How heart failure reshapes bone marrow to create inflammation-related immune memory
· Medical Xpressedited by Sadie Harley, reviewed by Robert Egan
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Heart failure (HF) is a condition in which the heart is not able to pump blood effectively. However, its effects go beyond pumping and circulation. HF is also known to cause a lasting form of innate immune memory in stem cells that synthesize blood and progenitor cells that are present in the bone marrow (BM). This can result in the production of immune cells that promote inflammation and worsen heart function. However, the exact mechanism of this process remained unclear.
A research team including Professor Katsuhito Fujiu from the Department of Integrative Physiology, Institute of Science Tokyo (Science Tokyo), Japan; Professor Ichiro Manabe from the Department of Systems Medicine, Graduate School of Medicine, Chiba University, Japan, and others set out to fill this knowledge gap.
They examined two important BM cell populations in mouse models: mesenchymal stromal cells (MSCs), which support blood cell development, and hematopoietic stem/progenitor cells (HSPCs), which synthesize blood and immune cells. The researchers investigated how interactions between these cells change during HF and contribute to lasting immune alterations.
Their findings are published in Nature Communications.
"We combined single-cell RNA sequencing, cell transplantation, molecular perturbation and analysis of human BM data to investigate how cardiac stress changes the BM niche," explains Fujiu.
Loss of bone marrow guardian cells
The researchers found that a population of leptin receptor-positive (Lepr⁺) MSCs in the BM plays an important role in transmitting the effects of cardiac stress to blood cell-forming stem cells.
Under normal conditions, a subset of these MSCs produces heparin-binding epidermal growth factor-like growth factor (HBEGF), a signaling protein that helps maintain balanced blood cell production. Because of this protective role, these HBEGF-producing MSCs can be thought of as "guardian cells" of the BM niche. However, HF causes a reduction in this MSC population and promotes the conversion of MSCs into fat-forming cells (adipocytes).
The loss of HBEGF changes how HSPCs develop. Reduced HBEGF signaling alters the development of HSPCs, pushing them toward producing more myeloid cells and increasing the number of inflammatory immune cells. In particular, the researchers observed an increase in CCR2ʰⁱ macrophages, a population associated with inflammatory responses in the heart.
When MSCs from mice with HF were transplanted with healthy blood cell progenitors, the recipient mice subsequently developed greater cardiac remodeling and dysfunction, demonstrating that altered MSCs can influence hematopoietic cells in ways that affect the heart.
A signaling shift toward fat formation
The researchers also identified the mechanism underlying the loss of these protective MSCs. HF suppresses Notch-HES1 signaling in Lepr⁺ MSCs. This reduction results in increased activity of PPARγ, a regulator of adipocyte formation, helping drive the MSCs toward an adipogenic state.
Reducing HBEGF specifically in MSCs similarly promoted myeloid-biased blood cell production and cardiac dysfunction, supporting a direct role for MSC-derived HBEGF in regulating this process.
Human findings suggest a similar pattern
The researchers then looked for evidence that this mechanism could also be relevant to humans. They identified a corresponding HBEGF-producing MSC population in human BM. They also found that people with HF had approximately 10-fold higher BM fat than matched healthy individuals.
"Our findings suggest that the changes in the BM environment observed in our experimental models may also be relevant to human HF," notes Fujiu. However, the obtained human data do not establish that increased BM fat causes HF.
Overall, the BM niche appears as an important component of the central innate immune memory associated with HF. Rather than only acting as a source of blood cells, the BM can respond to cardiac stress by changing its cellular environment, ultimately shaping the immune cells that reach the heart.
The study highlights the protective role of the HBEGF-producing MSC population and identifies pathways controlling its maintenance, including Notch–HES1 signaling, as potential areas for future investigation.
Publication details
Kohsaku Goto et al., Altered bone marrow niche forms central innate immune memory driving cardiac dysfunction, Nature Communications (2026). DOI: 10.1038/s41467-026-76178-z
Journal information: Nature Communications
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CardiologyAllergy and immunology Provided by Institute of Science Tokyo Who's behind this story?
Sadie Harley
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