The bone marrow continually produces millions of blood and immune cells, and this process depends on the coordinated work of stem, stromal and immune cells. Over time, the balance is disrupted due to aging, chronic inflammation or mutations, allowing altered cells to multiply undetected and leading to clonal hematopoiesis (CHH), occurring in 10-20% of people over 60 years of age. Although CGNP does not cause symptoms, it greatly increases the risk of blood cancer and cardiovascular disease.
Despite the high clinical significance of MDS and CGNP, it is not entirely clear what role the bone marrow microenvironment plays in their development. To understand why mutated HSC clones become dominant, an international team of scientists conducted a detailed molecular and spatial analysis of the bone marrow of participants in the BoHemE cohort study.
Using single-cell RNA sequencing, biopsy imaging, proteomics, and functional co-culture models, the scientists created a high-fidelity “map” of the bone marrow microenvironment in healthy donors and patients with MDS. This multicomponent approach showed that profound reorganization of cellular interactions begins long before the onset of symptoms. In particular, the researchers found a population of inflammatory stromal cells that gradually replaced the normal mesenchymal stromal cells that normally support stem cells.
In contrast to healthy MSCs, inflammatory MSCs release increased amounts of interferon-dependent cytokines and chemokines. These signals attract and activate interferon-sensitive T cells. Activated T cells increase inflammation, forming a self-perpetuating loop that causes chronic inflammation, disrupts normal hematopoiesis, and alters vascular structure.
It is noteworthy that the researchers did not find evidence that the mutated hematopoietic cells themselves in MDS trigger inflammation. This became clear thanks to the new computational tool SpliceUp, created at the Karolinska Institutet. SpliceUp can differentiate between mutated and normal cells in single-cell sequencing data by analyzing characteristic RNA splicing abnormalities. It turned out that in MDS it is the inflammatory network in the microenvironment of the bone marrow that comes to the fore and gradually displaces normal regenerative structures.