Heart failure triggers multimorbidity by altering stem cells, study reveals

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.May 28 2024

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

Despite medical advances, HF mortality is considerably high. Repeated hospitalization is a characteristic of HF, suggesting that HF elevates the risk of future HF events and contributes to multimorbidity. Chronic inflammation is recognized as a common pathological feature of most diseases comprising multimorbidity. Nevertheless, whether HF contributes to chronic inflammation and mechanisms driving HF-related multimorbidity are unclear.

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 descendants, and their impact on the skeletal muscle, heart, and kidneys. First, they investigated whether cardiac events alter HSCs and impact cardiac functions. To this end, HF was induced 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. BM transplantation (BMT) from control mice was also performed. Four months later, mice that received BM from HF mice had increased fibrosis and decreased cardiac function relative to those who received BM from control mice. These abnormalities were more prominent at six months.

Next, the researchers investigated whether TAC's HSC modulation impacts cardiac macrophages' development and function. Long-term HSCs from CD45.1 control mice and CD45.1/CD45.2 heterozygous TAC mice were co-transplanted into CD45.2 recipient mice. They found that neutrophils and monocytes in peripheral blood were more frequently derived from TAC HSCs than control HSCs, indicating a myeloid shift in the progeny.

This myeloid shift was also noted in TAC BM-derived peripheral blood cells. Cardiac Ly6C^lo CCR2⁺ macrophages were higher in TAC BM recipients, suggesting that HSCs exposed to TAC may likely differentiate into CCR2⁺ macrophages. Next, competitive transplantation experiments indicated that TAC modulates HSCs to generate more pro-inflammatory macrophages than tissue-resident ones.

Since tissue-resident macrophages protect the heart from stress and maintain homeostasis, this altered potential of TAC HSC-derived cells may impair homeostasis and trigger cardiac remodeling. This prompted investigations into whether TAC HSCs promote other organ pathologies. As such, renal injury responses were analyzed in recipients of BM from TAC mice, utilizing a unilateral ureteral obstruction (UUO) model.

Shortly after UUO was performed, monocyte-derived macrophages showed a pro-inflammatory Ly6C^hi phenotype. Nevertheless, Ly6C^lo macrophages increased within kidneys by days 2 and 3. Further, TAC BM recipients showed significantly worse interstitial fibrosis and tubular injury than controls a 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 injury site than controls. TAC BM mice also exhibited impaired regeneration and healing, with more prominent fibrosis in injured muscles. Further, the team explored the potential mechanisms underlying TAC-induced HSC alterations.

Transcriptomic analysis indicated that TAC impacted gene expression in Lin—Sca1+ cKit+ CD34- CD45.2+ CD48- CD150+ Flt3- HSCs. The genome-wide chromatin accessibility analysis showed that TAC also affected HSC epigenomes. Additionally, single-cell RNA sequencing was performed on CD45.2+ Lin—Sca1+ cKit+ CD34—Flt3^- HSCs. This revealed nine sub-populations with varying levels of HSC and multipotent progenitor markers.

Gene set enrichment analysis revealed the downregulation of nine gene sets, with the transforming growth factor (TGF)-β signaling being the top downregulated gene set. Besides, the team observed that active TGF-β1 levels were significantly reduced in the BM a week after TAC. Since TGF-β signaling is pivotal for HSC hibernation, cardiac stress may prevent the hibernation through reduced TGF-β signaling.

Consistently, there was a continuous increase in proliferating HSCs following TAC that was suppressed by TGF-β1 treatment. Finally, the researchers investigated whether TGF-β signaling inhibition in HSCs could promote HF. They found that the effects of inhibition on HSC transcriptome were similar to those of TAC, supporting that TGF-β may, at least partly, mediate the effects of TAC on HSCs.

Conclusions

The study highlighted that HSCs from HF mice lead to cardiac dysfunction and elevate the susceptibility of the skeletal muscle and kidneys to direct and indirect insults in recipient mice. Besides, TAC-experienced HSC descendants preferentially generate cardiac macrophages expressing inflammation and remodeling genes.

Moreover, HF induced HSC proliferation and myeloid skewing by repressing TGF-β, corresponding with reduced sympathetic nervous activity in the BM. Together, the findings reveal that the BM acts as a hub for stress response in HF; HSCs carry these stress memories, contributing to the further development of HF and multimorbidity.