GFI1 regulates chromatin state essential in human endothelial‐to‐haematopoietic transition

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Abstract

Objectives

During embryonic haematopoiesis, haematopoietic stem/progenitor cells (HSPCs) develop from hemogenic endothelial cells (HECs) though endothelial to haematopoietic transition (EHT). However, little is known about how EHT is regulated in human. Here, we report that GFI1 plays an essential role in enabling normal EHT during haematopoietic differentiation of human embryonic stem cells (hESCs).

Results

GFI1 deletion in hESCs leads to a complete EHT defect due to a closed chromatin state of hematopoietic genes in HECs. Mechanically, directly regulates important signaling pathways essential for the EHT such as PI3K signaling.etc.

Conclutions

Together, our findings reveal an essential role of GFI1 mediated epigenetic mechanism underlying human EHT during hematopoiesis.

Abstract

We found that GFI1 is essential for the generation of human haematopoietic progenitor cells (HPCs) through endothelial‐to‐haematopoietic transition (EHT). GFI1 deletion in human embryonic stem cells (hESCs) resulted in the absence of HPC commitment. Mechanically, GFI1 promoted the EHT process through directly binding and activating the PI3K signalling. In contrast, in mouse haematopoiesis, Gfi1 deletion alone did not significantly impair EHT. Our findings not only uncovered the essential role and mechanism of GFI1 in regulating human haematopoiesis but also highlighted the significance of hPSCs in modelling human physiology.

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Most cited references 28

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Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.

Keisuke Ito, Atsushi Hirao, Fumio Arai … (2006)

Hematopoietic stem cells (HSCs) undergo self-renewing cell divisions and maintain blood production for their lifetime. Appropriate control of HSC self-renewal is crucial for the maintenance of hematopoietic homeostasis. Here we show that activation of p38 MAPK in response to increasing levels of reactive oxygen species (ROS) limits the lifespan of HSCs in vivo. In Atm(-/-) mice, elevation of ROS levels induces HSC-specific phosphorylation of p38 MAPK accompanied by a defect in the maintenance of HSC quiescence. Inhibition of p38 MAPK rescued ROS-induced defects in HSC repopulating capacity and in the maintenance of HSC quiescence, indicating that the ROS-p38 MAPK pathway contributes to exhaustion of the stem cell population. Furthermore, prolonged treatment with an antioxidant or an inhibitor of p38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments. These data show that inactivation of p38 MAPK protects HSCs against loss of self-renewal capacity. Our characterization of molecular mechanisms that limit HSC lifespan may lead to beneficial therapies for human disease.

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Hematopoietic stem cells derive directly from aortic endothelium during development

Julien Y. Bertrand, Neil Chi, Buyung Santoso … (2010)

A major goal of regenerative medicine is to instruct formation of multipotent, tissue-specific stem cells from induced pluripotent stem cells (iPSCs) for cell replacement therapies. Generation of hematopoietic stem cells (HSCs) from iPSCs or embryonic stem cells (ESCs) is not currently possible, however, necessitating a better understanding of how HSCs normally arise during embryonic development. We previously showed that hematopoiesis occurs through four distinct waves during zebrafish development, with HSCs arising in the final wave in close association with the dorsal aorta. Recent reports have suggested that murine HSCs derive from hemogenic endothelial cells (ECs) lining the aortic floor1,2. Additional in vitro studies have similarly suggested that the hematopoietic progeny of ESCs arise through intermediates with endothelial potential3,4. In this report, we have utilized the unique strengths of the zebrafish embryo to image directly the birth of HSCs from the ventral wall of the dorsal aorta. Utilizing combinations of fluorescent reporter transgenes, confocal timelapse microscopy and flow cytometry, we have identified and isolated the stepwise intermediates as aortic hemogenic endothelium transitions to nascent HSCs. Finally, using a permanent lineage tracing strategy, we demonstrate that the HSCs generated from hemogenic endothelium are the lineal founders of the adult hematopoietic system.

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In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium.

Jean-Charles Boisset, Wiggert A. van Cappellen, Charlotte Andrieu-Soler … (2010)

Haematopoietic stem cells (HSCs), responsible for blood production in the adult mouse, are first detected in the dorsal aorta starting at embryonic day 10.5 (E10.5). Immunohistological analysis of fixed embryo sections has revealed the presence of haematopoietic cell clusters attached to the aortic endothelium where HSCs might localize. The origin of HSCs has long been controversial and several candidates of the direct HSC precursors have been proposed (for review see ref. 7), including a specialized endothelial cell population with a haemogenic potential. Such cells have been described both in vitro in the embryonic stem cell (ESC) culture system and retrospectively in vivo by endothelial lineage tracing and conditional deletion experiments. Whether the transition from haemogenic endothelium to HSC actually occurs in the mouse embryonic aorta is still unclear and requires direct and real-time in vivo observation. To address this issue we used time-lapse confocal imaging and a new dissection procedure to visualize the deeply located aorta. Here we show the dynamic de novo emergence of phenotypically defined HSCs (Sca1(+), c-kit(+), CD41(+)) directly from ventral aortic haemogenic endothelial cells.

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Author and article information

Contributors

Yi Wang: wangyi@jlu.edu.cn

Guangjin Pan:

ORCID: https://orcid.org/0000-0002-2378-7198

pan_guangjin@gibh.ac.cn

Journal

Journal ID (nlm-ta): Cell Prolif

Journal ID (iso-abbrev): Cell Prolif

Journal ID (doi): 10.1111/(ISSN)1365-2184

Journal ID (publisher-id): CPR

Title: Cell Proliferation

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 0960-7722

ISSN (Electronic): 1365-2184

Publication date (Electronic): 03 May 2022

Publication date Collection: May 2022

Volume: 55

Issue: 5 ( doiID: 10.1111/cpr.v55.5 )

Electronic Location Identifier: e13244

Affiliations

[ ¹ ] Department of Regenerative Medicine, School of Pharmaceutical Sciences Jilin University Changchun China

[ ² ] CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China

[ ³ ] Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China

[ ⁴ ] University of Chinese Academy of Sciences Beijing China

[ ⁵ ] Medical Research Center, People's Hospital of Longhua Shenzhen China

[ ⁶ ] Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing China

[ ⁷ ] The Seventh Affiliated Hospital, Sun Yat‐sen University Shenzhen China

Author notes

[*] [* ] Correspondence

Yi Wang, Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, China.

Email: wangyi@ 123456jlu.edu.cn

Guangjin Pan, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, China.

Email: pan_guangjin@ 123456gibh.ac.cn

Author information

Baoqiang Kang https://orcid.org/0000-0002-6676-3022

Tianyu Wang https://orcid.org/0000-0003-4169-8268

Guangjin Pan https://orcid.org/0000-0002-2378-7198

Article

Publisher ID: CPR13244

DOI: 10.1111/cpr.13244

PMC ID: 9136496

PubMed ID: 35504619

SO-VID: ae3b43d9-6680-427e-87c0-d13350142e08

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 17 March 2022

Date received : 27 December 2021

Date accepted : 10 April 2022

Page count

Figures: 6, Tables: 0, Pages: 12, Words: 6643

Funding

Funded by: Department of Science and Technology of Jilin Province , doi 10.13039/501100011789;

Award ID: 20200404121YY

Funded by: Education Department of Jilin Province , doi 10.13039/501100010211;

Award ID: JJKH20201122KJ

Funded by: National Key Research and Development Program of China, Stem Cell and Translational Research

Award ID: 2017YFA0102600

Funded by: Science and Technology Planning Project of Guangdong Province, China

Award ID: 2020B1212060052

Funded by: Strategic Priority Research Program of Chinese Academy of Sciences

Award ID: XDA16030504

Custom metadata

source-schema-version-number 2.0

cover-date May 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.6 mode:remove_FC converted:27.05.2022

ScienceOpen disciplines: Cell biology

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ScienceOpen disciplines: Cell biology

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GFI1 regulates chromatin state essential in human endothelial‐to‐haematopoietic transition

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Abstract

Objectives

Results

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Abstract

Related collections

Higher order chromatin architecture

Most cited references 28

Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells.

Hematopoietic stem cells derive directly from aortic endothelium during development

In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium.

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