Kale Atharva, Azar Mahmoud, Cheng Vanessa, Robertson Harry, Coulter Sally, Mehta Paulomi M, Julovi Sohel M, Patrick Ellis, Ghimire Kedar, Rogers Natasha M
Kidney Injury Group, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia.
Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
Diabetologia. 2025 Jun;68(6):1279-1297. doi: 10.1007/s00125-025-06409-3. Epub 2025 Mar 25.
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.
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.
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.
目的/假设：糖尿病是一种以β细胞逐渐丧失为特征的全球性健康负担。胰岛移植是1型糖尿病和低血糖无意识症患者公认的治疗方法，但由于移植后胰岛存活和功能有限，其更广泛的应用受到限制。诱导β细胞功能障碍和死亡的潜在分子机制仍不清楚，需要能够防止细胞丢失并维持胰岛素分泌的治疗药物作为潜在的治疗选择。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表达将在β细胞中表现出细胞保护作用。
我们使用了有/无CD47基因缺失的原代小鼠胰岛，以及接受CD47信号药理学破坏（siRNA或阻断抗体）的人胰岛和MIN6细胞。通过暴露于缺氧、高血糖或毒胡萝卜素在细胞中诱导代谢应激，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。检查有糖尿病和无糖尿病个体的人胰腺中CD47信号的证据。
外源性应激源强烈上调CD47及其高亲和力配体血小板反应蛋白-1（TSP1）的表达。限制CD47信号改善了衰老、凋亡、内质网应激、未折叠蛋白反应、自我更新和自噬的标志物，并维持了胰岛素分泌反应。我们还发现老年供体和2型糖尿病患者内分泌胰腺中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的表达均增加，TSP1的血浆水平也增加。
结论/解读：我们的研究提供了关于CD47作为胰岛功能障碍新调节因子的重要作用的关键见解，调节对应激的细胞保护反应。CD47可能在糖尿病发展和胰岛移植功能衰竭期间导致β细胞损伤。因此，在胰岛功能不足的情况下，限制CD47激活可能是一种潜在的治疗工具。
