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经 GATA1、FLI1 和 TAL1 正向编程的人多能干细胞转录因子水平决定巨核细胞与红细胞命运决定。

Transcription Factor Levels after Forward Programming of Human Pluripotent Stem Cells with GATA1, FLI1, and TAL1 Determine Megakaryocyte versus Erythroid Cell Fate Decision.

机构信息

Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge Blood Centre, Long Road, Cambridge CB2 0PT, UK; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Tennis Court Road, Cambridge CB2 1QR, UK.

Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Tennis Court Road, Cambridge CB2 1QR, UK.

出版信息

Stem Cell Reports. 2018 Dec 11;11(6):1462-1478. doi: 10.1016/j.stemcr.2018.11.001. Epub 2018 Nov 29.

DOI:10.1016/j.stemcr.2018.11.001
PMID:30503262
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6294717/
Abstract

The production of blood cells and their precursors from human pluripotent stem cells (hPSCs) in vitro has the potential to make a significant impact upon healthcare provision. We demonstrate that the forward programming of hPSCs through overexpression of GATA1, FLI1, and TAL1 leads to the production of a population of progenitors that can differentiate into megakaryocyte or erythroblasts. Using "rainbow" lentiviral vectors to quantify individual transgene expression in single cells, we demonstrate that the cell fate decision toward an erythroblast or megakaryocyte is dictated by the level of FLI1 expression and is independent of culture conditions. Early FLI1 expression is critical to confer proliferative potential to programmed cells while its subsequent silencing or maintenance dictates an erythroid or megakaryocytic fate, respectively. These committed progenitors subsequently expand and mature into megakaryocytes or erythroblasts in response to thrombopoietin or erythropoietin. Our results reveal molecular mechanisms underlying hPSC forward programming and novel opportunities for application to transfusion medicine.

摘要

从人类多能干细胞（hPSCs）体外生成血细胞及其前体细胞，有可能对医疗保健的提供产生重大影响。我们证明，通过过表达 GATA1、FLI1 和 TAL1 对 hPSCs 进行正向编程，可产生可分化为巨核细胞或成红细胞的祖细胞群体。使用“彩虹”慢病毒载体在单细胞中定量单个转基因的表达，我们证明向成红细胞或巨核细胞的细胞命运决定取决于 FLI1 表达水平，而与培养条件无关。早期 FLI1 表达对于赋予编程细胞增殖潜能至关重要，而其后的沉默或维持分别决定了红细胞或巨核细胞的命运。这些定向祖细胞随后在血小板生成素或促红细胞生成素的作用下扩增并成熟为巨核细胞或成红细胞。我们的研究结果揭示了 hPSC 正向编程的分子机制，并为输血医学的应用提供了新的机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/5ef4c5dfc36a/gr7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/c0a9cebe76ce/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/8d0d4ebe3ea6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/a5d93cc99643/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/a09d978a8890/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/c6827439d3e8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/5ef4c5dfc36a/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/9939b03117fc/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/355b6146e8c5/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/c0a9cebe76ce/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/8d0d4ebe3ea6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/a5d93cc99643/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/a09d978a8890/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/c6827439d3e8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46c7/6294717/5ef4c5dfc36a/gr7.jpg

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