期刊
NATURE BIOTECHNOLOGY
卷 38, 期 4, 页码 460-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41587-020-0430-6
关键词
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资金
- JDRF Career Development Award [5-CDA-2017-391-A-N]
- National Institutes of Health (NIH) [5R01DK114233]
- Washington University School of Medicine Department of Medicine
- NIH [R25GM103757, T32DK007120, T32DK108742]
- Washington University School of Medicine
- Children's Discovery Institute [CDI-CORE-2015-505]
- Foundation for Barnes-Jewish Hospital [3770]
- Washington University Diabetes Research Center [P30DK020579]
- Washington University Institute of Clinical and Translational Sciences [NIH UL1TR002345]
Generation of pancreatic beta 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 beta (SC-beta) cells with improved in vitro and in vivo function. SC-beta 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. Generation of pancreatic beta cells from stem cells is enhanced by manipulating the cytoskeleton.
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