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Haematopoiesis, the process of blood production, can be altered during the initiation or progression of many diseases. Cardiovascular disease (CVD) has been shown to be heavily influenced by changes to the haematopoietic system, including the types and abundance of immune cells produced. It is now well established that innate immune cells are increased in people with CVD, and the mechanisms contributing to this can be vastly different depending on the risk factors or comorbidities present. Many of these changes begin at the level of the haematopoietic stem and progenitor cells (HSPCs) that reside in the bone marrow (BM). In general, the HSPCs and downstream myeloid progenitors are expanded via increased proliferation in the setting of atherosclerotic CVD. However, HSPCs can also be encouraged to leave the BM and colonise extramedullary sites (i.e. the spleen). Within the BM, HSPCs reside in specialized microenvironments, often referred to as a niche. To date in depth studies assessing the damage or dysregulation that occurs in the BM niche in varying CVDs are scarce. In this review, we provide a general overview of the complex components and interactions within the BM niche and how they influence the function of HSPCs. Additionally, we discuss the main findings regarding changes in the HSPC niche that influence the progression of CVD. We hypothesize that understanding the influence of the BM niche in CVD will aid in delineating new pathways for therapeutic interventions.

Aim: Rheumatoid arthritis (RA) is associated with an approximately two-fold elevated risk of cardiovascular (CV)-related mortality. Patients with RA present with systemic inflammation including raised circulating myeloid cells, but fail to display traditional CV risk-factors, particularly dyslipidaemia. We aimed to explore if increased circulating myeloid cells is associated with impaired atherosclerotic lesion regression or altered progression in RA., Methods and Results: Using flow cytometry, we noted prominent monocytosis, neutrophilia, and thrombocytosis in two mouse models of RA. This was due to enhanced proliferation of the haematopoietic stem and progenitor cells (HSPCs) in the bone marrow and the spleen. HSPCs expansion was associated with an increase in the cholesterol content, due to a down-regulation of cholesterol efflux genes, Apoe, Abca1, and Abcg1. The HSPCs also had enhanced expression of key myeloid promoting growth factor receptors. Systemic inflammation was found to cause defective cellular cholesterol metabolism. Increased myeloid cells in mice with RA were associated with a significant impairment in lesion regression, even though cholesterol levels were equivalent to non-arthritic mice. Lesions from arthritic mice exhibited a less stable phenotype as demonstrated by increased immune cell infiltration, lipid accumulation, and decreased collagen formation. In a progression model, we noted monocytosis, enhanced monocytes recruitment to lesions, and increased plaque macrophages. This was reversed with administration of reconstituted high-density lipoprotein (rHDL). Furthermore, RA patients have expanded CD16+ monocyte subsets and a down-regulation of ABCA1 and ABCG1., Conclusion: Rheumatoid arthritis impairs atherosclerotic regression and alters progression, which is associated with an expansion of myeloid cells and disturbed cellular cholesterol handling, independent of plasma cholesterol levels. Infusion of rHDL prevented enhanced myelopoiesis and monocyte entry into lesions. Targeting cellular cholesterol defects in people with RA, even if plasma cholesterol is within the normal range, may limit vascular disease.

Purpose of Review: Hematopoietic stem cells (HSCs) reside in the bone marrow and are important in replenishing all cells in the blood through a process termed hematopoiesis. One of the defining characteristics of HSCs is that they must be able to balance their self-renewal capacity with their differentiation into committed blood cells in various blood lineages. For these events to occur, HSCs must be tightly regulated in the bone marrow by intrinsic and extrinsic factors to maintain steady hematopoiesis., Recent Findings: Recently, the effect on how metabolism regulates HSC function has received a great amount of attention. In particular, lipids have been found to participate in mitochondrial activity to maintain HSCs, a role previously overlooked due to HSCs being thought of as mostly glycolytic. Moreover, there has been a re-emergence of how adipocytes in the bone marrow can regulate HSCs., Summary: As these areas evolve, more studies are required to determine the exact contribution of lipids toward HSC maintenance. These studies will allow newer therapeutic targets to help reduce abnormal hematopoiesis such as myelopoiesis, which contributes to many metabolic diseases.

Endogenous anti-inflammatory annexin-A1 (ANX-A1) plays an important role in preserving left ventricular (LV) viability and function after ischaemic insults in vitro, but its long-term cardioprotective actions in vivo are largely unknown. We tested the hypothesis that ANX-A1-deficiency exaggerates inflammation, haematopoietic stem progenitor cell (HSPC) activity and LV remodelling in response to myocardial ischaemia in vivo. Adult ANX - A1 -/- mice subjected to coronary artery occlusion exhibited increased infarct size and LV macrophage content after 24-48 h reperfusion compared with wildtype (WT) counterparts. In addition, ANX - A1 -/- mice exhibited greater expansion of HSPCs and altered pattern of HSPC mobilisation 8 days post-myocardial infarction, with increased circulating neutrophils and platelets, consistent with increased cardiac inflammation as a result of increased myeloid invading injured myocardium in response to MI. Furthermore, ANX - A1 -/- mice exhibited significantly increased expression of LV pro-inflammatory and pro-fibrotic genes and collagen deposition after MI compared to WT counterparts. ANX-A1-deficiency increased cardiac necrosis, inflammation, hypertrophy and fibrosis following MI, accompanied by exaggerated HSPC activity and impaired macrophage phenotype. These findings suggest that endogenous ANX-A1 regulates mobilisation and differentiation of HSPCs. Limiting excessive monocyte/neutrophil production may limit LV damage in vivo. Our findings support further development of novel ANX-A1-based therapies to improve cardiac outcomes after MI.

Rheumatoid arthritis (RA) patients have an increased risk for cardiovascular disease (CVD), independent of traditional risk factors such as plasma cholesterol levels. Interestingly, RA patients have elevated activity of the sympathetic nervous system (SNS), which has been known to play an important role in producing and releasing hematopoietic stem and progenitor cells (HSPCs) to produce inflammatory monocytes, the major contributor to atherosclerotic-CVD. Here we investigated whether increased atherosclerotic progression in mice with RA was due to SNS overactivity. We administered 8wk old C57/B6 mice with KBxN serum to elicit RA and found that RA mice had elevated blood HSPCs and myeloid (monocytes/neutrophils) levels. Further investigation of the bone marrow (BM) revealed an expansion of the HSPC pool, with a strong skewing towards myeloid progenitors, explaining the elevation in blood myeloid populations. Sympathetic activity levels, indicated by tyrosine staining, was also increased in the BM of RA mice. Administering RA mice with propanolol (b1/b2 receptor antagonist) and SR59230A (b3 receptor antagonist) to block SNS activity, led to a reduction in blood HSPC and myeloid populations. To explore the role of RA in atherogenesis we fed Ldlr-/- mice a high fat/high cholesterol diet for 14wks to stimulate lesion development. Mice were then switched to a normal chow diet for 3 weeks to allow lesion regression. Mice were injected with KBxN and treated with or without b-blockers. Mice injected with KBxN had impaired lesion regression which was prevented with b-blockers, likely due to a reduction in HSPC mobilisation and myeloid expansion. Therefore, targeting the SNS in patients with RA with b-blockers may reduce the risk for CVD. [ABSTRACT FROM AUTHOR]

The regulation of HSC movement between the bone marrow (BM) microenvironment and the circulation remains an important clinical target in the setting of BM transplantation. The influence of parts of the nervous system, the sympathetic arm in particular, on BM niche function and mobilization have been investigated. However, the basal role of the cholinergic system in regulating HSC mobilisation is yet to be elucidated. We show that the cholinergic system and specifically the nicotinic -7 acetylcholine receptor (Chrna7) mediates alterations in the structure and function of the BM sinusoidal endothelial cells as well as perivascular stromal cells (LepR+). Inhibition of this receptor with MLA leads to a loss of integrity in the BM sinusoidal structures along with a loss in perivascular niche stem cell factor production. Blocking Chrna7 leads to mobilisation of functional HSCs without skewing that is typically present in G-CSF mobilization. This is suggested by single cell RNA sequencing of MLA mobilised peripheral HSCs that indicates a more balanced genetic lineage signature compared to those mobilised with G-CSF. In addition, administering MLA during G-CSF treatment leads to a synergetic effect, while stimulation of the Chrna7 receptor with GTS-21 blunts G-CSF induced HSC mobilisation. These findings suggest a novel role for the peripheral cholinergic system in HSC mobilisation via niche cell alterations that provides a G-CSF independent alternative route for BM transplantation. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.Methods: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI.Results: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes.Conclusions: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome. [ABSTRACT FROM AUTHOR]