New Intermediate Embryonic Stem Cell Type: A Breakthrough in Regenerative Medicine and Reproductive Technology
A groundbreaking study led by UT Southwestern has resulted in the derivation of a new type of embryonic stem cell, termed "XPSCs," from multiple species including mice, horses, and humans. This intermediate stem cell type has the unique ability to contribute to both intraspecies (within the same species) and interspecies (between different species) chimeras and can create precursors to sperm and eggs in a laboratory setting. Published in the prestigious journal Cell Stem Cell, these findings hold the potential to revolutionize fields such as basic biology, regenerative medicine, and reproductive technology.
Graphical Abstract
Understanding Pluripotency in Stem Cells
Embryonic stem cells are renowned for their pluripotency, the ability to differentiate into any cell type in the body. Cells in early embryos exhibit a range of distinct pluripotency programs that enable them to create various tissue types. Traditionally, research has focused on two primary stages of pluripotency in stem cells: "naïve" embryonic stem cells, which are typically observed around four days post-fertilization in mice, and "primed" epiblast stem cells, seen around seven days post-fertilization, shortly after the embryo implants into the uterus.
However, the intermediate stage between these two well-studied phases had remained elusive. This gap in understanding was due to the lack of a paradigm for maintaining cells in this intermediate state, which is hypothesized to possess unique properties such as the ability to contribute to chimeras and differentiate into primordial germ cells—the precursors to sperm and eggs.
The Breakthrough: XPSCs
Dr. Jun Wu, assistant professor of molecular biology at UT Southwestern and the lead author of the study, and his colleagues have successfully created intermediate pluripotent stem cells, which they named XPSCs. These cells were derived from mice, horses, and humans, marking a significant achievement in stem cell research.
The researchers achieved this breakthrough by cultivating early embryonic cells in an environment enriched with chemicals and growth factors that activate three critical signaling pathways: WNT, FGF, and TGF-β. This precise combination allowed the cells to maintain their intermediate pluripotent state, remaining stable and capable of multiplying without differentiation for approximately two years. This stability was crucial, as it allowed the researchers to conduct extensive studies on the properties and potential applications of XPSCs.
Potential Applications of XPSCs
The implications of this discovery are vast and could lead to numerous advancements in both basic and applied research:
-Evolutionary Biology and Genetic Research
By examining gene activity in XPSCs from different species and interspecies chimeras, researchers can gain insights into genetic signatures conserved through evolution. This knowledge could help unravel the complexities of developmental biology and the evolutionary relationships between species.
-Regenerative Medicine
Understanding how cells in chimeras communicate and coordinate their development could reveal strategies to accelerate the growth of tissues and organs from stem cells. This advancement is crucial for developing effective transplantation therapies, potentially addressing the shortage of donor organs.
-Reproductive Technology
One of the most exciting applications of XPSCs is their ability to differentiate into primordial germ cells. This capability opens up possibilities for creating sperm and eggs in vitro, which could revolutionize infertility treatments. Additionally, this technology could play a vital role in preserving endangered animal species by facilitating reproductive processes that are otherwise challenging or impossible.
Experimental Highlights
The team conducted several experiments to demonstrate the capabilities of XPSCs:
-Intraspecies Chimeras
The researchers created intraspecies chimeras by injecting mouse-derived XPSCs into early mouse embryos. These cells, tagged with a fluorescent protein, were traced throughout the development of the resulting offspring, confirming their contribution to various tissues in the body.
- Interspecies Chimeras
In a striking experiment, horse-derived XPSCs were injected into early mouse embryos. Despite the significant differences in gestational periods between mice and horses, the horse cells contributed to the development of mouse organs. This finding suggests that the signals from the host species’ cells play a crucial role in determining the developmental timelines of organs.
- Primordial Germ Cell Formation
Human XPSCs demonstrated their potential to differentiate into a variety of tissues, including primordial germ cells, when provided with the appropriate culture conditions. This experiment underscored the versatility and applicability of XPSCs across different species.
Challenges and Future Directions
Developing XPSCs was not without challenges. The conditions required to maintain naïve PSCs are opposite to those needed for primed PSCs. Naïve PSCs require the activation of the WNT pathway and suppression of FGF and TGF-β pathways, whereas primed PSCs need the suppression of WNT and activation of FGF and TGF-β pathways. To stabilize XPSCs, the researchers had to find a balanced culture environment that could maintain the intermediate pluripotency state.
The next steps in this research involve further exploration of the properties and applications of XPSCs. Scientists aim to use these cells to study mammalian pluripotency more deeply and dissect the molecular mechanisms governing primordial germ cell specification. Additionally, there is potential to apply this method to derive similar stem cells from other mammalian species, broadening the scope of research and applications.
Conclusion
The derivation of XPSCs represents a monumental advancement in stem cell research. By bridging the gap between naïve and primed pluripotency, XPSCs open new avenues for scientific exploration and practical applications in regenerative medicine, reproductive technology, and beyond. Dr. Jun Wu and his team have paved the way for future studies that could lead to significant breakthroughs in understanding development, treating infertility, and preserving endangered species. This discovery underscores the incredible potential of stem cell research to transform medicine and improve lives.
Citation: Wu, J., Yu, L., Wei, Y., Pinzon Arteaga, C. A., Sakurai, M., Schmitz, D. A., Zheng, C., Ballard, E. D., & Wu, J. (2020). Derivation of Intermediate Pluripotent Stem Cells Amenable to Chimera Formation and Primordial Germ Cell Specification. Cell Stem Cell, 27(6), 876-891.e10. https://doi.org/10.1016/j.stem.2020.11.008