Nearly every animal species, including humans, has blood cells. But blood is not the same across the animal kingdom. Different species have evolved different types of blood and immune cells, reflecting millions of years of adaptation against infection and disease.
Scientists already understand a great deal about the makeup and function of blood cells in humans and mice thanks to advances in hematology and immunology. What has remained unclear is how these cells first appeared and evolved over time. To answer those questions, researchers at Kyoto University set out to trace the origins and diversification of blood cells across the animal world.
Tracing Blood Back 700 Million Years
The team created a new analytical approach that compared gene expression patterns across many types of cells and animal species. Using this method, they built evolutionary family trees for blood cell lineages and estimated how these cells developed throughout animal evolution.
The researchers also compared blood cells with unicellular organisms in an effort to identify possible single-celled ancestors.
Among the human blood cell lineages examined, macrophages showed the strongest similarities to unicellular organisms. This finding suggests that the earliest blood cells may have resembled macrophages, which are immune cells that engulf harmful microbes and cellular debris.
The team also traced the gene FOS, which is widely expressed in blood cells across many animal species, back to a unicellular ancestor that lived about 700 million years ago. According to the researchers, this indicates that the first blood cells likely emerged around the same time multicellular animals first appeared on Earth.
How Modern Blood Cells Evolved
The findings suggest that early animals created the first blood cells by reusing genetic material inherited from ancient single-celled ancestors.
The analysis also revealed how different blood cell types may have branched off over time. Mast cells appear to have evolved from macrophages, while early versions of T cells and red blood cells later emerged from mast cells. The researchers also found that prototypic B cells branched directly from macrophages after mast cells had already separated.
By reconstructing this evolutionary history, the scientists were able to map a 700-million-year family tree of blood cells. Their results suggest that the development pathways of modern blood and immune cells still reflect this ancient evolutionary history.
A Living Link to Earth’s Earliest Life
The researchers say the study highlights how modern blood and immune cells may represent an extension of biological systems first established by single-celled ancestors hundreds of millions of years ago.
“I feel deeply moved by these findings, which represent the culmination of our work and illustrate that the differentiation pathways of vertebrate blood cells reflects the 700-million-year evolutionary history of these cells,” says team leader Hiroshi Kawamoto.
“When I let it sink in that this legacy from so long ago is circulating within my body as blood cells, I feel closer to our distant ancestors,” adds first author Yosuke Nagahata of the Institute of Evolutionary Biology, Spain.
The team believes the new analytical method developed for the study could also help researchers investigate the evolutionary origins of diseases such as cancer. They say this may lead to a better understanding of disease mechanisms and eventually contribute to new treatments.
The paper, “Animals have expanded the evolutionary legacy of unicellular ancestors in blood cells,” will be published May 29, 2026, in Proceedings of the National Academy of Sciences of the United States of America, with doi: 10.1073/pnas.2528110123.