Ancient Gene Reprograms Stem Cells to Create Living Chimeric Mouse

Scientists have reprogrammed mouse cells into pluripotent stem cells using a gene from choanoflagellates. These single-celled organisms are close relatives of animals. This finding reveals that key genes for stem cell formation existed in unicellular ancestors almost a billion years ago. Essentially, the researchers used the reprogrammed stem cells to create a chimeric mouse, demonstrating ancient genes’ compatibility with modern mammalian biology. This achievement highlights how evolutionary tools from primitive organisms can still function effectively in complex life forms. Moreover, the discovery redefines the evolutionary origins of stem cells and could inspire new breakthroughs in regenerative medicine.

The chimeric mouse on the left displays dark eyes and black fur patches, produced from stem cells with a choanoflagellate Sox gene. In contrast, the wildtype mouse on the right has red eyes and entirely white fur. The color variation arises from genetic markers used to differentiate the stem cells, not from the gene itself. Image: Gao Ya/Alvin Kin Shing Lee/Queen Mary University of London.

Researchers from London and Hong Kong Harness Ancient Choanoflagellate Genes to Create Living Mouse 

An international team of researchers has achieved a remarkable milestone, publishing their results in Nature Communications. They created mouse stem cells capable of developing into a fully formed mouse using genetic tools from an ancient unicellular organism that shares a common ancestor with animals–choanoflagellates. In this experiment, Dr. Alex de Mendoza from Queen Mary University of London, along with researchers from The University of Hong Kong, have used chimeric technology to create the mammalian organism. 

The term chimeric describes an organism or entity made up of cells, tissues, or genetic material from multiple sources. The name comes from the mythological Chimera, a creature combining parts of different animals. In biology, it refers to genetic chimeras or molecular chimeras. Genetic chimeras contain cells from different zygotes, such as mice with cells from their genome and injected stem cells. Molecular chimeras include engineered molecules like proteins that mix components from various origins. For instance, chimeric antigen receptor (CAR) T-cells are used in immunotherapy. Here, chimeric refers to the mouse containing traits and cells from the original embryo and reprogrammed stem cells.

This breakthrough offers fresh insights into the genetic origins of stem cells, reshaping our understanding of evolution. It also sheds light on the deep connection between animals and their ancient, single-celled relatives.

“By successfully creating a mouse using molecular tools derived from our single-celled relatives, we’re witnessing an extraordinary continuity of function across nearly a billion years of evolution,” said Dr. de Mendoza. “The study implies that key genes involved in stem cell formation might have originated far earlier than the stem cells themselves, perhaps helping pave the way for the multicellular life we see today.”

Sox and POU Key Genes Underpinning Mammalian Stem Cell Potential

Choanoflagellates carry versions of Sox and POU genes, which drive pluripotency—the ability to form any cell type—in mammalian stem cells. This finding challenges the assumption that these genes evolved exclusively within animals.

Furthermore, it highlights the adaptability of genetic tools, suggesting early life forms used similar mechanisms for cellular specialization. These processes likely existed long before multicellular organisms emerged, demonstrating evolution’s tendency to repurpose genetic traits.

Dr. de Mendoza explained, “Choanoflagellates don’t have stem cells, they’re single-celled organisms, but they have these genes, likely to control basic cellular processes that multicellular animals probably later repurposed for building complex bodies.”

Understanding stem cell evolution could improve methods for optimizing stem cell therapies. It might also enhance techniques for reprogramming cells to treat diseases or repair tissue.

Reprogramming ‘Differentiated’ Cells with Four Key Factors, Including Sox2 and Oct4

In 2012, Shinya Yamanaka’s Nobel Prize-winning work showed that stem cells could be created from “differentiated” cells by expressing four factors, including the Sox2 and Oct4 genes.

In this new study, researchers collaborated with Dr. Ralf Jauch’s lab at The University of Hong Kong’s Centre for Translational Stem Cell Biology. The team introduced Sox genes from choanoflagellates into mouse cells, replacing the Sox2 gene. This manipulation successfully reprogrammed the cells to a pluripotent stem cell state.

To test the reprogrammed cells, the team injected them into a developing mouse embryo. The resulting chimeric mouse displayed traits from both the donor embryo and the induced stem cells, such as black fur patches and dark eyes. This confirmed the critical role these ancient genes played in making stem cells compatible with animal development.

The research also traced the role of early Sox and POU proteins, which regulate genes by binding to DNA. These proteins, originally used by unicellular ancestors, later became crucial for stem cell formation and animal development.

Dr. Jauch explained, “Studying the ancient roots of these genetic tools lets us innovate with a clearer view of how pluripotency mechanisms can be tweaked or optimized.” He added that progress could come from testing synthetic versions of these genes, which may outperform the natural animal genes in specific situations.

Author

Bernice Lottering