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JAK activity regulates mesoderm cell fate by controlling MESP1 expression
Su Yao1, Yalin Zhu1, Fenglian He1
1Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
European Journal of Cell Biology
|August 25, 2024
Summary
Researchers identified CYT387, a JAK inhibitor, as a potent activator of MESP1 expression in mesodermal cells. This discovery enhances understanding of cardiac development and mesoderm cell fate regulation.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Molecular Cardiology
Background:
- Precise gene expression is crucial for cardiac development, guided by signaling pathways and transcription factors.
- MESP1 is a key transcription factor essential for cardiac development, but its regulatory mechanisms remain unclear.
- Understanding MESP1 regulation is vital for advancing cardiac regenerative medicine.
Purpose of the Study:
- To identify novel regulators of MESP1 expression in mesodermal cells.
- To investigate the role of JAK signaling in early mesoderm development and MESP1 transcription.
- To explore the potential of identified regulators in promoting cardiomyocyte differentiation.
Main Methods:
- Developed a high-content screen assay using human pluripotent stem cells (hPSCs) differentiated into mesodermal cells.
- Utilized CYT387, a JAK1/JAK2 kinase inhibitor, in the screen.
- Performed mechanistic studies involving calcium concentration and WNT signaling pathway analysis.
Main Results:
- Identified CYT387 as a potent activator of MESP1 expression in mesodermal cells.
- Demonstrated that CYT387 promotes cardiomyocyte differentiation in vitro.
- Mechanistically, JAK inhibition enhances MESP1 expression by reducing cytoplasmic calcium and activating WNT signaling.
Conclusions:
- JAK signaling plays a significant role in early mesodermal cells.
- Established a link between the JAK-STAT pathway and MESP1 transcriptional regulation.
- Provided new insights into the molecular mechanisms governing mesoderm and cardiac development.
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