美国索尔克生物研究所Ronald M. Evans研究组的研究显示，具有免疫逃逸型人胰岛类器官可以改善糖尿病。这一研究成果发表在2020年出版的国际学术期刊《自然》上。
据介绍，人胰岛类器官在治疗胰岛素依赖型糖尿病中具有重大前景，但仍有许多挑战。研究团队从诱导的多能干细胞中产生人胰岛类器官（HILOs），并显示非经典WNT4信号驱动的代谢成熟是它能够在体外受葡萄糖刺激分泌胰岛素所必需的。这些功能成熟的人胰岛类器官包含内分泌样细胞，移植后可以迅速重建在糖尿病NOD/SCID小鼠体内的血糖平衡。过表达免疫检查点蛋白编程的死亡配体1（PD-L1）可以保护HILO异种移植，使得它们能够在具有免疫能力的糖尿病小鼠中存活并恢复葡萄糖稳态50天。
此外，用interferon-γ进行体外刺激可以诱导内源性PD-L1表达并限制T细胞激活和移植排斥。具有血糖响应功能且能够免疫逃避人胰岛类器官的产生提供了一个有前景的糖尿病治疗方法。诱导多能干细胞产生的代谢成熟人胰岛类器官能够在糖尿病小鼠移植模型中重构胰岛素响应的胰岛功能，并且可以逃避免疫排斥型死亡。
附：英文原文
Title: Immune-evasive human islet-like organoids ameliorate diabetes
Author: Eiji Yoshihara, Carolyn OConnor, Emanuel Gasser, Zong Wei, Tae Gyu Oh, Tiffany W. Tseng, Dan Wang, Fritz Cayabyab, Yang Dai, Ruth T. Yu, Christopher Liddle, Annette R. Atkins, Michael Downes, Ronald M. Evans
Issue&Volume: 2020-08-19
Abstract: Islets derived from stem cells hold promise as a therapy for insulin-dependent diabetes, but there remain challenges towards achieving this goal1–6. Here we generate human islet-like organoids (HILOs) from induced pluripotent stem cells and show that non-canonical WNT4 signalling drives the metabolic maturation necessary for robust ex vivo glucose-stimulated insulin secretion. These functionally mature HILOs contain endocrine-like cell types that, upon transplantation, rapidly re-establish glucose homeostasis in diabetic NOD/SCID mice. Overexpression of the immune checkpoint protein programmed death-ligand 1 (PD-L1) protected HILO xenografts such that they were able to restore glucose homeostasis in immune-competent diabetic mice for 50 days. Furthermore, ex vivo stimulation with interferon-γ induced endogenous PD-L1 expression and restricted T cell activation and graft rejection. The generation of glucose-responsive islet-like organoids that are able to avoid immune detection provides a promising alternative to cadaveric and device-dependent therapies in the treatment of diabetes. Metabolically-mature human islet-like organoids generated from induced pluripotent stem cells are able to recapitulate insulin-responsive pancreatic islet function and avoid immunologic cell death in diabetic mouse transplantation models.
DOI: 10.1038/s41586-020-2631-z
Source: https://www.nature.com/articles/s41586-020-2631-z
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
