When a pathogen or other antigen activates a B cell, the cell begins proliferating and producing antibodies. Once the immune response resolves, most of the B cells die off, but some migrate to the bone marrow to persist as long-lived antibody secreting plasma cells.
While researchers knew that this process occurred, studying the cellular and molecular interactions in human bone marrow is difficult because of the inability to easily see the niche within the bone. Although animal and two-dimensional cell culture models have provided some insights, scientists sought to explore a more realistic human bone marrow niche.1,2
To do this, researchers at Georgia Institute of Technology and Vanderbilt University developed a human bone marrow-on-a-chip (BMOC) platform that recreated the cellular niches of this site.3 In a study published in Science Advances, the team used this system to explore the migration and localization of plasma cells in the human bone marrow.4
They showed that, while these cells remain in the bone marrow after migration, they continue to move within the niche. Additionally, the team identified important signals for the proper localization and retention of antibody secreting cells to the bone marrow, revealing the details of how these long-lived cells are maintained. This platform could help scientists better understand long-term immunity and the factors that influence certain diseases related to the bone marrow.
The BMOC consisted of three sets of channels seeded with different cells or media. First, the researchers cultured mesenchymal stromal cells in the central channel and differentiated these into various bone cells. This helped to form the unique matrix that would support the endosteal niche of the bone marrow, which maintains hematopoietic stem cells.
After this was established, they introduced more mesenchymal stromal cells to this matrix and seeded an outer channel with fibroblasts that would mature and produce the endothelial cells that would form vessel-like structures in a channel connected to the central line, giving rise to the perivascular niche.
To study how the bone marrow influences plasma cells, the researchers produced these cells using a human lymphoid organoid that one of the team’s previously developed.5 To replicate these cells traveling through the blood vessels, the researchers introduced the antibody secreting cells to the BMOC through the vessel-like channel.
Using time lapse microscopy, the researchers watched the plasma cells migrate toward the bone marrow niches through the recreated vessels. Upon exiting the vessels, the cells clustered against the endothelial cells in the perivascular niche. The researchers confirmed that the plasma cells responded to the homing chemokine C-X-C motif chemokine 12 (CXCL12) produced by bone marrow mesenchymal stromal cells and received survival signals through interaction with the adhesion molecule vascular cell adhesion molecule 1.
“The cells appeared to congregate in regions rich in survival signals, suggesting that specialized perivascular neighborhoods serve as safe harbors for long-term immune memory,” said Krishnendu Roy, a coauthor and biomedical engineer at Vanderbilt University, in a press release.
Cytokines also provide survival signals to plasma cells in the bone marrow, so the researchers introduced two molecules important to B cell survival to the BMOC. These increased the number of plasma cells that survived and matured, as determined by the expression of a maturation marker, after four days.
To further explore how the plasma cells localized in the BMOC, the researchers imaged the immune cells over 10 hours. They saw that during this time, the plasma cells migrated through the niche in a stop-and-go fashion; although the cells spent more time stationary in one place, the plasma cells occasionally moved to new areas within the perivascular niche.
Finally, the researchers created BMOC platforms missing either the bone-like matrix layer, the mesenchymal stromal cells, or both. In the absence of the bone-like matrix that formed the endosteal niche, the team saw that plasma cells were more motile as a result of less CXCL12 being present, but these cells had lower survival. This demonstrated that both bone marrow niches contribute important factors for the long-term maintenances of plasma cells.
By offering a window into the otherwise opaque world of human bone marrow, the researchers believe that their findings have shed light on a previously poorly understood area of immunology. “Classic immunology has often viewed plasma cells as largely sedentary,” said Georgia Institute of Technology engineer Ankur Singh in the same press release. “We found that many cells paused for extended periods, moved, stopped again, and continued exploring their surroundings.”
- Chu VT, Berek C. The establishment of the plasma cell survival niche in the bone marrow. Immunol Rev. 2013;251(1):177-188.
- Nguyen DC, et al. Factors of the bone marrow microniche that support human plasma cell survival and immunoglobulin secretion. Nat Commun. 2018;9(1):3698.
- Nelson MR, et al. A multi-niche microvascularized human bone marrow (hBM) on-a-chip elucidates key roles of the endosteal niche in hBM physiology. Biomaterials. 2021;270:120683.
- Kramer L, et al. Ex vivo bone marrow subniches influence the fate of human antibody-secreting cells. Sci Adv. 2026;12(37):eadz3976.
- Zhong Z, et al. Human immune organoids to decode B cell response in healthy donors and patients with lymphoma. Nat Mater. 2025;24(2):297-311.
