Study Reveals Heart Failure Induces Multimorbidity by Altering Stem Cells

A recent study published in the journal Science Immunology reported that heart failure (HF) promotes multimorbidity.

Despite advances in medical treatments, HF mortality remains high. Frequent hospitalizations are a hallmark of HF, suggesting that HF increases the risk of subsequent HF events and contributes to multimorbidity. Chronic inflammation is a common pathological feature of many diseases associated with multimorbidity. However, it is unclear whether HF contributes to chronic inflammation and the mechanisms driving HF-related multimorbidity.

The Study and Findings Researchers examined how HF-induced changes in hematopoietic stem cells (HSCs) and their monocyte descendants affect the skeletal muscle, heart, and kidneys. The study induced HF in mice by applying pressure overload through transverse aortic constriction (TAC) on the left ventricle. Bone marrow (BM) was collected four weeks later for transplantation into lethally irradiated mice, with control mice also undergoing BM transplantation. Four months later, mice that received BM from HF mice showed increased fibrosis and decreased cardiac function compared to those receiving BM from control mice, with these abnormalities becoming more pronounced at six months.

The researchers also investigated how TAC-induced HSC modulation impacts the development and function of cardiac macrophages. They co-transplanted long-term HSCs from control mice and TAC mice into recipient mice, finding that neutrophils and monocytes in peripheral blood were more frequently derived from TAC HSCs than control HSCs, indicating a myeloid shift. This shift was also noted in TAC BM-derived peripheral blood cells. Increased numbers of cardiac Ly6Clo CCR2+ macrophages in TAC BM recipients suggested that HSCs exposed to TAC likely differentiate into CCR2+ macrophages. Competitive transplantation experiments indicated that TAC-modulated HSCs generate more pro-inflammatory macrophages than tissue-resident ones.

The study further examined whether TAC HSCs promote other organ pathologies, analyzing renal injury responses in recipients of BM from TAC mice using a unilateral ureteral obstruction (UUO) model. Shortly after UUO, monocyte-derived macrophages showed a pro-inflammatory Ly6Chi phenotype, with Ly6Clo macrophages increasing in the kidneys by days two and three. TAC BM recipients exhibited significantly worse interstitial fibrosis and tubular injury than controls a week later. The researchers also explored whether HF-induced changes in HSCs contribute to sarcopenia, finding that TAC BM recipients had smaller cross-sectional areas of regenerated myofibers at injury sites and more prominent fibrosis in injured muscles.

The team conducted transcriptomic and genome-wide chromatin accessibility analyses, revealing that TAC affected gene expression and epigenomes in specific HSC sub-populations. Gene set enrichment analysis indicated downregulation of several gene sets, particularly the transforming growth factor (TGF)-β signaling pathway. Active TGF-β1 levels were significantly reduced in the BM a week after TAC. Since TGF-β signaling is crucial for HSC hibernation, reduced TGF-β signaling from cardiac stress may prevent hibernation, leading to increased HSC proliferation following TAC. TGF-β1 treatment suppressed this proliferation.

Finally, the study investigated whether TGF-β signaling inhibition in HSCs could promote HF. The effects of inhibition on the HSC transcriptome were similar to those of TAC, suggesting that TGF-β signaling may partially mediate TAC’s effects on HSCs.

Conclusions The study demonstrated that HSCs from HF mice lead to cardiac dysfunction and increase the susceptibility of skeletal muscle and kidneys to both direct and indirect insults in recipient mice. TAC-experienced HSC descendants preferentially generate cardiac macrophages that express inflammation and remodeling genes. Moreover, HF-induced HSC proliferation and myeloid skewing by repressing TGF-β corresponded with reduced sympathetic nervous activity in the BM. The findings reveal that the BM acts as a hub for stress response in HF, with HSCs carrying these stress memories and contributing to the further development of HF and multimorbidity.