Leukemia inhibitory factor: Recent advances and implications in biotechnology

Pinho, Vanessa; Fernandes, Mário Marques; Costa, André da; Machado, Raúl; Gomes, Andreia C.

doi:10.1016/j.cytogfr.2019.11.005

Cited by 21 publications

(18 citation statements)

References 66 publications

(116 reference statements)

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“…Likewise, IRF7 was shown to induce a pro-to-anti-inflammatory phenotypic shift in microglia 66 . Finally, LIF through its immunomodulatory and regenerative properties promotes survival of neurons and glia in several animal models of neurodegenerative disease, such as amyotrophic lateral sclerosis, MS, spinal cord injury and stroke 67 . These data suggest that HMG20A modulates reactive astrogliosis, both at its initiation as well as at its reabsorption.…”

Section: Discussionmentioning

confidence: 99%

The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity

Lorenzo¹,

Vázquez²,

López-Noriega³

et al. 2021

Theranostics

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Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocy...

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Section: Discussionmentioning

confidence: 99%

The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity

Lorenzo¹,

Vázquez²,

López-Noriega³

et al. 2021

Theranostics

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“…Leukemia inhibitory factor (LIF), a multifunctional cytokine involved in many diseases, including cancer, regulates cell proliferation, differentiation, and carcinogenesis 7 . It is a member of the interleukin‐6 cytokine family and activates cell signaling by binding to the leukemia inhibitory factor receptor/glycoprotein 130 (LIFR/gp130) heterodimer 8 .…”

Section: Introductionmentioning

confidence: 99%

Leukemia inhibitory factor promotes gastric cancer cell proliferation, migration, and invasion via the LIFR–Hippo–YAP pathway

Bian

Yang

Liang

et al. 2020

Annals of the New York Academy of Sciences

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The long‐term outcome of gastric cancer (GC) patients remains unsatisfactory despite some recent improvements. Leukemia inhibitory factor (LIF) is a prognostic biomarker for some solid tumors, however its role in GC remains unknown. In this study, we demonstrated that LIF and LIF receptor (LIFR) are overexpressed in GC tissues and established that a correlation exists between them. LIF and LIFR expression are associated with tumor differentiation, lymphovascular invasion, tumor stage, lymph node metastasis, and pTNM stage, indicating that they may be useful prognostic factors. LIF promoted GC cell proliferation, colony formation, invasion, migration, and tumor growth; it also promoted cell cycle progression and inhibited apoptosis; and knocking out the LIFR gene reversed the effects of LIF. LIF inhibited the activity of the Hippo pathway, resulting in reduced phosphorylation of YAP, increased YAP nuclear translocation, and increased cell proliferation. Finally, silencing YAP mRNA expression suppressed cell proliferation. Overall, the results demonstrate that LIF promotes the malignant biological behavior of GC cells through LIFR–Hippo–YAP signaling. LIF may therefore be a useful biomarker for GC.

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“…Likewise, IRF7 was shown to induce a pro-to-anti-inflammatory phenotypic shift in microglia [63]. Finally, LIF through its immunomodulatory and regenerative properties promotes survival of neurons and glia in several animal models of neurodegenerative disease, such as amyotrophic lateral sclerosis, MS, spinal cord injury and stroke [64]. These data suggest that HMG20A modulates astrogliosis, both at its initiation as well as at its reabsorption.…”

Section: Discussionmentioning

confidence: 99%

The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity

Lorenzo

Fuente-Martín

Mellado-Gil

et al. 2021

Preprint

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Rationale: We recently demonstrated that the Metabesity factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1/CoREST complex but its expression pattern and function in the adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (RT-PCR) and/or immunofluorescence in 1) the hypothalamus of mice exposed or not to a high-fat diet, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. To investigate the function and regulatory mechanism of HMG20A, RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. The regulatory function of HMG20A on astrogliosis was also assessed pharmacologically using ORY1001. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. Hmg20A expression was upregulated in diet-induced obesity and glucose-intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and astrogliosis. Expression levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways with a concomitant increase in apoptosis and reduced mitochondrial bioenergetics. Motoneuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. Astrogliosis was induced using ORY1001, a pharmacological inhibitor of the LSD1/CoREST complex, mimicking the effect of HMG20A. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low-grade inflammation, HMG20A expression is increased to induce astrogliosis in an attempt to preserve the neuronal network and glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote astrogliosis and increase the susceptibility of neurons to stress-mediated apoptosis. Such effects could be therapeutically reversed by ORY1001-induced astrogliosis.

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Leukemia inhibitory factor: Recent advances and implications in biotechnology

Cited by 21 publications

References 66 publications

The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity

The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity

Leukemia inhibitory factor promotes gastric cancer cell proliferation, migration, and invasion via the LIFR–Hippo–YAP pathway

The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity

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