A live-cell, high-content imaging survey of 206 endogenous factors across five stress conditions reveals context-dependent survival effects in mouse primary beta cells.
A live-cell, high-content imaging survey of 206 endogenous factors across five stress conditions reveals context-dependent survival effects in mouse primary beta cells.
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DOI：
10.1007/s00125-015-3552-5
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发表时间：
2015-06
期刊：
影响因子：
8.2
通讯作者：
Johnson, James D.
中科院分区：
文献类型：
--
作者：
Yang, Yu Hsuan Carol;Wills, Quin F.;Johnson, James D.
β细胞死亡是糖尿病的标志。目前尚不清楚与1型或2型糖尿病相关的特定细胞应激是否需要特定的因子来保护胰腺β细胞。没有系统的比较内源性可溶性因子的背景下，多种促凋亡条件已公布。在模拟5种1型或2型糖尿病相关应激的条件下培养原代小鼠胰岛细胞：基础5 mmol/l葡萄糖、细胞因子混合物（25 ng/ml TNF-α、10 ng/ml IL-1β、10 ng/ml IFN-γ）、1 μmol/l毒胡萝卜素、1.5 mmol/l棕榈酸酯和20 mmol/l葡萄糖（均不含血清）。我们通过多参数活细胞成像研究了206种内源性因子（根据其受体的胰岛表达选择）对胰岛细胞存活的影响。我们的调查指出，生存因素在旨在模拟不同类型糖尿病和疾病阶段的条件下表现出普遍的保护作用。例如，我们的调查和后续实验表明，OLFM 1是一种在多种条件下对小鼠和人类β细胞的新型保护因子。最引人注目的是，我们还发现了每个模型应激条件下的特定保护性生存因子。例如，脑信号蛋白4A（SEMA 4A）在无血清基线和无血清20 mmol/l葡萄糖条件下对胰岛细胞有毒，但在脂毒性的情况下具有保护作用。秩次乘积检验支持了我们观察结果的一致性。总的来说，我们的调查揭示了之前未识别的胰岛细胞生存因素，并表明它们在个体化医学中的潜在用途。本文的在线版本（doi：10.1007/s 00125 -015-3552-5）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Beta cell death is a hallmark of diabetes. It is not known whether specific cellular stresses associated with type 1 or type 2 diabetes require specific factors to protect pancreatic beta cells. No systematic comparison of endogenous soluble factors in the context of multiple pro-apoptotic conditions has been published. Primary mouse islet cells were cultured in conditions mimicking five type 1 or type 2 diabetes-related stresses: basal 5 mmol/l glucose, cytokine cocktail (25 ng/ml TNF-α, 10 ng/ml IL-1β, 10 ng/ml IFN-γ), 1 μmol/l thapsigargin, 1.5 mmol/l palmitate and 20 mmol/l glucose (all in the absence of serum). We surveyed the effects of a library of 206 endogenous factors (selected based on islet expression of their receptors) on islet cell survival through multi-parameter, live-cell imaging. Our survey pointed to survival factors exhibiting generalised protective effects across conditions meant to model different types of diabetes and stages of the diseases. For example, our survey and follow-up experiments suggested that OLFM1 is a novel protective factor for mouse and human beta cells across multiple conditions. Most strikingly, we also found specific protective survival factors for each model stress condition. For example, semaphorin4A (SEMA4A) was toxic to islet cells in the serum-free baseline and serum-free 20 mmol/l glucose conditions, but protective in the context of lipotoxicity. Rank product testing supported the consistency of our observations. Collectively, our survey reveals previously unidentified islet cell survival factors and suggest their potential utility in individualised medicine. The online version of this article (doi:10.1007/s00125-015-3552-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
4.8
作者：
Beith, Jennifer L.;Alejandro, Emilyn U.;Johnson, James D.
通讯作者：
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影响因子：
4.8
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影响因子：
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通讯作者：
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影响因子：
4.3
作者：
Johnson, James D.;Alejandro, Emilyn U.
通讯作者：
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