A recent study published in the journal Science Immunology reported that heart failure (HF) promotes multimorbidity.
Despite medical advances, mortality with heart failure is significantly high. Recurrent hospitalization is a hallmark of HF, suggesting that HF ​​increases the risk of future HF events and contributes to comorbidity. Chronic inflammation is recognized as a common pathological feature of most diseases involving multimorbidity. However, it is unclear whether HF contributes to chronic inflammation and the mechanisms leading to HF-related multimorbidity.
Study: Heart failure promotes multimorbidity through innate immune memory. Image credit: CalypsoArt / Shutterstock
The study and findings
In the present study, researchers examined HF-induced changes in hematopoietic stem cells (HSCs), their monocyte progeny, and their effect on skeletal muscle, heart, and kidney. First, they investigated whether cardiac events alter HSCs and affect cardiac functions. To this end, HF was induced in mice by applying pressure overload via transverse aortic constriction (TAC) to the left ventricle.
Bone marrow (BM) was harvested four weeks later for transplantation into lethally irradiated mice. BM transplantation (BMT) from control mice was also performed. Four months later, mice that received BM from HF mice had increased fibrosis and reduced heart function relative to those that received BM from control mice. These abnormalities were most apparent at six months.
Next, the researchers investigated whether HSC modulation of TAC affects the development and function of cardiac macrophages. Long-lived HSCs from control CD45.1 and CD45.1/CD45.2 heterozygous TAC mice were co-transplanted into CD45.2 recipient mice. They found that neutrophils and monocytes in the peripheral blood were more frequently derived from TAC HSCs than from control HSCs, indicating a myeloid shift in the progeny.
This myeloid shift was also noted in peripheral blood cells derived from TAC BM. Cardiac Ly6Chere CCR2+ Macrophages were higher in TAC BM recipients, suggesting that HSCs exposed to TAC may differentiate into CCR2+ macrophages. Subsequently, competitive transplantation experiments showed that TAC modulates HSCs to generate more proinflammatory macrophages than those resident in the tissue.
Since tissue-resident macrophages protect the heart from stress and maintain homeostasis, this altered potential of TAC HSC-derived cells may impair homeostasis and induce cardiac remodeling. This led to investigations into whether TAC HSCs promote other organ pathologies. Therefore, renal injury responses were analyzed in BM recipients from TAC mice, using a unilateral ureteral obstruction (UUO) model.
Shortly after performing UUO, monocyte-derived macrophages showed proinflammatory Ly6CHello phenotype. Nevertheless, Ly6Chere Macrophages increased within the kidneys on days 2 and 3. Furthermore, TAC BM recipients showed significantly worse interstitial fibrosis and tubular damage than controls one week later. Next, the team investigated whether HF-induced changes in HSCs contribute to sarcopenia.
Accordingly, four weeks after cardiotoxin administration, TAC BM recipients had smaller cross-sectional areas of regenerated myofibers at the site of injury than controls. TAC BM mice also showed reduced regeneration and healing, with more prominent fibrosis in the injured muscles. Further, the team investigated the potential mechanisms underlying TAC-induced HSC alterations.
Transcriptional analysis showed that TAC affected gene expression in Lin—Sca1+ cKit+ CD34- CD45.2+ CD48- CD150+ Flt3- HSCs. Genome-wide chromatin accessibility analysis showed that TAC also affected HSC epigenomes. Additionally, monocyte RNA sequencing was performed on CD45.2+ Lin—Sca1+ cKit+ CD34—Flt3– HSCs. This revealed nine subpopulations with varying levels of HSCs and pluripotent progenitor markers.
Gene set enrichment analysis revealed the downregulation of nine gene sets, with transforming growth factor (TGF)-β signaling being the top down-regulated gene set. In addition, the team observed that the levels of active TGF-β1 were significantly reduced in the BM one week after TAC. Since TGF-β signaling is crucial for HSC inactivation, cardiac stress may prevent inactivation through reduced TGF-β signaling.
Consistently, there was a sustained increase in proliferating HSCs after TAC that was suppressed by TGF-β1 treatment. Finally, the researchers investigated whether inhibiting TGF-β signaling in HSCs could promote heart failure. They found that the effects of inhibition on HSC transcription were similar to those of TAC, suggesting that TGF-β may, at least in part, mediate the effects of TAC on HSCs.
conclusions
The study highlighted that HSCs from HF mice lead to cardiac dysfunction and increase the susceptibility of skeletal muscle and kidney to direct and indirect insults in the recipient mice. In addition, TAC-experienced HSC progeny preferentially generate cardiac macrophages that express inflammation and remodeling genes.
In addition, HF induced HSC proliferation and myeloid distortion by suppressing TGF-β, corresponding to reduced sympathetic nerve activity in the BM. Together, the findings reveal that the BM acts as a hub for the stress response in HF. HSCs carry these stress memories, contributing to the further development of heart failure and multimorbidity.
