Hematopoietic Stem/Progenitor Cell Proliferation and Differentiation Is Differentially Regulated by High-Density and Low-Density Lipoproteins in Mice

Abstract

RationaleHematopoietic stem/progenitor cells (HSPC) are responsible for maintaining the blood system as a result of their self-renewal and multilineage differentiation capacity. Recently, studies have suggested that HDL cholesterol may inhibit and impaired cholesterol efflux may increase HSPC proliferation and differentiation.ObjectivesWe hypothesized that LDL may enhance HSPC proliferation and differentiation while HDL might have the opposing effect which might influence the size of the pool of inflammatory cells.Methods and ResultsHSPC number and function were studied in hypercholesterolemic LDL receptor knockout (LDLr−/−) mice on high fat diet. Hypercholesterolemia was associated with increased frequency of HSPC, monocytes and granulocytes in the peripheral blood (PB). In addition, an increased proportion of BM HSPC was in G2M of the cell cycle, and the percentage of HSPC and granulocyte-macrophage progenitors (GMP) increased in BM of LDLr−/− mice. When BM Lin-Sca-1+cKit+ (i.e. “LSK”) cells were cultured in the presence of LDL in vitro we also found enhanced differentiation towards monocytes and granulocytes. Furthermore, LDL promoted lineage negative (Lin−) cells motility. The modulation by LDL on HSPC differentiation into granulocytes and motility was inhibited by inhibiting ERK phosphorylation. By contrast, when mice were infused with human apoA-I (the major apolipoprotein of HDL) or reconstituted HDL (rHDL), the frequency and proliferation of HSPC was reduced in BM in vivo. HDL also reversed the LDL-induced monocyte and granulocyte differentiation in vitro.ConclusionOur data suggest that LDL and HDL have opposing effects on HSPC proliferation and differentiation. It will be of interest to determine if breakdown of HSPC homeostasis by hypercholesterolemia contributes to inflammation and atherosclerosis progression.

Adrenocortical Scavenger Receptor Class B Type I Deficiency Exacerbates Endotoxic Shock and Precipitates Sepsis-Induced Mortality in Mice

“…If the mechanisms remain to be identified, the potential discrepancy between our study and BM transplantation studies (16) may reside in a role of SR-BI in BMresident hematopoietic stem and progenitor cells (HSPC). Indeed, some recent data indicated that SR-BI might play a critical role in HSPC biology, notably in HSPC differentiation and proliferation in response to LDL and HDL (27,28). Moreover, we observed a trend for increased survival of CLP-treated hypomSR-BI; LysM-Cre mice, which would also not support a major protective function for SR-BI expressed in cells of myeloid origin.…”

The systemic milieu as a mediator of dietary influence on stem cell function during ageing

“…It has also been demonstrated that low-density lipids (LDLs) increase, whereas high-density lipids (HDLs) decrease HSC number (Feng et al, 2012;Murphy et al, 2011). In addition, hormones known to be elevated in obesity, such as leptin, may also increase HSC numbers as evidence by elevated numbers following exogenous application of this hormone to ex vivo cultures (Dias et al, 2013).…”

27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy

“…Nonetheless, it is possible that in addition to regulating ERα function, 27HC also influences HSCs through effects on bile acid biosynthesis. Our results offer a potential explanation for the long-standing observation that increased cholesterol levels are associated with increased HSPC mobilization in mice and humans (11)(12)(13)(14)(15)(16). 27HC levels increase as cholesterol levels increase (6).…”

“…Nonetheless, cholesterol is known to promote HSC proliferation and mobilization (11)(12)(13). Patients with hypercholesterolemia mobilize larger numbers of CD34 + cells following treatment with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) as compared with patients with lower cholesterol levels (14).…”