Chemically defined and growth factor-free system for highly efficient endoderm induction of human pluripotent stem cells

被引:1
作者
Zhao, Zhiju [2 ,3 ,4 ,5 ,6 ]
Zeng, Fanzhu [2 ,3 ,7 ]
Nie, Yage [2 ,3 ]
Lu, Gang [4 ,5 ,6 ]
Xu, He [2 ,3 ]
En, He [2 ,3 ]
Gu, Shanshan [2 ,3 ]
Chan, Wai-Yee [4 ,5 ,6 ]
Cao, Nan [2 ,3 ]
Wang, Jia [1 ,2 ,3 ]
机构
[1] Univ Hlth & Rehabil Sci, Sch Hlth & Life Sci, Qingdao 266071, Shandong, Peoples R China
[2] Sun Yat Sen Univ, Zhongshan Sch Med, Guangzhou 510080, Guangdong, Peoples R China
[3] Sun Yat Sen Univ, Key Lab Stem Cells & Tissue Engn, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China
[4] Chinese Univ Hong Kong, Sch Biomed Sci, CUHK SDU Joint Lab Reprod Genet, Hong Kong, Peoples R China
[5] Chinese Univ Hong Kong, Hong Kong Branch, CAS Ctr Excellence Anim Evolut & Genet, Hong Kong 999077, Peoples R China
[6] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Key Lab Regenerat Med,Minist Educ, Hong Kong 999077, Peoples R China
[7] Tech Univ Munich, Sch Med, Dept Plast & Hand Surg, Klinikum Rechts Isar, D-81675 Munich, Germany
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
PROMOTES CARDIAC DIFFERENTIATION; DERIVATION;
D O I
10.1016/j.stemcr.2024.11.012
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Definitive endoderm (DE) derived from human pluripotent stem cells (hPSCs) holds great promise for cell-based therapies and drug discovery. However, current DE differentiation methods required undefined components and/or expensive recombinant proteins, limiting their scalable manufacture and clinical use. Homogeneous DE differentiation in defined and recombinant protein-free conditions remains a major challenge. Here, by systematic optimization and high-throughput screening, we report a chemically defined, small-molecule-based defined system that contains only four components (4C), enabling highly efficient and cost-effective DE specification of hPSCs in the absence of recombinant proteins. 4C-induced DE can differentiate into functional hepatocytes, lung epithelium, and pancreatic b cells in vitro and multiple DE derivatives in vivo. Genomic accessibility analysis reveals that 4C reconfigures chromatin architecture to allow key DE transcription factor binding while identifying TEAD3 as a novel key regulator of the process. This system may facilitate mass production of DE derivatives for drug discovery, disease modeling, and cell therapy.
引用
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页数:10
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