Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice

Kubota, Yoshiaki; Hirashima, Masanori; Kishi, Kazuo; Stewart, Colin L.; Suda, Toshio

doi:10.1172/jci34882

Cited by 58 publications

(89 citation statements)

References 24 publications

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“…Although LIF has been implicated in retinal development (Elliott et al, 2006) and lack of LIF was recently reported to increase microvessel density in the retina (Kubota et al, 2008), retinal morphology of Lif -/-mice was similar to wild-type mice at all ages tested. Retinal cell layers were well established and distribution of rods and cones was inconspicuous (Fig.…”

Section: Lack Of Lif Accelerates Photoreceptor Degeneration In a Modementioning

confidence: 81%

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Joly¹,

Lange²,

Thiersch³

et al. 2008

J. Neurosci.

117

167

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Survival and death of photoreceptors in degenerative diseases of the retina is controlled by a multitude of genes and endogenous factors. Some genes may be involved in the degenerative process itself whereas others may be part of an endogenous defense system. We show in two models of retinal degeneration that photoreceptor death strongly induces expression of leukemia inhibitory factor (LIF) in a subset of Muller glia cells in the inner nuclear layer of the retina. LIF expression is essential to induce an extensive intraretinal signaling system which includes Muller cells and photoreceptors and is characterized by an upregulation of Edn2, STAT3, FGF2 and GFAP. In the absence of LIF, Muller cells remain quiescent, the signaling system is not activated and retinal degeneration is strongly accelerated. Intravitreal application of recombinant LIF induces the full molecular pathway including the activation of Muller cells in wild-type and Lif -/-mice. Interruption of the signaling cascade by an Edn2 receptor antagonist increases whereas activation of the receptor decreases photoreceptor cell death. Thus, LIF is essential and sufficient to activate an extensive molecular defense response to photoreceptor injury. Our data establish LIF as a Muller cell derived neuronal survival factor which controls an intrinsic protective mechanism that includes Edn2 signaling to support photoreceptor cell survival and to preserve vision in the injured retina.

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Section: Lack Of Lif Accelerates Photoreceptor Degeneration In a Modementioning

confidence: 81%

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Joly¹,

Lange²,

Thiersch³

et al. 2008

J. Neurosci.

117

167

View full text Add to dashboard Cite

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“…7E). It is accepted that immature weakly GFAP-positive astrocytes induce proliferation of ECs but that this is gradually reduced as their level of GFAP expression increases (Kubota et al, 2008;West et al, 2005). This was suggested to be caused by the expression of VEGF in immature astrocytes.…”

Section: Research Articlementioning

confidence: 99%

“…In the course of retinal angiogenesis, astrocytes act as proangiogenic accessory cells, as described above; however, upon becoming overlaid with ECs, it has been suggested that their proangiogenic activity ceases and they instead stabilize newly developed blood vessels (West et al, 2005;Kubota et al, 2008). Anatomical analysis has revealed that astrocytes expressing low levels of glial fibrillary acidic protein (GFAP) firstly invade the retina, gradually express higher levels of GFAP, and become quiescent (Chu et al, 2001;Gariano, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Anatomical analysis has revealed that astrocytes expressing low levels of glial fibrillary acidic protein (GFAP) firstly invade the retina, gradually express higher levels of GFAP, and become quiescent (Chu et al, 2001;Gariano, 2003). Therefore, it has been suggested that ECs might change astrocyte characteristics (Zhang and Stone, 1997), with several lines of evidence suggesting that leukemia inhibitory factor (LIF) derived from ECs is a direct maturation factor for immature astrocytes in vitro (Mi et al, 2001) and in vivo (Kubota et al, 2008). However, the mechanism responsible for controlling LIF production by ECs for maturation of astrocytes has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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A role for endothelial cells in promoting the maturation of astrocytes through the apelin/APJ system in mice

et al. 2012

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SUMMARYInteractions between astrocytes and endothelial cells (ECs) are crucial for retinal vascular formation. Astrocytes induce migration and proliferation of ECs via their production of vascular endothelial growth factor (VEGF) and, conversely, ECs induce maturation of astrocytes possibly by the secretion of leukemia inhibitory factor (LIF). Together with the maturation of astrocytes, this finalizes angiogenesis. Thus far, the mechanisms triggering LIF production in ECs are unclear. Here we show that apelin, a ligand for the endothelial receptor APJ, induces maturation of astrocytes mediated by the production of LIF from ECs. APJ (Aplnr)-and Aplndeficient mice show delayed angiogenesis; however, aberrant overgrowth of endothelial networks with immature astrocyte overgrowth was induced. When ECs were stimulated with apelin, LIF expression was upregulated and intraocular injection of LIF into APJ-deficient mice suppressed EC and astrocyte overgrowth. These data suggest an involvement of apelin/APJ in the maturation process of retinal angiogenesis.

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“…Vegf gene expression is immediately suppressed in the area covered by the vasculature. 17,20 To investigate the regulatory system for retinal vascular development, we generated retinal neuron-specific Hif-1α knockout mice. These mice showed a delay in retinal vascular development because of a decreased number of endothelial tip cells with fewer filopodial extensions located at the leading edge of the spreading vasculature.…”

Section: Hypoxia Response In Retinal Developmentmentioning

confidence: 99%

Roles of Hypoxia Response in Retinal Development and Pathophysiology

Kurihara

2017

Keio J. Med.

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The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-typespecific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells. We found that these genes in the different types of retinal cells contribute in various ways to the homeostasis of ocular vascular and visual function. We hypothesized that the activation of HIFs is likely involved in the development and progress of retinal diseases, and we subsequently confirmed the pathological roles of HIFs in animal models of neovascular and atrophic ocular diseases. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapy is a first-line treatment widely used for neovascular retinal diseases. However, alternative or additional targets are now required because several recent large-scale clinical trials and animal studies, including our own research, have indicated that VEGF antagonism may induce retinal vascular and neuronal degeneration. We have identified and confirmed a microRNA as a candidate for an alternative target against neovascular retinal diseases, and we are now working to establish a novel HIF inhibitor for clinical use based on the disease mechanism that we identified.

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Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice

Cited by 58 publications

References 24 publications

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

A role for endothelial cells in promoting the maturation of astrocytes through the apelin/APJ system in mice

Roles of Hypoxia Response in Retinal Development and Pathophysiology

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