Ex vivo bone marrow subniches influence the fate of human antibody-secreting cells

Abstract

Long-term humoral immunity relies on long-lived plasma cells in the bone marrow (BM). However, the processes governing plasma cell transport, positioning, and longevity within the BM niche remain poorly understood, especially in humans. Most existing knowledge comes from mouse studies or limited human-based models, which makes translating findings to human biology challenging. Here, we introduce a physiologically relevant human bone marrow-on-a-chip (hBMOC) model to investigate the behavior and interactions of human immune organoid-derived antibody-secreting cells (ASCs) within the human BM microenvironment. The hBMOC model is microvascular and perfusable and incorporates both endosteal and perivascular niches. We demonstrate that human ASCs migrate through blood vessels, accumulating and clustering in perivascular areas where they are closely associated with critical survival factors. In addition, we found that the presence of the endosteal niche substantially affects human ASC survival, movement, and retention, underscoring the dynamic interactions among human BM subniches that regulate ASC activity. We observed that a subset of human ASCs exhibits a dynamic stop-and-go migration pattern partially regulated by CXCR4-CXCL12 signaling. These findings provide direct insight into human ASC biology that has remained poorly defined, including their niche-specific localization, survival, and migratory dynamics within a three-dimensional human bone marrow microenvironment. Our results emphasize the distinct and cooperative roles of perivascular and endosteal compartments in supporting human ASC fate, offering previously inaccessible mechanistic insights into how human BM niches regulate plasma cells. This work lays the groundwork for studying plasma cell aging, vaccine durability, and disease-related dysfunction in human ASC maintenance and persistence.