Leptin and IL-6 Family Cytokines Synergize to Stimulate Müller Glia Reprogramming and Retina Regeneration

Zhao, Xiangfu; Wei, Jin; Powell, Curtis; Ramachandran, Rajesh; Myers, Martin G.; Goldman, Daniel

doi:10.1016/j.celrep.2014.08.047

Cited by 151 publications

(192 citation statements)

References 46 publications

(116 reference statements)

Supporting

Mentioning

185

Contrasting

Order By: Relevance

“…Only cells such as Müller cells (but not endothelial cells) that express IL-6R are able to signal through classical IL-6 signaling. Conversely, IL-6 trans-signaling, which is mediated by binding of IL-6 to the soluble form of the IL-6 receptor (sIL-6R) and gp130, is thought to be the more pro-inflammatory and pro-angiogenic pathway[77,96,99,102–112]. In diabetic patients, correlations between increased levels of IL-6 and the development of complications in the eye have been made[113–118].…”

Section: Release Of Growth Factors and Pro-/anti-inflammatory Cytokinmentioning

confidence: 99%

Müller cells and diabetic retinopathy

2017

View full text Add to dashboard Cite

Müller cells are one of the primary glial cell types found in the retina and play a significant role in maintaining retinal function and health. Since Müller cells are the only cell type to span the entire width of the retina and have contact to almost every cell type in the retina they are uniquely positioned to perform a wide variety of functions necessary to maintaining retinal homeostasis. In the healthy retina, Müller cells recycle neurotransmitters, prevent glutamate toxicity, redistribute ions by spatial buffering, participate in the retinoid cycle, and regulate nutrient supplies by multiple mechanisms. Any disturbance to the retinal environment is going to influence proper Müller cell function and well being which in turn will affect the entire retina. This is evident in a disease like diabetic retinopathy where Müller cells contribute to neuronal dysfunction, the production of pro-angiogenic factors leading to neovascularization, the set up of a chronic inflammatory retinal environment, and eventual cell death. In this review, we highlight the importance of Müller cells in maintaining a healthy and functioning retina and discuss various pathological events of diabetic retinopathy in which Müller cells seem to play a crucial role. The beneficial and detrimental effects of cytokine and growth factor production by Müller cells on the microvasculature and retinal neuronal tissue will be outlined. Understanding Müller cell functions within the retina and restoring such function in diabetic retinopathy should become a cornerstone for developing effective therapies to treat diabetic retinopathy.

show abstract

Section: Release Of Growth Factors and Pro-/anti-inflammatory Cytokinmentioning

confidence: 99%

Müller cells and diabetic retinopathy

2017

View full text Add to dashboard Cite

show abstract

“…Although repression of Notch can stimulate a small increase in the expression of de-differentiation markers including Ascl1a, this is not sufficient to produce a strong proliferative response in the retina; additional damage related signals are necessary [66, 69, 68]. The identities of many of these damage induced molecules have been uncovered in recent years [66, 68, 70-72] , but more work is needed in understanding the details of how they interact with the Notch signaling pathway.…”

Section: Pro-regenerative Speciesmentioning

confidence: 99%

“…The release of cytokines following injury, including IL-6, leads to stimulation of gp130-coupled cytokine receptors, and activation of the Jak/Stat pathway [70]. The repression of the Notch pathway also induces Stat3, suggesting that in the mature fish retina Notch may inhibit Jak/Stat ligands [69].…”

Section: Pro-regenerative Speciesmentioning

confidence: 99%

The Regulation of Notch Signaling in Retinal Development and Regeneration

Mills

Goldman

2017

Curr Pathobiol Rep

Self Cite

View full text Add to dashboard Cite

Purpose of review Notch signaling is an important component of retinal progenitor cell maintenance and MG specification during development, and its manipulation may be critical for allowing MG to re-enter the cell cycle and regenerate neurons in adults. In mammals, MG respond to retinal injury by undergoing a gliotic response rather than a regenerative one. Understanding the complexities of Notch signaling may allow for strategies that enhance regeneration over gliosis. Recent findings Notch signaling is regulated at multiple levels, and is interdependent with various other signaling pathways in both the receptor and ligand expressing cells. The precise spatial and temporal patterning of Notch components is necessary for proper retinal development. Regenerative species undergo a dynamic regulation of Notch signaling in MG upon injury, whereas non-regenerative species fail to productively regulate Notch. Summary Notch signaling is malleable, such that the altered composition of growth and transcription factors in the developing and mature retinas result in different Notch mediated responses. Successful regeneration will require the manipulation of the retinal environment to foster a dynamic rather than static regulation of Notch signaling in concert with other reprogramming and differentiation factors.

show abstract

“…Because JAK/STAT is required for regeneration in tissues as diverse as the grasshopper leg to the mouse liver (Yamada et al, 1997;Bando et al, 2013;Cressman et al, 1996;Li et al, 2002;Wuestefeld et al, 2003;Zhao et al, 2014), dissecting the function of this highly conserved pathway is essential for our understanding of regenerative processes. To achieve this, we employed an imaginal disc model of tissue stress, which utilizes ectopic expression of the TNFα homologue Eiger (Smith-Bolton et al, 2009) (Fig.…”

Section: Introductionmentioning

confidence: 99%

JAK/STAT signalling mediates cell survival in response to tissue stress

et al. 2016

View full text Add to dashboard Cite

Tissue homeostasis relies on the ability of tissues to respond to stress. Tissue regeneration and tumour models in Drosophila have shown that c-Jun amino-terminal kinase (JNK) acts as a prominent stress-response pathway promoting injury-induced apoptosis and compensatory proliferation. A central question remaining unanswered is how both responses are balanced by activation of a single pathway. Signalling through the Janus kinase/Signal transducers and activators of transcription (JAK/STAT) pathway, which is a potential JNK target, is implicated in promoting compensatory proliferation. While we observe JAK/STAT activation in imaginal discs upon damage, our data demonstrate that JAK/STAT and its downstream effector Zfh2 promote the survival of JNK signalling cells. The JNK component fos and the pro-apoptotic gene hid are regulated in a JAK/STAT-dependent manner. This molecular pathway restrains JNK-induced apoptosis and spatial propagation of JNK signalling, thereby limiting the extent of tissue damage, as well as facilitating systemic and proliferative responses to injury. We find that the pro-survival function of JAK/STAT also drives tumour growth under conditions of chronic stress. Our study defines the function of JAK/STAT in tissue stress and illustrates how crosstalk between conserved signalling pathways establishes an intricate equilibrium between proliferation, apoptosis and survival to restore tissue homeostasis.

show abstract

Leptin and IL-6 Family Cytokines Synergize to Stimulate Müller Glia Reprogramming and Retina Regeneration

Cited by 151 publications

References 46 publications

Müller cells and diabetic retinopathy

Müller cells and diabetic retinopathy

The Regulation of Notch Signaling in Retinal Development and Regeneration

JAK/STAT signalling mediates cell survival in response to tissue stress

Contact Info

Product

Resources

About