Dataset Information

Inhibition of mTORC1 by ER stress impairs neonatal ?-cell expansion and predisposes to diabetes in the Akita mouse.

ABSTRACT: Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of ?-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in ?-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to ?-cell dysfunction is marked impairment of ?-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal ?-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate ?-cells was sufficient to rescue postnatal ?-cell growth, and to improve diabetes. We propose a scenario for the development of permanent neonatal diabetes, possibly also common forms of diabetes, where early-life events inducing ER stress affect ?-cell mass expansion due to mTOR inhibition.

SUBMITTER: Riahi Y

PROVIDER: S-EPMC6294551 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the <i>Akita</i> mouse.

Riahi Yael Y Israeli Tal T Yeroslaviz Roni R Chimenez Shoshana S Avrahami Dana D Stolovich-Rain Miri M Alter Ido I Sebag Marina M Polin Nava N Bernal-Mizrachi Ernesto E Dor Yuval Y Cerasi Erol E Leibowitz Gil G

eLife 20181109

Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in <i>Akita</i> mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in β-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to β-cell dysfunction is marked impairment of β-cell growth durin ...[more]

PMID: 30412050

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Project description:BackgroundEarly-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2Akita mouse model.MethodsIns2Akita mice at 24 weeks of age received intravitreal injections of CD140b-positive ASCs (1000 cells/1 μL) or 20× conditioned media from cytokine-primed ASCs (ASC-CM, 1 μL). Age-matched wildtype mice that received saline served as controls. Visual function experiments and histological analyses were performed 3 weeks post intravitreal injection. Biochemical and molecular analyses assessed the ASC-CM composition and its biological effects.ResultsThree weeks post-injection, Ins2Akita mice that received ASCs had ameliorated decreased b-wave amplitudes and vascular leakage but failed to improve visual acuity, whereas Ins2Akita mice that received ASC-CM demonstrated amelioration of all aforementioned visual deficits. The ASC-CM group demonstrated partial amelioration of retinal GFAP immunoreactivity and DR-related gene expression but the ASC group did not. While Ins2Akita mice that received ASCs exhibited occasional (1 in 8) hemorrhagic retinas, mice that received ASC-CM had no adverse complications. In vitro, ASC-CM protected against TNFα-induced retinal endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrated several anti-inflammatory proteins including TSG-6 being highly expressed in cytokine-primed ASC-CM.ConclusionsASCs or their secreted factors mitigate retinal complications of diabetes in the Ins2Akita model. Further investigation is warranted to determine whether ASCs or their secreted factors are safe and effective therapeutic modalities long-term as current locally delivered therapies fail to effectively mitigate the progression of early-stage DR. Nonetheless, our study sheds new light on the therapeutic mechanisms of adult stem cells, with implications for assessing relative risks/benefits of experimental regenerative therapies for vision loss.

Dataset Information

Inhibition of mTORC1 by ER stress impairs neonatal ?-cell expansion and predisposes to diabetes in the Akita mouse.

Publications

Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the <i>Akita</i> mouse.

Similar Datasets

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