In view of the aforementioned role of circulating HSPCs, it is clear that their numerical and functional perturbation implies profound and severe clinical sequelae, including increased mortality [114]. So far, the dysfunctions of circulating HSPCs have mostly been studied and interpreted in view of their pro-angiogenic counterpart, namely the EPC progeny. Countless studies have mechanistically detailed the alterations promoted by different pathological contexts on the main EPC functional processes, including BM mobilization, migration, homing, and differentiation [10,75,115], overlooking that CD34+ cells, as HSPCs, are sources not only of pro-angiogenic cells but also of immune system cells. The profound link existing between HSPCs and cardiovascular system was made more evident by the clonal hematopoiesis of indeterminate potential (CHIP) a clinical condition in which the mutation in only handful genes, specifically DNMT3A (DNA MethylTransferase 3 Alpha), TET2 (ten eleven translocation (Tet) methylcytosine dioxygenase), AXL1 (AneXeLekto receptor tyrosine kinase), PPM1D (Protein Phosphatase, Mg2+/Mn2+ Dependent 1D), JAK2 (Janus Kinase 2), TP53 (Tumor Protein p53), SF3B1 (Splicing Factor 3b Subunit 1), and SRSf2 (Serine/arginine-Rich Splicing factor 2) in HSPCs promotes the accumulation of clones of mutated leukocytes that populate the PB. This pre-malignant state, although considered as the first step towards leukemia, rarely develops malignancy (only 0.5% to 1% per year, hence the term ”indeterminate potential”), but represents a potent and independent cardiovascular risk factor (40% increase) [116]. Concerning the mechanisms proposed to link CHIP and cardiovascular events, it has been observed that in mice engineered to bear mutations in genes commonly involved in CHIP (e.g., Tet2), there was an increased expression of proinflammatory mediators implicated in the pathogenesis of atherosclerosis, such as cytokines interleukin (IL)-1b and IL-6 [117]. Similarly, atherosclerosis, hypercholesterolemia, hypertension, and diabetes are associated with the elevation of hematopoiesis with a myeloid bias that suggests a contribution of inflammatory leukocytes to the development and progression of CVD. In this regard, Terenzi et al. demonstrated, by a multiparametric flow cytometry assay, profound differences in circulating proangiogenic and proinflammatory progenitor cell content between patients with T2D and age-matched control subjects [118]. Specifically, patients with T2D displayed an increased frequency of proinflammatory myeloid cells and decreased frequency of circulating monocytes with an M2 phenotype, which is associated with proangiogenic and anti-inflammatory functions, and a reduction of proangiogenic CD34+ progenitor cells with primitive (CD133) and migratory (CXCR4) phenotypes. The flow cytometric assessment of the balance between circulating vascular regenerative progenitor cells and inflammatory cells in patients with T2D could represent a promising translational approach for identifying patients with T2D at increased risk for cardiovascular comorbidities [118]. Interestingly, preclinical and clinical evidence showed that different pathological milieus, including diabetes, are able to redirect HSPC differentiation toward pro-inflammatory and harmful cell populations with pro-calcific and profibrotic properties [119,120,121,122,123,124] by molecular and epigenetic mechanisms that could already take place at the BM level (Figure 4) [125].