The Roles of Cholesterol and Its Metabolites in Normal and Malignant Hematopoiesis

Abstract

Hematopoiesis is sustained throughout life by hematopoietic stem cells (HSCs) that are capable of self-renewal and differentiation into hematopoietic progenitor cells (HPCs). There is accumulating evidence that cholesterol homeostasis is an important factor in the regulation of hematopoiesis. Increased cholesterol levels are known to promote proliferation and mobilization of HSCs, while hypercholesterolemia is associated with expansion of myeloid cells in the peripheral blood and links hematopoiesis with cardiovascular disease. Cholesterol is a precursor to steroid hormones, oxysterols, and bile acids. Among steroid hormones, 17β-estradiol (E2) induces HSC division and E2-estrogen receptor α (ERα) signaling causes sexual dimorphism of HSC division rate. Oxysterols are oxygenated derivatives of cholesterol and key substrates for bile acid synthesis and are considered to be bioactive lipids, and recent studies have begun to reveal their important roles in the hematopoietic and immune systems. 27-Hydroxycholesterol (27HC) acts as an endogenous selective estrogen receptor modulator and induces ERα-dependent HSC mobilization and extramedullary hematopoiesis. 7α,25-dihydroxycholesterol (7α,25HC) acts as a ligand for Epstein-Barr virus-induced gene 2 (EBI2) and directs migration of B cells in the spleen during the adaptive immune response. Bile acids serve as chemical chaperones and alleviate endoplasmic reticulum stress in HSCs. Cholesterol metabolism is dysregulated in hematologic malignancies, and statins, which inhibit de novo cholesterol synthesis, have cytotoxic effects in malignant hematopoietic cells. In this review, recent advances in our understanding of the roles of cholesterol and its metabolites as signaling molecules in the regulation of hematopoiesis and hematologic malignancies are summarized.

Keywords: cholesterol; hematologic malignancies; hematopoiesis; hematopoietic stem cells; oxysterols; steroids.

Figure 1

Model of the hematopoietic hierarchy. A hierarchical structure of the adult hematopoietic system based on studies by us and others using mice. HSCs reside at the top of the hierarchy and give rise to MPPs and potentially MEPs. MPPs generate HPCs and MEPs, and HPCs generate GMPs and CLPs. Mature cells are developed from these oligopotent progenitors, MEPs, GMPs, and CMPs, through intermediate progenitors. Some lineage relationships are under debate.

Figure 2

Cholesterol synthetic/metabolic pathways. Pathways of cholesterol biosynthesis (top), bile acid biosynthesis (bottom left), and steroidogenesis (bottom right) are presented. Enzymes that catalyze the conversions are shown adjacent to the arrows.

Figure 3

E2 and 27HC differentially regulate HSC division and mobilization during pregnancy. Pregnancy upregulates E2–ERα and 27HC–ERα signaling. E2–ERα signaling induces HSC division in the bone marrow. 27HC–ERα signaling induces HSC mobilization into the circulation and spleen, and augments splenic erythropoiesis.