Animals have expanded the evolutionary legacy of unicellular ancestors in blood cells

Y Yosuke Nagahata (Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University) Y Yuji Nishimura (Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University) R Ryota Kaitani (Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University) J Jason Cheok Kuan Leong (Research Center for Integrative Evolutionary Science, The Graduate University for Advanced Studies (SOKENDAI)) I Izumi Oda-Ishii (Department of Zoology, Graduate School of Science, Kyoto University) H Hisanori Kohtsuka (Misaki Marine Biological Station, School of Science, The University of Tokyo) S Shinya Abe (Laboratory of Immune Regulation, Institute for Life and Medical Sciences, Kyoto University) T Tasuku Ishida (Department of Zoology, Graduate School of Science, Kyoto University) M Marina Carmona-Rivas (Department of Complexity of Life, Institut de Biologia Evolutiva (Consejo Superior de Investigaciones Científicas-Universitat Pompeu Fabra)) S Sebastian R. Najle E Elena Casacuberta (Department of Complexity of Life, Institut de Biologia Evolutiva (Consejo Superior de Investigaciones Científicas-Universitat Pompeu Fabra)) K Koichi Ikuta (Laboratory of Immune Regulation, Institute for Life and Medical Sciences, Kyoto University) T Toru Miura (Misaki Marine Biological Station, School of Science, The University of Tokyo) M Michio Ogasawara (Department of Biology, Graduate School of Science, Chiba University) N Naoki Irie (Research Center for Integrative Evolutionary Science, The Graduate University for Advanced Studies (SOKENDAI)) Y Yutaka Satou (Department of Zoology, Graduate School of Science, Kyoto University) I Iñaki Ruiz-Trillo H Hiroshi Kawamoto (Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University)

Abstract

Blood cells are common and unique to animals, enabling them to address critical challenges of defense and transport. Thus, their evolution represents a defining innovation in metazoan multicellular life. However, their evolutionary trajectory about how blood cells emerged and diversified throughout animal history remains unclear. Here, we present a combination of bioinformatics and functional data that demonstrate that the metazoan blood cell program most likely originated through the repurposing of an ancestral premetazoan toolkit governed by Fos . This primordial program established the macrophage-like initial blood cells at the metazoan root. Then, the first lineage bifurcation at the origin of Bilateria drove the emergence of a specialized mast/killer lineage, characterized by acquisition of granular proteases for antiparasitic defense. Subsequent deuterostome/vertebrate innovations branched T/NK and erythrocyte/thrombocyte lineages from mast cells while B cells derived from macrophages. Our data also show that a prototypic thymus formed at the gill edges of a chordate ancestor. In line with the evolutionary history, the modern hematopoietic pathway shows a vestige of the phylogeny; differentiation potentials of phylogenetically old cell lineages expressing Fos such as macrophages and mast cells are widely retained, and ancient HSCs with limited lineage potentials have been inherited as origo-lineage progenitors. Our framework provides the history of blood cells showing an adaptive innovation built upon ancient unicellular foundations.

Article Details

Volume / Issue Vol. 123, Issue 23
Published June 09, 2026
ISSN 0027-8424
Publisher National Academy of Sciences

Authors (18)

Y

Yosuke Nagahata

Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University

Y

Yuji Nishimura

Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University

R

Ryota Kaitani

Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University

J

Jason Cheok Kuan Leong

Research Center for Integrative Evolutionary Science, The Graduate University for Advanced Studies (SOKENDAI)

I

Izumi Oda-Ishii

Department of Zoology, Graduate School of Science, Kyoto University

H

Hisanori Kohtsuka

Misaki Marine Biological Station, School of Science, The University of Tokyo

S

Shinya Abe

Laboratory of Immune Regulation, Institute for Life and Medical Sciences, Kyoto University

T

Tasuku Ishida

Department of Zoology, Graduate School of Science, Kyoto University

M

Marina Carmona-Rivas

Department of Complexity of Life, Institut de Biologia Evolutiva (Consejo Superior de Investigaciones Científicas-Universitat Pompeu Fabra)

S

Sebastian R. Najle

E

Elena Casacuberta

Department of Complexity of Life, Institut de Biologia Evolutiva (Consejo Superior de Investigaciones Científicas-Universitat Pompeu Fabra)

K

Koichi Ikuta

Laboratory of Immune Regulation, Institute for Life and Medical Sciences, Kyoto University

T

Toru Miura

Misaki Marine Biological Station, School of Science, The University of Tokyo

M

Michio Ogasawara

Department of Biology, Graduate School of Science, Chiba University

N

Naoki Irie

Research Center for Integrative Evolutionary Science, The Graduate University for Advanced Studies (SOKENDAI)

Y

Yutaka Satou

Department of Zoology, Graduate School of Science, Kyoto University

I

Iñaki Ruiz-Trillo

H

Hiroshi Kawamoto

Laboratory of Immunology, Institute for Life and Medical Sciences, Kyoto University