Heart failure induces alterations in bone marrow mesenchymal stromal cells expressing the leptin receptor that promote innate immune memory in hematopoietic stem and progenitor cells, leading to inflammatory macrophage accumulation in the heart and worsened cardiac remodeling.
Key Findings
Results
Transplanting bone marrow mesenchymal stromal cells from heart failure mice together with healthy hematopoietic cells caused inflammatory macrophages to accumulate in the heart and worsened cardiac remodeling.
The experiment involved co-transplanting LepR+ stromal cells from heart failure mice with healthy hematopoietic stem and progenitor cells into recipient mice.
Inflammatory macrophage accumulation in the heart was observed as a downstream consequence of the altered stromal cell signaling.
Cardiac remodeling was worsened compared to controls receiving stromal cells from healthy donors.
This finding established that the bone marrow stromal niche, not just hematopoietic cells, is a driver of innate immune memory contributing to cardiac pathology.
Results
Heart failure reduced a stromal subpopulation that produces heparin-binding epidermal growth factor (HB-EGF) and suppressed growth factor signaling in hematopoietic cells.
A specific subpopulation of LepR+ bone marrow mesenchymal stromal cells was identified as the source of HB-EGF.
Heart failure caused a reduction in this HB-EGF-producing stromal subpopulation.
The reduction in HB-EGF production led to suppressed growth factor signaling in hematopoietic stem and progenitor cells.
This mechanistic finding links the stromal niche alteration to changes in hematopoietic cell programming associated with innate immune memory.
Results
Heart failure activated a fat-forming (adipogenic) program in bone marrow mesenchymal stromal cells.
LepR+ mesenchymal stromal cells in the bone marrow underwent activation of an adipogenic differentiation program in the context of heart failure.
This adipogenic shift represents a functional reprogramming of the bone marrow niche under heart failure conditions.
The activation of this fat-forming program was identified as part of the mechanistic basis by which heart failure alters the bone marrow microenvironment.
Results
An equivalent LepR+ stromal subpopulation exists in human bone marrow, and heart failure was associated with increased bone marrow fat in humans.
The study identified a human counterpart to the mouse LepR+ bone marrow mesenchymal stromal cell subpopulation.
Clinical data showed an association between heart failure and increased bone marrow adiposity in human patients.
This translational finding supports the relevance of the mouse mechanistic findings to human heart failure.
The results identify the bone marrow microenvironment as a conserved regulator of innate immune memory across species.
Background
Bone marrow mesenchymal stromal cells expressing the leptin receptor (LepR+) influence hematopoietic stem and progenitor cells to promote cardiac pathology in the setting of heart failure.
LepR+ bone marrow mesenchymal stromal cells were identified as a key cellular component of the bone marrow niche regulating hematopoietic programming.
The influence of these stromal cells on hematopoietic stem and progenitor cells was shown to promote downstream cardiac pathology.
This builds on prior work showing that heart failure induces innate immune memory in hematopoietic stem and progenitor cells contributing to recurrence of heart failure and impaired stress responses in multiple organs.
The current study extends this prior framework by demonstrating that the bone marrow microenvironment itself, through LepR+ stromal cells, is a central regulator of this memory.
What This Means
This research investigates how heart failure changes the bone marrow environment in ways that make the immune system behave abnormally, ultimately worsening heart disease. The scientists focused on a specific type of support cell in the bone marrow called leptin receptor-positive mesenchymal stromal cells (LepR+ MSCs). These cells normally help regulate the production and behavior of blood and immune cells. The study found that when an animal has heart failure, these support cells change: a subset that normally produces an important growth factor (called HB-EGF) shrinks, and the remaining cells start converting into fat cells instead of performing their normal functions. These changes alter the programming of blood-forming stem cells in ways that cause them to produce inflammatory immune cells (macrophages) that accumulate in the heart and worsen its remodeling and function.
To prove that the altered bone marrow environment alone can cause cardiac harm, the researchers transplanted stromal cells from heart-failure mice together with healthy blood-forming cells into recipient mice. Even though the blood-forming cells were healthy, the diseased stromal environment was enough to reprogram them to produce inflammatory macrophages and damage the heart. This demonstrates that the bone marrow 'niche' — the structural and cellular environment surrounding blood stem cells — acts as a kind of memory system for past disease, perpetuating inflammation even after the initial insult. Importantly, the researchers also found an equivalent cell population in human bone marrow and showed that heart failure patients have increased bone marrow fat, suggesting the same process occurs in people.
This research suggests that the bone marrow microenvironment is not just a passive bystander in heart disease but an active participant that encodes and sustains a form of immune memory contributing to the recurrence and progression of heart failure. These findings open potential new avenues for understanding why heart failure tends to worsen over time and why patients who have had one episode are at heightened risk for further cardiac events, pointing to the bone marrow niche as a possible future therapeutic target.
Goto K, Nakayama Y, Sugita J, Oshima T, Kani K, Kobayashi A, et al.. (2026). Altered bone marrow niche forms central innate immune memory driving cardiac dysfunction.. Nature communications. https://doi.org/10.1038/s41467-026-76178-z