch signaling pathways to inhibit retina regeneration

eLife ◽

10.7554/elife.55137 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Mi-Sun Lee ◽

Jin Wan ◽

Daniel Goldman

Keyword(s):

Notch Signaling ◽

Signaling Pathways ◽

Signaling Pathway ◽

Neuronal Degeneration ◽

Muller Glia ◽

Müller Glia ◽

Retina Regeneration ◽

Retinal Injury ◽

Multipotent Progenitors ◽

Tgfb Signaling

Neuronal degeneration in the zebrafish retina stimulates Müller glia (MG) to proliferate and generate multipotent progenitors for retinal repair. Controlling this proliferation is critical to successful regeneration. Previous studies reported that retinal injury stimulates pSmad3 signaling in injury-responsive MG. Contrary to these findings, we report pSmad3 expression is restricted to quiescent MG and suppressed in injury-responsive MG. Our data indicates that Tgfb3 is the ligand responsible for regulating pSmad3 expression. Remarkably, although overexpression of either Tgfb1b or Tgfb3 can stimulate pSmad3 expression in the injured retina, only Tgfb3 inhibits injury-dependent MG proliferation; suggesting the involvement of a non-canonical Tgfb signaling pathway. Furthermore, inhibition of Alk5, PP2A or Notch signaling rescues MG proliferation in Tgfb3 overexpressing zebrafish. Finally, we report that this Tgfb3 signaling pathway is active in zebrafish MG, but not those in mice, which may contribute to the different regenerative capabilities of MG from fish and mammals.

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Inflammation and matrix metalloproteinase 9 (Mmp-9) regulate photoreceptor regeneration in adult zebrafish

10.1101/518365 ◽

2019 ◽

Author(s):

Nicholas J. Silva ◽

Mikiko Nagashima ◽

Jingling Li ◽

Laura Kakuk-Atkins ◽

Milad Ashrafzadeh ◽

...

Keyword(s):

Stem Cell ◽

Matrix Metalloproteinase ◽

Matrix Metalloproteinase 9 ◽

Muller Glia ◽

Neuronal Regeneration ◽

Müller Glia ◽

Adult Zebrafish ◽

Cellular Expression ◽

Anti Inflammatory ◽

Metalloproteinase 9

AbstractBrain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following sterile photoreceptor ablation anti-inflammatory treatment suppresses both the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia, the intrinsic retinal stem cell, and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the maturation and survival of the regenerated cones. Anti-inflammatory treatment in mutants rescues the defects in cone maturation and survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during photoreceptor regeneration and the requirement of Mmp-9 for the survival of regenerated cones.Significance StatementThe innate immune system is activated by neuronal death, and recent studies demonstrate that in zebrafish neuroinflammation is required for neuronal regeneration. The roles of inflammatory cytokines are being investigated, however, the function of the inflammatory protease, matrix metalloprotease Mmp-9, in neuronal regeneration is unknown. We show herein that in adult zebrafish retinal inflammation governs the proliferative phase of the stem cell-based regeneration of rod and cone photoreceptors and determine the specific roles for Mmp-9 in photoreceptor regeneration. This study provides the first mechanistic insights into the potential role of Mmp-9 and serves to link neuroinflammation, stem cell-based regeneration of photoreceptors and human photoreceptor disease.

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