Report on the National Eye Institute Audacious Goals Initiative: Replacement of Retinal Ganglion Cells from Endogenous Cell Sources

Vetter, Monica L.; Hitchcock, Peter F.

doi:10.1167/tvst.6.2.5

Cited by 13 publications

(13 citation statements)

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“…Our data add details to the intrinsic immune response in the retina that is required for stem cell-based regeneration of photoreceptors. It is interesting to note that in the transcriptomes of Müller glia in both zebrafish and mouse models of photoreceptor degeneration the activation of cytokine pathways is conserved (Roesch et al, 2012;Sifuentes et al, 2016), suggesting that modulating intrinsic cellular mechanisms may be a promising therapeutic avenue to regenerate retinal neurons (Vetter et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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

Silva

Nagashima

et al. 2019

Preprint

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51Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and 52 glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the 53 zebrafish retina and determine the cellular expression and function of the inflammatory 54 protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Animals 55 of either sex were used in this study. Following photoreceptor ablation, anti-inflammatory 56 treatment suppresses the number of injury-induced progenitors and regenerated 57 photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia, the intrinsic retinal 58 stem cell, and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over 59 production of injury-induced progenitors and regenerated photoreceptors, but over time the 60 absence of Mmp-9 compromises the maturation and survival of the regenerated cones. Anti-61 inflammatory treatment in mutants rescues the defects in cone maturation and survival. These 62 data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function 63 during photoreceptor regeneration and the requirement of Mmp-9 for the survival of regenerated 64 cones. 65 66 67 68 69 70 71 72 73 74 75 3 Significance Statement 76 77 The innate immune system is activated by neuronal death, and recent studies demonstrate that 78 in zebrafish neuroinflammation is required for neuronal regeneration. The roles of inflammatory 79 cytokines are being investigated, however, the function of the inflammatory protease, matrix 80 metalloprotease Mmp-9, in neuronal regeneration is unknown. We show herein that in adult 81 zebrafish retinal inflammation governs the proliferative phase of the stem cell-based 82 regeneration of rod and cone photoreceptors and determine the specific roles for Mmp-9 in 83 photoreceptor regeneration. This study provides the first mechanistic insights into the potential 84 role of Mmp-9 in retinal regeneration and serves to link neuroinflammation, stem cell-based 85 regeneration of photoreceptors and human photoreceptor disease. 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 2013; Zhao et al., 2014). Following a photolytic lesion, dying photoreceptors secrete Tnf-a, to 129 which Müller glia respond by partial dedifferentiation, synthesis of Tnf-a and entry into the cell 130 cycle (Nelson et al., 2013). Mechanical lesions induce the expression of leptin and Il-6 family 131 cytokines in Müller glia and Müller glia-derived progenitors and is required for injury-induced 132 proliferation (Zhao et al., 2014).133 Matrix metalloproteinase 9 (Mmp-9) is a secreted protease that plays a prominent role in 134 tissue development and homeostasis by acting on extracellular molecules, including adhesion 135

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Section: Discussionmentioning

confidence: 99%

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

Silva

Nagashima

et al. 2019

Preprint

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“…The design of new strategies to increase the proliferative and neurogenic potential of mammalian Müller glia is one of the areas of interest in the development of regenerative therapies for retinal degenerative diseases (Vetter and Hitchcock, 2017;Yao et al, 2018). Attempts to apply in vivo the transcription factor Ascl1, either alone or in combination with other factors such as miRNA or drugs that impact chromatin organization, interfered with the neurogenic potential of Müller glia.…”

Section: Discussionmentioning

confidence: 99%

“…Concern has also been raised about direct transfer of proteins between donor and host cells that could have misled the identification of donor cell integration, although no material transfer has yet been detected in RGCs (Boudreau-Pinsonneault and Cayouette, 2018;Nickerson et al, 2018;Pearson et al, 2016;Santos-Ferreira et al, 2016;Singh et al, 2016). An alternative approach is to promote de novo genesis of RGCs in adult retina via in vivo reprogramming (Vetter and Hitchcock, 2017).…”

Section: Introductionmentioning

confidence: 99%

De novo genesis of retinal ganglion cells by targeted expression of Klf4 in vivo

et al. 2019

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Retinal ganglion cell (RGC) degeneration is a hallmark of glaucoma, the most prevalent cause of irreversible blindness. Thus, therapeutic strategies are needed to protect and replace these projection neurons. One innovative approach is to promote de novo genesis of RGCs via manipulation of endogenous cell sources. Here, we demonstrate that the pluripotency regulator gene Krüppel-like factor 4 (Klf4) is sufficient to change the potency of lineage-restricted retinal progenitor cells to generate RGCs in vivo. Transcriptome analysis disclosed that the overexpression of Klf4 induces crucial regulators of RGC competence and specification, including Atoh7 and Eya2. In contrast, loss-offunction studies in mice and zebrafish demonstrated that Klf4 is not essential for generation or differentiation of RGCs during retinogenesis. Nevertheless, induced RGCs (iRGCs) generated upon Klf4 overexpression migrate to the proper layer and project axons aligned with endogenous fascicles that reach the optic nerve head. Notably, iRGCs survive for up to 30 days after in vivo generation. We identified Klf4 as a promising candidate for reprogramming retinal cells and regenerating RGCs in the retina. This article has an associated 'The people behind the papers' interview.

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“…The design of new strategies to increase the proliferative and neurogenic potential of mammalian Muller glia is one of the areas of interest to develop regenerative therapies for retinal degenerative diseases (Vetter et al, 2017). Attempts to apply the transcription factor Ascl1, either alone or in combination with other factors such as miRNA or drugs that impact the chromatin organization, interfered with the neurogenic potential of Müller glia, but did not lead to the generation of ganglion cells (Pollak et al, 2013; Ueki et al, 2015; Jorstad et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Though promising, low integration efficiency, as well as rejection by the host pose significant challenges to cell therapy. An alternative approach is to promote de novo genesis of RGCs in adult retina via in vivo reprogramming (Vetter et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

De novogenesis of retinal ganglion cells by targeted expression of KLF4in vivo

Rocha-Martins

Toledo

Santos-França

et al. 2018

Preprint

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Retinal ganglion cell (RGC) degeneration is a hallmark of glaucoma, the most prevalent cause of irreversible blindness. Thus, innovative therapeutic strategies are needed to protect and replace these projection neurons. It has been shown that endogenous glial cells of the retina, Müller cells, can be directly reprogrammed into late-born retinal interneurons. However, since RGCs are the first neurons born during development, the replacement of damaged RGCs requires the reprograming to an early neurogenic state.Here, we demonstrate that the pluripotency regulator Klf4 is sufficient to reprogram the potency of lineage-restricted retinal progenitor cells (RPCs) to generate RGCs in vivo.Transcriptome analysis disclosed that the overexpression of Klf4 induces crucial regulators of RGC competence and specification, including Atoh7 and Eya2. In contrast, loss-of-function studies in mice and zebrafish demonstrated that Klf4 is not essential for generation or differentiation of RGCs during retinogenesis. Nevertheless, induced RGCs (iRGCs) generated upon Klf4 overexpression migrate to the proper layer and project axons aligned with endogenous fascicles that reach the optic nerve head.Notably, iRGCs survive for up to 30 days after in vivo reprogramming. Finally, we demonstrate that Klf4 converts Müller cells into neurons that express markers of RGCs.Altogether, we identified Klf4 as a promising tool to reprogram retinal cells and regenerate RGCs in the mature retina. Significance StatementCell fate determination is a key process for development, regeneration and for the design of therapeutic strategies that involve cellular reprogramming. This work shows that the manipulation of a single pluripotency regulator (Klf4) is sufficient to reprogram restricted progenitor cells in vivo. These reprogrammed progenitors reacquire the potency to generate retinal ganglion cells. Ganglion cell degeneration is the leading cause of irreversible blindness; therefore, manipulation of ganglion cell competence is of relevance for human health. Our findings point to Klf4 as a promising tool to develop therapeutic strategies for the replacement of damaged ganglion cells.1 1 among the cells that underwent recombination (CRE+) when MG CTR and MG KLF4 groups were compared ( Figure 7E-H). These results raise the possibility that Klf4 may reprogram activated Müller glial cells to the RGC fate. DiscussionWe show here that although Klf4 is not essential for RGC generation during retinal development in either mouse or zebrafish retinas, it is sufficient to induce de novo genesis of RGCs in vivo outside their developmental window. Late retinal progenitors overexpressing Klf4 exit the cell cycle prematurely, reside mostly in the ganglion cell and inner plexiform layers, contain molecular signatures of RGCs, and project axons towards the initial segment of the optic nerve. Notably, cell cycle exit was accompanied by strong upregulation of Atoh7, a master regulator of the transcription network for RGC differentiation. Even though KLF4-induced RGCs (iRGCs) d...

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Report on the National Eye Institute Audacious Goals Initiative: Replacement of Retinal Ganglion Cells from Endogenous Cell Sources

Cited by 13 publications

References 103 publications

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

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

De novo genesis of retinal ganglion cells by targeted expression of Klf4 in vivo

De novogenesis of retinal ganglion cells by targeted expression of KLF4in vivo

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