Reprogramming of adult rod photoreceptors prevents retinal degeneration

Montana, Cynthia L.; Kolesnikov, Alexander V.; Shen, Susan Q.; Myers, Connie A.; Kefalov, Vladimir J.; Corbo, Joseph C.

doi:10.1073/pnas.1214387110

Cited by 75 publications

(80 citation statements)

References 48 publications

(54 reference statements)

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“…Inspiringly, an increasing number of reports have demonstrated that lineage reprogramming can be achieved in vivo Inagawa et al, 2012;Jayawardena et al, 2012;Li et al, 2014b;Mathison et al, 2012;Montana et al, 2013;Niu et al, 2013;Qian et al, 2012;Rouaux and Arlotta, 2013;Song et al, 2012;Torper et al, 2013;Zhou et al, 2008). Recently, it has been reported that glial cells, especially astrocytes, can be converted into functional neuroblasts or neurons in vivo Niu et al, 2013;Torper et al, 2013).…”

Section: Strategies To Produce Large Numbers Of Induced Cells For Tramentioning

confidence: 95%

Direct Lineage Reprogramming: Strategies, Mechanisms, and Applications

2015

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The direct lineage reprogramming of one specialized cell type into another using defined factors has fundamentally re-shaped traditional concepts regarding the epigenetic stability of differentiated cells. With the rapid increase in cell types generated through direct conversion in recent years, this strategy has become a promising approach for producing functional cells. Here, we review recent advances in lineage reprogramming, including the identification of novel reprogramming factors, underlying molecular mechanisms, strategies for generating functionally mature cells, and assays for characterizing induced cells. We also discuss progress toward the application of lineage reprogramming and the major future challenges for this strategy.

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Section: Strategies To Produce Large Numbers Of Induced Cells For Tramentioning

confidence: 95%

Direct Lineage Reprogramming: Strategies, Mechanisms, and Applications

2015

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“…Accumulating evidence indicates that mature retinal neurons are plastic and can undergo fate reprogramming. For example, ablating the Nrl gene in mature rod photoreceptors results in partial transformation of rod cells toward a cone cell fate, accompanied by altered rod nuclear morphology and enhanced cell survival (53). It is possible that Jak-STAT signaling directly influences the chromatin structure of photoreceptor cells in a cell autonomous fashion.…”

Section: Discussionmentioning

confidence: 99%

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in multiple retinal degeneration animal models. Recently, CNTF has been evaluated in clinical trials for the inherited degenerative disease retinitis pigmentosa (RP) and for dry agerelated macular degeneration (AMD). Despite its potential as a broad-spectrum therapeutic treatment for blinding diseases, the target cells of exogenous CNTF and its mechanism of action remain poorly understood. We have shown previously that constitutive expression of CNTF prevents photoreceptor death but alters the retinal transcriptome and suppresses visual function. Here, we use a lentivirus to deliver the same secreted human CNTF used in clinical trials to a mouse model of RP. We found that low levels of CNTF halt photoreceptor death, improve photoreceptor morphology, and correct opsin mislocalization. However, we did not detect corresponding improvement of retinal function as measured by the electroretinogram. Disruption of the cytokine receptor gp130 gene in Müller glia reduces CNTF-dependent photoreceptor survival and prevents phosphorylation of STAT3 and ERK in Müller glia and the rest of the retina. Targeted deletion of gp130 in rods also demolishes neuroprotection by CNTF and prevents further activation of Müller glia. Moreover, CNTF elevates the expression of LIF and endothelin 2, thus positively promoting Müller and photoreceptor interactions. We propose that exogenous CNTF initially targets Müller glia, and subsequently induces cytokines acting through gp130 in photoreceptors to promote neuronal survival. These results elucidate a cellular mechanism for exogenous CNTF-triggered neuroprotection and provide insight into the complex cellular responses induced by CNTF in diseased retinas.C iliary neurotrophic factor (CNTF) belongs to a small subfamily of cytokines and has long been recognized as a potent neuroprotective molecule in the vertebrate retina (1). Enhancement of photoreceptor survival by CNTF has been demonstrated in multiple animal models of retinal degeneration, ranging from zebrafish to canine (2). Interestingly, CNTF is effective in rescuing retinal degeneration due to various causes, including mutations in genes expressed by photoreceptors or the retinal pigment epithelium (RPE), as well as those induced by strong light, neurotoxins, or antibodies. In addition, CNTF prolongs the survival of retinal ganglion cells (3-5) and promotes axonal growth in optic nerve crush or transection models (6-8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9, 10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11-14). However, despite its clinical signifi...

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“…Several lines of evidence support this bipotent precursor model: (1) some rod and cone marker [i.e. Nrl and Thrβ2 (TRβ2)] overlap has been observed during development (Ng et al, 2011); (2) Nrl expression in developing cones can partially convert cells to a rod identity (Oh et al, 2007); and (3) removing Nrl from adult rods can partially convert them into cones (Montana et al, 2013). An alternative explanation (Fig.…”

Section: Transcriptional Network Regulating Photoreceptor Identitymentioning

confidence: 99%

Photoreceptor cell fate specification in vertebrates

2015

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Photoreceptors -the light-sensitive cells in the vertebrate retinahave been extremely well-characterized with regards to their biochemistry, cell biology and physiology. They therefore provide an excellent model for exploring the factors and mechanisms that drive neural progenitors into a differentiated cell fate in the nervous system. As a result, great progress in understanding the transcriptional network that controls photoreceptor specification and differentiation has been made over the last 20 years. This progress has also enabled the production of photoreceptors from pluripotent stem cells, thereby aiding the development of regenerative medical approaches to eye disease. In this Review, we outline the signaling and transcription factors that drive vertebrate photoreceptor development and discuss how these function together in gene regulatory networks to control photoreceptor cell fate specification.

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Reprogramming of adult rod photoreceptors prevents retinal degeneration

Cited by 75 publications

References 48 publications

Direct Lineage Reprogramming: Strategies, Mechanisms, and Applications

Direct Lineage Reprogramming: Strategies, Mechanisms, and Applications

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Photoreceptor cell fate specification in vertebrates

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