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

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 t...

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Main Authors: Hongtao Wang, Mengge Wang, Yu Wang, Yuqi Wen, Xiaoyuan Chen, Dan Wu, Pei Su, Wen Zhou, Lihong Shi, Jiaxi Zhou
Format: Article
Language:English
Published: BMC 2020-04-01
Series:Stem Cell Research & Therapy
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13287-020-01653-3
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author Hongtao Wang
Mengge Wang
Yu Wang
Yuqi Wen
Xiaoyuan Chen
Dan Wu
Pei Su
Wen Zhou
Lihong Shi
Jiaxi Zhou
author_facet Hongtao Wang
Mengge Wang
Yu Wang
Yuqi Wen
Xiaoyuan Chen
Dan Wu
Pei Su
Wen Zhou
Lihong Shi
Jiaxi Zhou
author_sort Hongtao Wang
collection DOAJ
description 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.
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spelling doaj.art-049e17266f2d49adb5af722fb8291f5a2022-12-22T03:57:50ZengBMCStem Cell Research & Therapy1757-65122020-04-0111111210.1186/s13287-020-01653-3MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cellsHongtao Wang0Mengge Wang1Yu Wang2Yuqi Wen3Xiaoyuan Chen4Dan Wu5Pei Su6Wen Zhou7Lihong Shi8Jiaxi Zhou9State 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 CollegeState 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 CollegeState 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 CollegeState 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 CollegeState 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 CollegeState 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 CollegeState 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 CollegeDepartment of Hematology, Xiangya Hospital, Central South UniversityState 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 CollegeState 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 CollegeAbstract 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.http://link.springer.com/article/10.1186/s13287-020-01653-3MSX2TGF-β signalingEndothelial to hematopoietic transitionHuman embryonic stem cellsHematopoietic differentiation
spellingShingle Hongtao Wang
Mengge Wang
Yu Wang
Yuqi Wen
Xiaoyuan Chen
Dan Wu
Pei Su
Wen Zhou
Lihong Shi
Jiaxi Zhou
MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells
Stem Cell Research & Therapy
MSX2
TGF-β signaling
Endothelial to hematopoietic transition
Human embryonic stem cells
Hematopoietic differentiation
title MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells
title_full MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells
title_fullStr MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells
title_full_unstemmed MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells
title_short MSX2 suppression through inhibition of TGFβ signaling enhances hematopoietic differentiation of human embryonic stem cells
title_sort msx2 suppression through inhibition of tgfβ signaling enhances hematopoietic differentiation of human embryonic stem cells
topic MSX2
TGF-β signaling
Endothelial to hematopoietic transition
Human embryonic stem cells
Hematopoietic differentiation
url http://link.springer.com/article/10.1186/s13287-020-01653-3
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