Heart Failure Promotes Multimorbidity through Innate Immune Memory

Research Background

Despite significant medical advances, the mortality rate of heart failure (HF) remains high, necessitating new therapeutic targets. HF patients often experience acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. This indicates pathological interactions between these comorbidities, although the specific mechanisms remain unclear. Chronic inflammation is now considered a common pathological feature in multimorbidity. Innate immune memory is not only associated with host defense against infections but also involves the development of non-infectious diseases. Our recent findings suggest that tissue-resident macrophages play a key role in maintaining cardiac health, but under cardiac stress, macrophages exhibit diverse functional and phenotypic changes. However, whether HF promotes chronic inflammation in multiple organs and the underlying mechanisms remain to be studied.

Source of Paper

This research paper was written by Yukiteru Nakayama, Katsuhito Fujiu, among others. The primary authors are from the departments of Cardiovascular Medicine and Advanced Cardiology at the University of Tokyo. The paper was published on May 24, 2024, in Science Immunology (sci. immunol. 9, ade3814 (2024)).

Research Process

Experimental Design

To investigate whether cardiac events like HF alter the impact of hematopoietic stem cells (HSCs) and their progeny on cardiac function, we induced HF in mice using transverse aortic constriction (TAC) technique. Four weeks later, we collected bone marrow (BM) from HF and control mice and transplanted it into young, lethally irradiated, but healthy mice. Four months post-transplant, the recipient mice with BM from HF mice exhibited decreased cardiac function and increased fibrosis, which became more pronounced at six months.

Changes in HSC Differentiation Potential

To explore whether TAC affects HSC differentiation potential, we performed cotransplantation experiments with long-term HSCs (CD45+Lin−Sca1+cKit+CD34−Flt3−CD150+CD48−). Flow cytometry revealed an increased proportion of monocytes and neutrophils in the progeny of TAC HSCs compared to control HSCs, along with an increase in cardiac Ly6Clow CCR2+ macrophages, but no significant change in Ly6Clow CCR2− macrophages. These results suggest that TAC-experienced HSCs are more prone to differentiate into CCR2+ macrophages.

Competitive Transplantation of HSCs and BM Potential

To further analyze the impact of TAC on HSCs, we conducted a series of competitive transplantation experiments. Using enhanced green fluorescent protein (EGFP) labeled mice, wild-type mice, and CD45.1/CD45.2 congenic mice, we consistently observed a myeloid skewing tendency in TAC HSCs and reduced efficiency in differentiating into cardiac macrophages.

Transcriptome and Chromatin Accessibility Analysis

Global chromatin accessibility analysis and single-cell RNA sequencing (scRNA-Seq) identified suppressed TGF-β signaling pathways in TAC HSCs, corresponding with reduced bone marrow sympathetic nerve activity. Further experiments showed that TGF-β-suppressed HSC transplants exacerbated cardiac dysfunction, indicating that TAC induces epigenomic changes in HSCs by inhibiting TGF-β signaling, thus altering their capacity to generate cardiac macrophage subsets.

HSC Variant Tracking

Using DNA barcoding technology to trace HSC progeny, we found significant differences in clonal contributions of individual HSCs to blood and tissue macrophages, indicating heterogeneity in the differentiation potential of different HSC subsets. Since cells derived from TAC HSCs tended to repopulate circulating monocytes rather than cardiac or renal macrophages, TAC-experienced HSCs may contain relatively small and/or damaged subsets capable of generating tissue macrophages.

“Stress Memory” of HSCs

The study also found that cardiac pressure overload induced HSC proliferation and myeloid skewing phenomena related to suppressed TGF-β activation. In vivo 3D bone marrow imaging (CLARITY) and enzyme-linked immunosorbent assay (ELISA) indicated reduced active TGF-β levels in the bone marrow post-TAC. Subsequent experiments confirmed the importance of the sympathetic nervous system in mediating TAC’s impact on the bone marrow and demonstrated that TAC-induced HSC changes could persist, leaving stress memory in HSCs.

Induced Renal and Skeletal Muscle Vulnerability through Bone Marrow Transplantation

We further investigated whether TAC-induced changes in HSCs enhance pathological responses in other organs. Using a unilateral ureteral obstruction (UUO) model, mice transplanted with TAC bone marrow exhibited more significant tubular damage and interstitial fibrosis compared to controls. Additionally, cells derived from TAC HSCs exacerbated defects in skeletal muscle healing and regeneration post-injury.

Methods and Materials

The study used C57BL/6J mice, housed in pathogen-free conditions at the University of Tokyo. All experiments were approved by the University’s ethics committee and adhered strictly to the relevant guidelines. The study aimed to explore the role of HF-induced HSC and innate immune memory and to understand the impact of HF on the differentiation patterns of HSCs and their progeny.

Research Conclusions

This study demonstrates that heart failure alters the epigenome and differentiation potential of hematopoietic stem cells, thereby affecting the cells and stress response mechanisms in the heart, kidneys, and skeletal muscles. Since tissue-resident macrophages are crucial for maintaining organ health and responding to stress, these findings reveal that HSCs may carry “stress memory” under cardiac pressure, making them key drivers of recurring HF events and multimorbidity.

Research Value

This study not only deepens our theoretical understanding of the role of HSCs in the mechanisms of heart failure but also provides potential new targets for treating heart failure and its related comorbidities. By modulating TGF-β signaling pathways in the bone marrow, it may be possible to inhibit or reverse tissue damage and dysfunction caused by HF to some extent. This brings new hope for future cardiovascular disease treatments.