High-Efficiency Induction of Neural Conversion in Human ESCs and Human Induced Pluripotent Stem Cells with a Single Chemical Inhibitor of Transforming Growth Factor Beta Superfamily Receptors
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Chemical compounds have emerged as powerful tools for modulating ESC functions and deriving induced pluripotent stem cells (iPSCs), but documentation of compound-induced efficient directed differentiation in human ESCs (hESCs) and human iPSC (hiPSCs) is limited. By screening a collection of chemical compounds, we identified compound C (also denoted as dorsomorphin), a protein kinase inhibitor, as a potent regulator of hESC and hiPSC fate decisions. Compound C suppresses mesoderm, endoderm, and trophoectoderm differentiation and induces rapid and high-efficiency neural conversion in both hESCs and hiPSCs, 88.7% and 70.4%, respectively. Interestingly, compound C is ineffective in inducing neural conversion in mouse ESCs (mESCs). Large-scale kinase assay revealed that compound C targets at least seven transforming growth factor beta (TGF-β) superfamily receptors, including both type I and type II receptors, and thereby blocks both the Activin and bone morphogenesis protein (BMP) signaling pathways in hESCs. Dual inhibition of Activin and BMP signaling accounts for the effects of compound C on hESC differentiation and neural conversion. We also identified muscle segment homeobox gene 2 (MSX2) as a downstream target gene of compound C and a key signaling intermediate of the BMP pathway in hESCs. Our findings provide a single-step cost-effective method for efficient derivation of neural progenitor cells in adherent culture from human pluripotent stem cells. Therefore, it will be uniquely suitable for the production of neural progenitor cells in large scale and should facilitate the use of stem cells in drug screening and regenerative medicine and study of early human neural development.
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Neural differentiation can be initiated in NGD by adding dorsomorphin.
“Neural differentiation can be initiated in NGD by addition of a small molecule inhibitor of TGFβ signaling (dorsomorphin) 15.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [15]
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- Authors
- Zhou, J., Su, P., Li, D., Tsang, S., Duan, E., & Wang, F.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Wang, Fei
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-10-01
- Volume
- 28
- Issue
- 10
- Pages
- 1741-1750
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- PMC
- PMC3322377
- OpenAlex
- W2015650885
- Cited by
- 168
- References
- 37
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 14 · 2018: 9 · 2017: 14 · 2016: 16 · 2015: 17 · 2014: 21 · 2013: 21 · 2012: 29
- FWCI
- 8.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (0953267)
- National Natural Science Foundation of China (30728022)
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- National Institute of General Medical Sciences (R01GM083812, GM-83812)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- compound C, human induced pluripotent stem cells, human embryonic stem cells, activin signaling, BMP signaling, Msx2, neural progenitor cells, directed differentiation, protein kinase inhibitors, mouse embryonic stem cells
- MeSH terms
- Cell Differentiation, Cell Line, Humans, Neurons, Pyrazoles, Pyrimidines, Blotting, Western, Receptors, Transforming Growth Factor beta, Protein Kinase Inhibitors, Embryonic Stem Cells, Induced Pluripotent Stem Cells
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