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.

Circulating Progenitor Cells in Patients With Coronary Artery Disease and Renal Insufficiency

“…We found that this relationship is age-dependent, and the presence of renal function impairment is independently associated with lower CPC counts, but only in the older age group. This novel observation is concordant with previous studies that have shown that presence of CV risk factors at a relatively young age is associated with either normal or higher CPC counts, reflecting an endogenous reparative response to subclinical vascular injury related to risk factor exposure ( 12 , 13 ). This mobilization of CPCs into the peripheral circulation is exhausted at an older age after continued exposure to injurious stimuli ( 14 ).…”

“…Previous work from our group has shown that presence of “traditional” CV risk factors including diabetes, hypertension, hypercholesterolemia, and smoking early in life is associated with higher CPC counts ( 12 , 13 ). This stimulation is likely a result of mobilization of progenitors from the bone marrow in response to the risk factor–mediated injury, and represents activation of the endogenous regenerative or reparative systems ( 5 , 13 , 14 ). It is worth noting that continuous exposure to risk factors with age leads to depletion in CPC counts ( 14 ).…”

Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis

“…A number of reports suggest their numbers increase with disease activity in patients with vasculitis and other vascular disorders and that progenitor repair cells become exhausted in disease (Figure 2). 47,48 ECFCs can be cultured from patients and analysed for pathophysiological properties and epigenetic markers and this approach has the potential to inform precision cardiovascular medicine. EMVs are extracellular vesicles of 0.2-5 lm diameter that are produced by ECs in response to a variety of stimuli.…”

<p>Alterations in the Levels of Circulating and Endothelial Progenitor Cells Levels in Young Adults with Type 1 Diabetes: A 2-Year Follow-Up from the Observational METRO Study</p>

“…Of note, the unchanged levels of this cellular pool may reflect the rate of extra-medullary hematopoiesis in the spleen, which could provide another peripheral reservoir of hematopoietic stem cells. 17 Reduction in MAGE, expressing mean differences from glycemic peaks to nadirs, predicted the increase in CD34 + CPCs and CD34 + KDR + EPCs in the overall population, suggesting that glucose variability can adversely impact on mechanisms of vascular repair. Among CPCs individual phenotypes, CD34+ cells, together with CD34 + CD133 + cells were most frequently associated with cardiovascular outcomes and death.…”