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A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
Published on: May 12, 2017
Depletion of Sorcs3 Activates Totipotency in Mouse Embryonic Stem Cells by Modulating Key Signaling Pathways
Wenhao Zhang1, Xinyu Mao1, Yu He2
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Animal Resources Center and Reproductive Regulation, and Institute of Transplantation Medicine, Nankai University, Tianjin, 300350, China.
Abstract:
Totipotency represents the greatest potential to yield an entire individual alongside its associated extraembryonic tissues, albeit transiently. Nevertheless, achieving sustainable totipotent stem cells remains an intriguing yet challenging endeavor. Here, it is reported that Sorcs3 depletion in murine embryonic stem cells (ESCs) enables robust differentiation into both embryonic and extraembryonic lineages, resulting in a totipotent-like state. Notably, Sorcs3 knockout (SKO)-ESCs can efficiently self-assemble into typical blastocyst-like structures, offering a versatile model for studying early embryonic development. Comprehensive analyses reveal that totipotency in SKO-ESCs is related to Tfap2c gene activation. Deletion of Tfap2c significantly reduces the developmental potential of SKO-ESCs across all the examined phenotypes, underscoring its critical role. Furthermore, single-cell transcriptome analysis of SKO-ESCs reveals that inhibition of the TGF-β, PI3K-AKT, and lysosome pathways drives totipotency activation, which is validated by the introduction of corresponding inhibitors into wild-type ESC cultures. Together, the findings facilitate the establishment of totipotent stem cells in a defined medium and provide a universal platform for studying totipotency.
Insights
Depleting Sorcs3 in mouse embryonic stem cells (ESCs) creates totipotent-like cells. These cells, crucial for early development research, activate the Tfap2c gene and self-assemble into blastocyst-like structures.
Area of Science:
- Stem cell biology
- Developmental biology
- Genetics
Background:
- Totipotency, the ability to form a complete organism and extraembryonic tissues, is transient in early development.
- Establishing sustainable totipotent stem cells is a significant challenge in regenerative medicine.
Purpose of the Study:
- To investigate the role of Sorcs3 in murine embryonic stem cells (ESCs).
- To explore the potential of Sorcs3-depleted ESCs in achieving a totipotent-like state.
- To establish a model for studying early embryonic development and totipotency.
Main Methods:
- Sorcs3 knockout (SKO) in murine ESCs.
- Analysis of differentiation into embryonic and extraembryonic lineages.
- Formation of blastocyst-like structures.
- Gene expression analysis (Tfap2c).
- Single-cell transcriptome analysis.
- Pathway inhibition studies (TGF-β, PI3K-AKT, lysosome).
Main Results:
- Sorcs3 depletion in ESCs induced a totipotent-like state, enabling differentiation into both embryonic and extraembryonic lineages.
- SKO-ESCs self-assembled into blastocyst-like structures, serving as a model for early development.
- Totipotency in SKO-ESCs was linked to Tfap2c gene activation; its deletion impaired developmental potential.
- Inhibition of TGF-β, PI3K-AKT, and lysosome pathways activated totipotency in ESCs.
Conclusions:
- Sorcs3 depletion is a viable strategy for generating totipotent-like ESCs.
- Tfap2c is a critical regulator of totipotency in this model.
- Targeting specific signaling pathways can induce totipotency in ESCs.
- This research provides a platform for studying totipotency and establishing stem cells in defined media.
