Awakening the regenerative potential of the mammalian retina

Martin, James F.; Poché, Ross A.

doi:10.1242/dev.182642

Cited by 27 publications

(26 citation statements)

References 55 publications

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“…Many microglial studies in fish examine photoreceptor regeneration [ 112 , 158 , 173 ]. These types of studies on cellular and molecular mechanisms and inflammation have the potential to elucidate the regenerative potential of mammalian tissues [ 174 , 175 ]. In zebrafish, acute inflammation is necessary to induce neuronal regeneration [ 121 , 176 ].…”

Section: Translational Studies In Fish and Mammalian Modelsmentioning

confidence: 99%

Role of Macrophages and Microglia in Zebrafish Regeneration

Var

Byrd-Jacobs

2020

IJMS

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Currently, there is no treatment for recovery of human nerve function after damage to the central nervous system (CNS), and there are limited regenerative capabilities in the peripheral nervous system. Since fish are known for their regenerative abilities, understanding how these species modulate inflammatory processes following injury has potential translational importance for recovery from damage and disease. Many diseases and injuries involve the activation of innate immune cells to clear damaged cells. The resident immune cells of the CNS are microglia, the primary cells that respond to infection and injury, and their peripheral counterparts, macrophages. These cells serve as key modulators of development and plasticity and have been shown to be important in the repair and regeneration of structure and function after injury. Zebrafish are an emerging model for studying macrophages in regeneration after injury and microglia in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. These fish possess a high degree of neuroanatomical, neurochemical, and emotional/social behavioral resemblance with humans, serving as an ideal simulator for many pathologies. This review explores literature on macrophage and microglial involvement in facilitating regeneration. Understanding innate immune cell behavior following damage may help to develop novel methods for treating toxic and chronic inflammatory processes that are seen in trauma and disease.

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Section: Translational Studies In Fish and Mammalian Modelsmentioning

confidence: 99%

Role of Macrophages and Microglia in Zebrafish Regeneration

Var

Byrd-Jacobs

2020

IJMS

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“…Unlike mammals, which possess a limited capacity for tissue regeneration, zebrafish have the ability to regenerate tissues and organs, such as fins, heart, brain, spinal cord, and retina (Gemberling, Bailey, Hyde, & Poss, ; Kizil, Kaslin, Kroehne, & Brand, ; Lenkowski & Raymond, ). Studies using zebrafish have identified cellular and molecular mechanisms which may unlock the regenerative potential of mammalian tissues (Martin & Poché, ; Ueki et al, ). Such mechanisms include inflammation.…”

Section: Introductionmentioning

confidence: 99%

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

Silva

Nagashima

et al. 2020

Glia

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Brain 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 photoreceptor ablation, anti-inflammatory treatment suppresses the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia 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 survival of the regenerated cones. At all time-points studied, the levels of tnf-α are significantly elevated in mutant retinas.Anti-inflammatory treatment in mutants rescues the defects in cone survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during neuronal regeneration and the requirement of Mmp-9 for the survival of regenerated cones.

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“…Zebrafish MGs in injured retinas have been shown to be both the donors and the receivers of some extracellular diffusible factors, which transduce injury signals downstream to converge on a few main signaling pathways, and mediate proliferative and neurogenic effects [3,4,7]. To date the donor origins have not been fully identified.…”

Section: Accepted Articlementioning

confidence: 99%

“…These extracellular cues commonly act synergistically to activate MG reprogramming [6,9,10], suggesting that stressed or dead neurons, together with active microglia, coordinate injured zebrafish retina to cross a certain threshold to dramatically activate MG reprogramming. These injury-induced growth factors and cytokines converge downstream on some main intracellular signaling pathways, such as MAPK/pERK, PI3K, JAK/pSTAT3, Wnt/β-catenin and Hippo pathways (see recent detailed review articles [3,4,7]).…”

Section: Accepted Articlementioning

confidence: 99%

In vivo glial trans‐differentiation for neuronal replacement and functional recovery in central nervous system

et al. 2021

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The adult mammalian central nervous system (CNS) is deficient in intrinsic machineries to replace neurons lost in injuries or progressive degeneration. Various types of these neurons constitute neural circuitries wired to support vital sensory, motor, and cognitive functions. Based on the pioneer studies in cell lineage conversion, one promising strategy is to convert in vivo glial cells into neural progenitors or directly into neurons that can be eventually rewired for functional recovery. We first briefly summarize the well‐studied regeneration‐capable CNS in the zebrafish, focusing on their postinjury spontaneous reprogramming of the retinal Müller glia (MG). We then compare the signaling transductions, and transcriptional and epigenetic regulations in the zebrafish MGs with their mammalian counterparts, which perpetuate certain barriers against proliferation and neurogenesis and thus fail in MG‐to‐progenitor conversion. Next, we discuss emerging evidence from mouse studies, in which the in vivo glia‐to‐neuron conversion could be achieved with sequential or one‐step genetic manipulations, such as the conversions from retinal MGs to interneurons, photoreceptors, or retinal ganglion cells (RGCs), as well as the conversions from midbrain astrocytes to dopaminergic or GABAergic neurons. Some of these in vivo studies showed considerable coverage of subtypes in the newly induced neurons and partial reestablishment in neural circuits and functions. Importantly, we would like to point out some crucial technical concerns that need to be addressed to convincingly show successful glia‐to‐neuron conversion. Finally, we present challenges and future directions in the field for better neural function recovery.

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Awakening the regenerative potential of the mammalian retina

Cited by 27 publications

References 55 publications

Role of Macrophages and Microglia in Zebrafish Regeneration

Role of Macrophages and Microglia in Zebrafish Regeneration

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

In vivo glial trans‐differentiation for neuronal replacement and functional recovery in central nervous system

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