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靶向细胞骨架可以诱导人类多能干细胞产生胰岛细胞
2020-02-25 14:58

美国华盛顿大学医学院Jeffrey R. Millman团队在研究中取得进展。他们发现靶向细胞骨架可以诱导人类多能干细胞(hPSCs)的胰腺分化。这一研究成果在线发表在2020年2月24日出版的《自然-生物技术》上。

研究人员建立了肌动蛋白细胞骨架状态与促进胰腺谱系特异性胰腺转录因子表达之间的联系。单细胞RNA测序表明,不同程度的肌动蛋白聚合可将细胞偏向于不同的内胚层谱系,这些有利于聚合细胞骨架的条件会强烈抑制神经原蛋白3诱导的内分泌分化。利用latrunculin A在内分泌诱导过程中解聚细胞骨架,研究人员开发了一种二维分化方案,用于生成人多能干细胞衍生的β(SC-β)细胞,这些细胞具有改良的体内和体外功能。从四个hPSC分化而来的SC-β细胞表现出第一阶段和第二阶段动态葡萄糖刺激的胰岛素分泌。将类似胰岛大小的sc--β细胞聚集体移殖到糖尿病小鼠中可以以接近人胰岛速率的功效改善小鼠糖尿病的表型,并至少维持正常血糖9个月。

据介绍,由人类多能干细胞产生胰岛β细胞有望成为糖尿病的细胞替代疗法。

附:英文原文

Title: Targeting the cytoskeleton to direct pancreatic differentiation of human pluripotent stem cells

Author: Nathaniel J. Hogrebe, Punn Augsornworawat, Kristina G. Maxwell, Leonardo Velazco-Cruz, Jeffrey R. Millman

Issue&Volume: 2020-02-24

Abstract: Generation of pancreatic β cells from human pluripotent stem cells (hPSCs) holds promise as a cell replacement therapy for diabetes. In this study, we establish a link between the state of the actin cytoskeleton and the expression of pancreatic transcription factors that drive pancreatic lineage specification. Bulk and single-cell RNA sequencing demonstrated that different degrees of actin polymerization biased cells toward various endodermal lineages and that conditions favoring a polymerized cytoskeleton strongly inhibited neurogenin 3-induced endocrine differentiation. Using latrunculin A to depolymerize the cytoskeleton during endocrine induction, we developed a two-dimensional differentiation protocol for generating human pluripotent stem-cell-derived β (SC-β) cells with improved in vitro and in vivo function. SC-β cells differentiated from four hPSC lines exhibited first- and second-phase dynamic glucose-stimulated insulin secretion. Transplantation of islet-sized aggregates of these cells rapidly reversed severe preexisting diabetes in mice at a rate close to that of human islets and maintained normoglycemia for at least 9 months.

DOI: 10.1038/s41587-020-0430-6

Source: https://www.nature.com/articles/s41587-020-0430-6

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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