With support from the National Institutes of Health, a team of scientists have developed a laboratory model that reveals how antibody-producing plasma cells migrate, mature, and survive in human bone marrow. According to its developers, the platform combines a lymph node that mimics an organoid with a tissue chip that mimics bone marrow, and supports studies into the key stages of plasma cell development. Full details of the work are published in a new Science Advances study titled “Ex Vivo Bone Marrow Subniches Influence the Fate of Human Antibody-Secreting Cells.”
The work was done by scientists from Georgia Tech and Vanderbilt University. The human lymphoid organoid was developed by a team led by Ankur Singh, PhD, a professor of bioengineering and director of the Center for Immunoengineering at Georgia Tech. They developed it by isolating B cells from human tonsil tissue and blood sources and growing them in an environment similar to lymphoid tissue. They used inactivated influenza virus to overcome challenges associated with culturing B cells and getting to transform into antibody secreting plasma cells.
Meanwhile, scientists in the lab of Krishnendu Roy, PhD, dean of engineering and professor of biomedical engineering at Vanderbilt University, designed a microfluidics-based vascularized microenvironment for the bone marrow chip that mimics the conditions found in human bone marrow. Essentially, they tried to “mimic the structure, fundamental biological functions, and spatial microenvironments” of human bone marrow in order “to ask questions about human organ-like behavior in this more simplified model,” Roy explained.
As explained by the developers, the final model is assembled within a three-by-five stack of 96-well plastic plates, that are each less than half-an-inch thick. It features multiple channels that are coated with a gel-like material similar to bone marrow with nutrients and growth factors to support plasma cell function and maintenance. Its layers correspond to an area at the outer edge of the bone marrow cavity, known as the endosteal subniche, where plasma cells are stored. The model also replicates an area deeper inside the center of the bone marrow, the perivascular subniche, which surrounds a network of blood vessels, where plasma cells proliferate and are activated.
“It is nearly impossible to achieve high imaging resolution of plasma cells in living human bone marrow,” Singh said. Though it is possible to “do some level of imaging in the bone marrow of a mouse” which is where some previous efforts have been focused.
Now with this new model, scientists will be able to run new types of experiments. “A fundamental question [that] our study addresses [is] why it is that when B cells are ready to make antibodies, they relocate from lymph nodes, the spleen, and other organs and enter and take up residence in bone marrow,” Singh said. “Another is a question of the role that the environment of bone marrow plays in orienting those cells and responses to reinfection.”
Furthermore, the model can be seeded with cells from unique patient populations to study things like the effects of aging on plasma cell function. It could also be used to study cells from people with autoimmune or allergic diseases to understand how autoimmunity or allergy-promoting plasma cells are produced and maintained. Other studies could focus on addressing questions such as why B cells show a stop-and-go pattern of movement and whether it is part of a migration pattern in the bone marrow.
