Bone Marrow Niche: Key Factors for Plasma Cells Longevity

The research revealed that the combined stimulus of the MSC secretome and hypoxia induces a profound metabolic switch within the plasma cell.

Recent breakthrough in Immunology has shown that there are some specific

microenvironmental factors within the bone marrow (BM) that are required for sustaining the viability and functions of Human Long-Lived Plasma Cells (LLPCs), indispensable for long-term humoral immunity. While initial Antibody-Secreting Cells, found in the blood are transient & their longevity relies on successfully establishing residence within this protective BM niche. The researchers engineered an in-vitro, cell-free BM mimic that sustained antibody secreting cell’s viability for over 50 days, thereby defining the requiring components of the LLPC survival niche: soluble products secreted by primary BM Mesenchymal Stromal Cells (MSCs), the cytokine APRIL, and the maintenance of a hypoxic (low oxygen) environment. The study found that while the MSC secretome provided core scaffolding, APRIL significantly potentiated survival, with hypoxia further enhancing viability over the longest culture periods.

The mechanisms driving this longevity were elucidated through a combined analysis of MSC secretome proteomics and differential RNA transcriptomics. This approach identified two key MSC-secreted survival factors, fibronectin (FN-1) and YWHAZ. Crucially, the research revealed that the combined stimulus of the MSC secretome and hypoxia induces a profound metabolic switch within the plasma cell. This switch involves the downregulation of the mTORC1 (master regulator of cell growth and high metabolic activity) signalling pathway. By suppressing mTORC1, the cell transits into a state of metabolic quiescence essential for its decades-long survival.

In conclusion, this research precisely delineates the cellular and molecular components of the human LLPC survival niche, identifying the necessity of the MSC secretome, APRIL ,and hypoxia for sustained viability. Furthermore, it firmly establishes the suppression of mTORC1 signaling as the core mechanism underlying plasma cell longevity. This mechanistic understanding is fundamental, providing a clear molecular framework for developing interventions aimed at modulating the duration and quality of immune memory, with potential applications in designing more effective vaccines and in selectively eliminating pathogenic plasma cells implicated in autoimmune diseases.

References:

https://www.nature.com/articles/s41467-018-05853-7