期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2020.00109
关键词
cell identity; cell fate; differentiation; endocrine progenitors; signaling; pathway analyses
资金
- Research Council of Norway [NFR 247577, 251041]
- Novo Nordic Foundation [NNF15OC0015054]
- NIH/NIGMS [R01 GM132129]
- Bergen Forskningsstiftelse [BFS2014REK02]
- Western Norway Regional Health Authority (Bergen Stem Cell Consortium)
- Diabetesforbundets forskningsfond
Generating insulin-producing beta-cells from human induced pluripotent stem cells is a promising cell replacement therapy for improving or curing insulin-dependent diabetes. The transplantation of end-stages differentiating cells into living hosts was demonstrated to improve beta-cell maturation. Nevertheless, the cellular and molecular mechanisms outlining the transplanted cells' response to the in vivo environment are still to be properly characterized. Here we use global proteomics and large-scale imaging techniques to demultiplex and filter the cellular processes and molecular signatures modulated by the immediate in vivo effect. We show that in vivo exposure swiftly confines in vitro generated human pancreatic progenitors to single hormone expression. The global proteome landscape of the transplanted cells was closer to native human islets, especially in regard to energy metabolism and redox balance. Moreover, our study indicates a possible link between these processes and certain epigenetic regulators involved in cell identity. Pathway analysis predicted HNF1A and HNF4A as key regulators controlling the in vivo islet-promoting response, with experimental evidence suggesting their involvement in confining islet cell fate following xeno-transplantation.
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