Widespread presence of bone marrow-like hematopoietic stem cell niche in invertebrate skeletons.

Skeletal harboring of hematopoietic stem cells (HSCs) is generally considered as vertebrate-specific innovation during water-to-land transition. However, this long-standing view has not been rigorously evaluated as hematopoietic sites remain poorly understood in most invertebrate groups. We report, to our knowledge, the first discovery of abundant HSCs in adult mollusk shells, an invertebrate hematopoietic niche resembling vertebrate bone marrow (BM). Cell-lineage analysis and functional assays reveal the developmental origin of HSCs during larval shell formation and their participation in hemocyte-mediated shell regeneration and soft-body blood supply. Widespread skeleton-related HSC-like cells are found in diverse invertebrate groups and bony fish group, suggesting skeletons as a universal niche for animal HSCs and HSC-skeleton association preceding vertebrate water-to-land transition. Comparison of invertebrate and vertebrate skeletal HSCs enables the macroevolutionary profiling of a core-set of animal HSC regulators. Our findings would boost fundamental paradigm shifts for hematopoiesis and stem cell research in invertebrates and provide the redefined understanding of vertebrate BM evolution and water-to-land transition.