The mechanisms of pathological extramedullary hematopoiesis in diseases

Abstract

Extramedullary hematopoiesis (EMH) is the expansion and differentiation of hematopoietic stem and progenitor cells outside of the bone marrow. In postnatal life, as a compensatory mechanism for ineffective hematopoiesis of the bone marrow, pathological EMH is triggered by hematopoietic disorders, insufficient hematopoietic compensation, and other pathological stress conditions, such as infection, advanced tumors, anemia, and metabolic stress. Pathological EMH has been reported in many organs, and the sites of pathological EMH may be related to reactivation of the embryonic hematopoietic structure in these organs. As a double-edged sword (blood and immune cell supplementation as well as clinical complications), pathological EMH has been widely studied in recent years. In particular, pathological EMH induced by late-stage tumors contributes to tumor immunosuppression. Thus, a deeper understanding of the mechanism of pathological EMH may be conducive to the development of therapies against the pathological processes that induce EMH. This article reviews the recent progress of research on the cellular and molecular mechanisms of pathological EMH in specific diseases.

Keywords: Atherosclerosis; Erythropoiesis; Inflammation; Myelofibrosis; Niche; Thalassemia.

Fig. 1

Bone marrow and splenic niches. Macrophages, megakaryocytes, endothelial cells, mesenchymal stromal cells, osteoblasts, blood vessels, perivascular mesenchymal stem cells, adipocytes, extracellular matrix proteins, and nervous system constitute the bone marrow niche and maintain the hematopoiesis. Endothelial and stromal cells, macrophages, and blood vessels constitute the splenic niche and participate in the activation and maintenance of EMH via secreting some chemokines or soluble factors

Fig. 2

EMH upon infection. TLRs and pro-inflammatory cytokines can directly or indirectly induce the HSPCs proliferation and myeloid differentiation in peripheral inflammation or infection. During MCMV infection, activated Ly49H or NKG2D NK cells release perforin to control virus transmission, which are essential for EMH maintenance. Moreover, STAT1 signaling in myeloid cells suppressed viral replication and promoted the development of splenic erythroid and megakaryocytic lineage during infection

Fig. 3

EMH during neoplasms. Tumor-induced CD45⁺EPC inhibit anti-tumor T cell immune response by ROS production and CD45⁻EPC promote tumor growth through artemin secretion. Besides, tumor-derived PDGF-BB induces EPO production by targeting stromal cells that express PDGFR-β, and high EPO level promotes tumor growth through stimulating tumor angiogenesis and inducing EMH

Fig. 4

EMH during anemia. Erythroblastic island, composed of a central macrophage and surrounding erythroblasts, is essential for erythropoiesis in bone marrow and spleen. In thalassemia, anemia and the resulting hypoxia increase EPO level in serum, which activate the EPOR/JAK2 pathway. The sustained phosphorylation of JAK2 triggers erythroid excessive proliferation and EMH, leading to hepatosplenomegaly. In myelofibrosis condition, the activation of the CXCL12/CXCR4 pathway and downregulation of GATA1 promote EMH and splenomegaly

Fig. 5

EMH during metabolic stress. Under pregnancy, high estrogen and 27HC cause HSPCs mobilization and spleen enlargement. The deficiency of ABCA1 and ABCG1 in macrophages and dendritic cells, which results in the defects of cholesterol efflux pathways, induces the HSPC, CMP, and GMP mobilization and EMH through the elevated IL-23, IL-17, and G-CSF. However, in diabetics, the G-CSF-induced HSPCs mobilization is reduced. In atherosclerosis stress, atherosclerosis-induced EMH increases the production of monocytes and further promotes plaque growth. GM-CSF and IL-3 mediate splenic HSPCs expansion and monocytopoiesis