Secreted GDF15 maintains transcriptional responses during DNA damage-mediated senescence in human beta cells.

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Nayara Rampazzo Morelli, Camille Préfontaine, Jasmine Pipella, Peter J Thompson
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Abstract

Type 1 diabetes (T1D) is a chronic metabolic disease resulting from an autoimmune destruction of pancreatic beta cells. Beta cells activate various stress responses during the development of T1D, including senescence, which involves cell cycle arrest, prosurvival signaling, and a proinflammatory secretome termed the senescence-associated secretory phenotype (SASP). We previously identified growth and differentiation factor 15 (GDF15) as a major SASP factor in human islets and human EndoC-βH5 beta cells in a model of DNA damage-mediated senescence that recapitulates features of senescent beta cells in T1D. Soluble GDF15 has been shown to exert protective effects on human and mouse beta cells during various forms of stress relevant to T1D; therefore, we hypothesized that secreted GDF15 may play a prosurvival role during DNA damage-mediated senescence in human beta cells. We found that elevated GDF15 secretion was associated with endogenous senescent beta cells in an islet preparation from a T1D donor, supporting the validity of our DNA damage model. Using antibody-based neutralization, we found that secreted endogenous GDF15 was not required for senescent human islet or EndoC cell viability. Rather, neutralization of GDF15 led to reduced expression of specific senescence-associated genes, including GDF15 itself and the prosurvival gene BCL2-like protein 1 (BCL2L1). Taken together, these data suggest that SASP factor GDF15 is not required to sustain senescent human islet viability, but it is required to maintain senescence-associated transcriptional responses.NEW & NOTEWORTHY Beta cell senescence is an emerging contributor to the pathogenesis of type 1 diabetes, but candidate therapeutic targets have not been identified in human beta cells. In this study, we examined the role of a secreted factor, GDF15, and found that although it is not required to maintain viability during senescence, it is required to fine-tune gene expression programs involved in the senescence response during DNA damage in human beta cells.

分泌的 GDF15 可在 DNA 损伤介导的人类 β 细胞衰老过程中维持转录反应。
1 型糖尿病(T1D)是一种慢性代谢性疾病,由胰腺β细胞的自身免疫性破坏引起。在 T1D 的发展过程中,β 细胞会激活各种应激反应,包括衰老,其中涉及细胞周期停滞、促生存信号转导和一种称为衰老相关分泌表型(SASP)的促炎症分泌组。我们之前在一个DNA损伤介导的衰老模型中发现,生长与分化因子15(GDF15)是人胰岛和人EndoC-βH5β细胞中的主要SASP因子,该模型再现了T1D中衰老β细胞的特征。可溶性 GDF15 已被证明在与 T1D 相关的各种形式的应激过程中对人类和小鼠的 beta 细胞具有保护作用,因此我们假设分泌型 GDF15 可能在人类 beta 细胞 DNA 损伤介导的衰老过程中发挥促生存作用。我们发现,在一名 T1D 供体的胰岛制备物中,GDF15 分泌的升高与内源性衰老的 beta 细胞有关,这支持了我们的 DNA 损伤模型的有效性。通过抗体中和,我们发现分泌的内源性 GDF15 并不是衰老的人胰岛或 EndoC 细胞存活所必需的。相反,中和 GDF15 会导致特定衰老相关基因的表达减少,包括 GDF15 本身和前生存基因 BCL2L1。总之,这些数据表明,SASP因子GDF15不是维持衰老人胰岛活力所必需的,但它是维持衰老相关转录反应所必需的。
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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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