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通过抑制 TGFβ 信号通路抑制 MSX2 可增强人胚胎干细胞的造血分化。

MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells.

机构信息

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.

Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Tianjin, 300020, China.

出版信息

Stem Cell Res Ther. 2020 Apr 5;11(1):147. doi: 10.1186/s13287-020-01653-3.

DOI:10.1186/s13287-020-01653-3
PMID:32248833
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7132876/
Abstract

BACKGROUND

Strategies of generating functional blood cells from human pluripotent stem cells (hPSCs) remain largely unsuccessful due to the lack of a comprehensive understanding of hematopoietic development. Endothelial-to-hematopoietic transition (EHT) serves as the pivotal mechanism for the onset of hematopoiesis and is negatively regulated by TGF-β signaling. However, little is known about the underlying details of TGF-β signaling during EHT.

METHODS

In this study, by applying genome-wide gene profiling, we identified muscle segment homeobox2 (MSX2) as a potential mediator of TGF-β signaling during EHT. We generated MSX2-deleted human embryonic stem cell (hESC) lines using the CRISPR/Cas9 technology and induced them to undergo hematopoietic differentiation. The role of MSX2 in hematopoiesis and functional regulation of TGFβ signaling in EHT was studied.

RESULTS

We identified MSX2 as a novel regulator of human hematopoiesis. MSX2 deletion promotes the production of hematopoietic cells from hESCs. Functional and bioinformatics studies further demonstrated that MSX2 deletion augments hematopoietic differentiation of hESCs by facilitating EHT. Mechanistically, MSX2 acts as a downstream target of TGFβ signaling to mediate its function during EHT.

CONCLUSIONS

Our results not only improve the understanding of EHT, but may also provide novel insight into the efficient production of functional blood cells from hPSCs for regenerative medicine.

摘要

背景

由于对造血发育缺乏全面了解，因此从人类多能干细胞（hPSC）生成功能性血细胞的策略在很大程度上仍然不成功。内皮细胞向造血细胞的转变（EHT）是造血起始的关键机制，受 TGF-β信号转导的负调控。然而，对于 EHT 过程中 TGF-β信号转导的潜在细节知之甚少。

方法

在这项研究中，我们通过应用全基因组基因谱分析，确定肌肉节同源框 2（MSX2）是 EHT 期间 TGF-β信号转导的潜在介质。我们使用 CRISPR/Cas9 技术生成了 MSX2 缺失的人类胚胎干细胞（hESC）系，并诱导它们进行造血分化。研究了 MSX2 在造血和 EHT 中 TGFβ信号的功能调节中的作用。

结果

我们确定 MSX2 是人类造血的新调节因子。MSX2 缺失促进了 hESC 产生造血细胞。功能和生物信息学研究进一步表明，MSX2 缺失通过促进 EHT 增强了 hESC 的造血分化。从机制上讲，MSX2 作为 TGFβ信号转导的下游靶标，在 EHT 期间介导其功能。

结论

我们的研究结果不仅提高了对 EHT 的认识，而且可能为从 hPSC 高效产生功能性血细胞以用于再生医学提供新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/b9908539d49c/13287_2020_1653_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/db4dbffae140/13287_2020_1653_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/632c5c7c0300/13287_2020_1653_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/64a73a3d306d/13287_2020_1653_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/35f4a2bb1d17/13287_2020_1653_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/b9908539d49c/13287_2020_1653_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/db4dbffae140/13287_2020_1653_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/632c5c7c0300/13287_2020_1653_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/64a73a3d306d/13287_2020_1653_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/35f4a2bb1d17/13287_2020_1653_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c9/7132876/b9908539d49c/13287_2020_1653_Fig5_HTML.jpg

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Endothelial-to-haematopoietic transition: an update on the process of making blood.内皮细胞向造血细胞的转变：血液生成过程的最新进展。
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MEIS2 regulates endothelial to hematopoietic transition of human embryonic stem cells by targeting TAL1.MEIS2 通过靶向 TAL1 调节人胚胎干细胞的内皮向造血转化。
Stem Cell Res Ther. 2018 Dec 7;9(1):340. doi: 10.1186/s13287-018-1074-z.
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MSX2 Initiates and Accelerates Mesenchymal Stem/Stromal Cell Specification of hPSCs by Regulating TWIST1 and PRAME.
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Correction to: MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells.对《通过抑制TGFβ信号通路抑制MSX2增强人胚胎干细胞的造血分化》的更正
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