Bone marrow-on-a-chip reveals how immune cells survive

Researchers have developed a laboratory model that makes it possible to study how antibody-producing plasma cells migrate, mature and survive within human bone marrow. The platform combines a lymph node-like organoid with a bone marrow-on-a-chip, providing researchers with a new way to investigate processes that are difficult to observe directly in humans.

The model, developed by researchers at Georgia Tech and Vanderbilt University, is described in Science Advances. It could contribute to research into long-term immunity following infection or vaccination, as well as autoimmune diseases, allergies and blood cancers.

Understanding long-term immunity

Plasma cells develop from B cells and produce antibodies that help protect the body against infections. Long-lived plasma cells residing in bone marrow are particularly important because they can maintain antibody production over extended periods after infection or vaccination.

However, researchers still do not fully understand why developing plasma cells migrate from lymph nodes, the spleen and other tissues to bone marrow, or how the bone marrow environment enables them to survive. Studying these processes directly is challenging. High-resolution imaging of plasma cells inside living human bone marrow is extremely difficult, meaning much of the existing knowledge has been derived from animal models.

To create an alternative, the Georgia Tech team developed a human lymphoid organoid using B cells isolated from human tonsil tissue and blood. The cells were grown in a microenvironment designed to mimic lymphoid tissue. Researchers then used inactivated influenza virus to stimulate B cells to develop into antibody-secreting plasma cells.

Recreating the bone marrow environment

Researchers at Vanderbilt University subsequently introduced these plasma cells into a microfluidic bone marrow chip. The system recreates several structural and biological characteristics of human bone marrow, including a vascularized microenvironment containing nutrients and growth factors that support plasma cells. The chip is incorporated into a stack of 96-well plates measuring approximately 7.6 by 12.7 centimetres. Inside, multiple channels and a gel-like material reproduce aspects of the bone marrow environment.

Importantly, the model represents two distinct regions. The endosteal subniche, located near the outer edge of the bone marrow cavity, provides an environment where plasma cells can reside. The perivascular subniche represents areas surrounding blood vessels deeper within the marrow, where plasma cells can proliferate and become activated.

Researchers can image cells within these environments and observe their responses to signalling proteins. This allows them to systematically investigate how different bone marrow niches influence plasma cell development, behaviour and longevity.

Studying disease in human cells

The platform could also provide opportunities to investigate how plasma cell biology changes between different groups of people. Researchers could, for example, introduce cells from older individuals to study the effects of ageing on plasma cell function.

Cells from people with autoimmune diseases or allergies could similarly be used to investigate how plasma cells responsible for harmful antibody responses develop and persist. Because abnormal plasma cell activity can also contribute to blood cancers, the model could potentially support research in that area as well. The researchers also see possibilities for testing potential treatments aimed at preventing infections, reducing autoimmune responses or inhibiting allergies.

Questions remain

The model does not reproduce the full complexity of the human body. Instead, it recreates selected structures, biological functions and spatial environments that allow specific aspects of plasma cell behaviour to be studied under controlled laboratory conditions.

Several questions remain. The researchers want to investigate, among other things, why B cells show a distinctive “stop-and-go” movement pattern and whether this reflects continuous migration through the wider bone marrow environment. By combining human immune cells with engineered lymphoid and bone marrow environments, the platform provides a new experimental tool for studying how lasting antibody responses are established and maintained.

Tumor-on-a-chip research

Last year, researchers at the University of Pennsylvania developed a tumor-on-a-chip platform that allowed scientists to observe how solid tumors resist attacks from engineered immune cells. The transparent microengineered device recreated a vascularized human lung tumor and enabled real-time study of interactions between CAR T-cells, cancer cells and the tumor microenvironment.

Using the model, researchers found that endothelial cells lining tumor blood vessels produce short-lived chemical signals that help guide CAR T-cells toward tumors. They identified the enzyme DPP4 as a factor that breaks down these signals. Treatment with the DPP4 inhibitor vildagliptin, already approved for type 2 diabetes, preserved the signals and enabled more CAR T-cells to reach and attack tumor cells.