Study links heart failure to bone marrow changes driving inflammation

A recent study conducted at Science Tokyo indicates that heart failure (HF) modifies the bone marrow (BM) by depleting specific cells responsible for regulating inflammation. The findings suggest that cardiac stress diminishes a population of mesenchymal stromal cells (MSCs) that produce heparin-binding EGF-like growth factor (HBEGF). This reduction disrupts protective signaling pathways, altering blood-forming stem cells and encouraging the development of inflammatory macrophages.

The role of guardian cells

Heart failure is defined as the inability of the heart to pump blood effectively, but its impact extends beyond circulation. The condition induces lasting innate immune memory in hematopoietic stem and progenitor cells (HSPCs) within the BM. These changes lead to the production of immune cells that exacerbate inflammation and worsen cardiac function. Until now, the precise mechanisms behind this process remained unclear.

Researchers identified a subset of leptin receptor-positive (Lepr+) MSCs as critical "guardian cells" in the BM niche. Under normal conditions, these cells secrete HBEGF, a protein essential for maintaining balanced blood cell production. However, HF causes a decline in this MSC population and triggers their conversion into fat-forming adipocytes.

Mechanisms of cellular change

The loss of HBEGF significantly impacts HSPC development. Reduced signaling pushes these cells toward myeloid lineage production, increasing the count of inflammatory immune cells. Specifically, the team observed a rise in CCR2hi macrophages, a group linked to inflammatory responses in the heart. Experiments involving mice demonstrated that transplanting MSCs from HF-affected animals with healthy progenitors led to greater cardiac remodeling and dysfunction in recipients. This confirms that altered MSCs influence hematopoietic cells in ways that negatively affect the heart.

The study uncovered the molecular pathway driving this loss. HF suppresses Notch-HES1 signaling in Lepr+ MSCs, which subsequently increases the activity of PPARγ, a regulator of adipocyte formation. This shift drives MSCs toward an adipogenic state. When researchers specifically reduced HBEGF in MSCs, it similarly promoted myeloid-biased blood-cell production and cardiac dysfunction, highlighting the direct regulatory role of MSC-derived HBEGF.

Implications for human health

To determine if these findings apply to humans, the team analyzed human BM data. They identified a corresponding HBEGF-producing MSC population in human subjects. Additionally, individuals with HF exhibited approximately 10-fold higher levels of BM fat compared to matched healthy controls.

"Our findings suggest that the changes in the BM environment observed in our experimental models may also be relevant to human HF," stated Professor Katsuhito Fujiu from the Department of Integrative Physiology at Institute of Science Tokyo. He noted, however, that the human data do not prove that increased BM fat causes HF.

The research was published in Volume 17 of Nature Communications on August 26, 2026. The work involved a collaborative effort including Professor Ichiro Manabe from Chiba University, Project Clinical Doctor Kohsaku Goto from The University of Tokyo, and Project Leader Yukiteru Nakayama from the Tokyo Metropolitan Institute of Medical Science, alongside researchers from Osaka University and the International University of Health and Welfare.

Overall, the BM niche emerges as a central component of innate immune memory associated with HF. Rather than merely serving as a source for blood cells, the BM responds to cardiac stress by altering its cellular environment, ultimately shaping the immune cells that reach the heart. The study highlights potential therapeutic targets, including pathways controlling MSC maintenance such as Notch–HES1 signaling.