Circulating stem cells and cardiovascular outcomes: from basic science to the clinic

Abstract

The cardiovascular and haematopoietic systems have fundamental inter-relationships during development, as well as in health and disease of the adult organism. Although haematopoietic stem cells (HSCs) emerge from a specialized haemogenic endothelium in the embryo, persistence of haemangioblasts in adulthood is debated. Rather, the vast majority of circulating stem cells (CSCs) is composed of bone marrow-derived HSCs and the downstream haematopoietic stem/progenitors (HSPCs). A fraction of these cells, known as endothelial progenitor cells (EPCs), has endothelial specification and vascular tropism. In general, the levels of HSCs, HSPCs, and EPCs are considered indicative of the endogenous regenerative capacity of the organism as a whole and, particularly, of the cardiovascular system. In the last two decades, the research on CSCs has focused on their physiologic role in tissue/organ homoeostasis, their potential application in cell therapies, and their use as clinical biomarkers. In this review, we provide background information on the biology of CSCs and discuss in detail the clinical implications of changing CSC levels in patients with cardiovascular risk factors or established cardiovascular disease. Of particular interest is the mounting evidence available in the literature on the close relationships between reduced levels of CSCs and adverse cardiovascular outcomes in different cohorts of patients. We also discuss potential mechanisms that explain this association. Beyond CSCs' ability to participate in cardiovascular repair, levels of CSCs need to be interpreted in the context of the broader connections between haematopoiesis and cardiovascular function, including the role of clonal haematopoiesis and inflammatory myelopoiesis.

Keywords: Biomarkers; Bone marrow; Haematopoiesis; Inflammation; Myelopoiesis; Outcomes; Regeneration; Stem cells.

Figure 1

Origin and fate of circulating stem cells in the vascular system. In the embryo, haematopoietic stem cells arise from the haemogenic endothelium. This haemato-vascular overlap explains why haematopoietic stem cell, haematopoietic stem/progenitor cells, and endothelial progenitor cells are endowed with vascular tropism. In the adult, haematopoiesis transfers to the bone marrow, where two stem cell compartments, haematopoietic stem cells, and mesenchymal stem cells, contribute to circulating stem cells. Circulating osteoprogenitors can arise from both haematopoietic stem/progenitor cells and mesenchymal stem cells and may contribute to ectopic vascular calcification observed within advanced atherosclerotic plaques. In parallel, the arterial wall contains a hierarchy of vascular stem cells that can be isolated from peripheral blood as endothelial colony forming cells. While the endothelial differentiation capacity of endothelial colony forming cell is well-established in vitro and in vivo, it is probably less efficient for endothelial progenitor cell and haematopoietic stem/progenitor cell (question mark).

Figure 2

Major topics in circulating stem cell research. Three areas of research related to bone marrow-derived circulating stem cells include exploration of their (i) physiologic role in ischaemia, angiogenesis and vascular repair; (ii) therapeutic potential for treatment of cardiac or peripheral ischaemia; and (iii) utility as diagnostic and/or prognostic markers.

Figure 3

Circulating stem cells and the natural history of atherosclerosis. Changes in circulating stem cells throughout the lifespan with either healthy aging or aging with cardiovascular risk factors or cardiovascular disease. The green line shows no appreciable age-related decline in circulating stem cell in individuals free of cardiovascular risk factors, with an ability to mobilize circulating stem cells during injury. The red line shows age-related trends in circulating stem cells in individuals exposed to cardiovascular risk factors or cardiovascular disease, characterized by a higher circulating stem cell level when young due potentially to risk factor-mediated compensatory mobilization, followed by progressive age-related decline due to exhaustion, and an impaired mobilization response to injury. CVD, cardiovascular disease.

Figure 4

Prognostic role of circulating stem cells: an updated meta-analysis. The forest plot shows pooled hazard ratios derived from individual studies investigating the association between low levels (below specific cut-offs) of circulating haematopoietic stem/progenitor cells and endothelial progenitor cells and cardiovascular events (mostly defined as atherosclerotic events or cardiovascular death), cardiovascular death, or all-cause death. Pooled hazard ratio, their 95% confidence intervals and attributed weights, calculated using the random effect model are shown. Tests for heterogeneity among summary statistics (Q and I²) were not statistically significant. An expanded version of the figure is provided in the Supplementary material online, Appendix.

Figure 5

Interplay among risk factors, stem cells, myelopoiesis, and atherosclerosis. Most traditional risk factors for atherosclerotic cardiovascular disease have been associated with leucocytosis due to excess myelopoiesis in the bone marrow. With the exception of diabetes, risk factors also result in an enhanced mobilization of circulating stem cells from the bone marrow to peripheral blood. Diabetes instead causes an impaired ability to mobilize stem cells and a depletion of circulating stem cells. Circulating stem cells can be buffered in the spleen, where haematopoietic stem cells and haematopoietic stem/progenitor cells establish extra-medullary haematopoiesis, providing a peripheral reservoir of inflammatory cells. Thus, the extent to which risk factors stimulate haematopoietic stem/progenitor cell mobilization may not be related to circulating stem cell levels in the circulation. Mature inflammatory cells generated in the bone marrow and/or the spleen can reach the vessel wall and contribute to atherosclerosis development or progression. HSC, haematopoietic stem cells; HSPC, haematopoietic stem and progenitor cells; SNS, sympathetic nervous system. Green arrows indicate stimulatory effects of risk factors, whereas red arrows indicate inhibitory effects.