通过CD47激活调节胰岛应激反应

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Atharva Kale, Mahmoud Azar, Vanessa Cheng, Harry Robertson, Sally Coulter, Paulomi M. Mehta, Sohel M. Julovi, Ellis Patrick, Kedar Ghimire, Natasha M. Rogers
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引用次数: 0

摘要

目的/假设糖尿病是一种全球性的健康负担,其特征是β细胞逐渐减少。胰岛移植是一种公认的治疗1型糖尿病和低血糖患者的方法,但胰岛移植后的生存和功能有限,限制了其广泛应用。诱导β细胞功能障碍和死亡的潜在分子机制尚不清楚,保护细胞损失和维持胰岛素分泌的治疗药物是潜在的治疗选择。CD47是一种参与细胞应激反应的细胞表面蛋白,但其在β细胞功能中的作用仍相对未被探索。我们假设调节CD47的表达会在β细胞中显示出细胞保护作用。方法我们使用CD47基因缺失或不缺失的小鼠胰岛,以及CD47信号通路(siRNA或阻断抗体)受到药物破坏的人胰岛和MIN6细胞。通过暴露于缺氧、高血糖或thapsigargin诱导细胞代谢应激,并评估未折叠蛋白反应、细胞存活和胰岛素分泌功能的标志物。研究人员检查了患有和不患有糖尿病的人的胰腺,以寻找CD47信号的证据。结果CD47及其高亲和力配体血栓反应蛋白-1 (TSP1)的表达在外源应激条件下明显上调。限制CD47信号传导可改善衰老、凋亡、内质网应激、未折叠蛋白反应、自我更新和自噬等标志物,并维持胰岛素分泌反应。我们还发现,在老年供体和2型糖尿病患者的内分泌胰腺中,CD47和衰老标志物的表达同时上调。1型糖尿病患者胰腺中CD47和TSP1的表达增加,血浆中TSP1的水平也增加。结论/解释我们的研究为CD47作为胰岛功能障碍的一种新型调节剂的重要作用提供了关键的见解,调节细胞对应激的保护反应。CD47可能在糖尿病发展和胰岛移植功能衰竭过程中导致β细胞损伤。因此,限制CD47的激活可能是胰岛功能不足的潜在治疗工具。图形抽象
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Regulating islet stress responses through CD47 activation

Aims/hypothesis

Diabetes is a global health burden characterised by incremental beta cell loss. Islet transplantation is a recognised treatment for individuals with type 1 diabetes and hypoglycaemia unawareness but broader application is constrained by limited islet survival and function post-transplantation. The underlying molecular mechanisms that induce beta cell dysfunction and demise remain unclear, and therapeutic agents that protect against cellular loss and maintain insulin secretion are in demand as potential treatment options. CD47 is a cell surface protein implicated in cellular stress responses but its role in beta cell function remains relatively unexplored. We hypothesised that modulating CD47 expression would demonstrate a cytoprotective effect in beta cells.

Methods

We used primary murine islets with/without genetic deletion of CD47, as well as human islets and MIN6 cells subjected to pharmacological disruption of CD47 signalling (siRNA or blocking antibody). Metabolic stress was induced in cells by exposure to hypoxia, hyperglycaemia or thapsigargin, and markers of the unfolded protein response, cell survival and insulin secretory function were assessed. Human pancreases from individuals with and without diabetes were examined for evidence of CD47 signalling.

Results

Expression of CD47 and its high affinity ligand thrombospondin-1 (TSP1) was robustly upregulated by exogenous stressors. Limiting CD47 signalling improved markers of senescence, apoptosis, endoplasmic reticulum stress, unfolded protein response, self-renewal and autophagy, and maintained insulin secretory responses. We also found concurrent upregulated expression of CD47 and senescence markers in the endocrine pancreas of aged donors and those with type 2 diabetes. Both CD47 and TSP1 expression were increased in pancreases of humans with type 1 diabetes, as were plasma levels of TSP1.

Conclusions/interpretation

Our study provides key insights into the essential role of CD47 as a novel regulator of islet dysfunction, regulating cytoprotective responses to stress. CD47 may contribute to beta cell damage during the development of diabetes and failure of islet transplant function. Therefore, limiting CD47 activation may be a potential therapeutic tool in conditions where islet function is inadequate.

Graphical Abstract

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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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