Altered Bone Marrow Niche Forms Central Innate Immune Memory Driving Cardiac Dysfunction

We previously showed that heart failure (HF) induces innate immune memory in hematopoietic stem/progenitor cells (HSPCs), which crucially contributes to HF recurrence and impaired stress responses in multiple organs. While bone marrow (BM) niches maintain hematopoietic homeostasis, their role in innate immune memory remains poorly understood, despite their critical function in long-term HSPC regulation. Here, we demonstrate that BM Lepr+ mesenchymal stromal cells (MSCs) influence HSPCs to promote cardiac pathology in HF. Co-transplantation of Lepr+ MSCs from HF mice with healthy HSPCs resulted in proinflammatory macrophage accumulation in the heart and enhanced cardiac remodeling, indicating that MSCs skew HSPC differentiation toward pathological myelopoiesis. Mechanistically, HF reduced heparin-binding EGF-like growth factor (HBEGF) expression in MSCs by diminishing a distinct HBEGF-expressing MSC subpopulation. Interactome analysis revealed suppression of EGF signaling in HSPCs. MSC-specific Hbegf knockdown enhanced cardiac dysfunction after pressure overload. HF also activated the adipogenic program in MSCs, which correlated with depletion of Hbegf+ MSCs. Notably, a HBEGF+ MSC subpopulation exists in human BM, and HF was associated with increased BM adiposity in humans. Our results identify the BM niche as a key regulator of trained immunity and a potential therapeutic target in HF.