The association of erythroblasts with macrophages promotes erythroid proliferation and maturation: a 30-kD heparin-binding protein is involved in this contact

Abstract

Although the association of erythroblasts with macrophages has been well documented in the human bone marrow, the function and identification of the intimate contacts occurring between the membranes of these two cell types in the physiology of erythropoiesis is not known. Using in vitro cultures of human peripheral blood derived erythroid progenitors, we have shown the presence of erythroblastic islands consisting of a central macrophage surrounded by a ring of erythroblasts that undergo terminal maturation leading to enucleation. However, when cultures were carried in the absence of intact macrophages, erythroid cells matured to the late erythroblast stage but failed to enucleate. Furthermore, the number of erythroid cells was markedly reduced in macrophage-depleted cultures, suggesting that the erythroblast-macrophage contact promotes proliferation and terminal maturation of erythroid cells leading to their enucleation. To examine the molecule(s) involved in the interaction between erythroblasts and macrophages, we have used a cell attachment assay involving incubation of solubilized surface-labeled erythroblasts with macrophage membrane proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. Erythroblast surface proteins specifically attached to a 30-kD protein from macrophage membranes, whereas no adhesion was seen to the protein standards. An apparently similar protein of 30 kD was also detected on erythroblasts and was shown to mediate erythroblast-erythroblast contact in addition to the erythroblast-macrophage contact. The extraction of plasma membranes with Triton X-100 showed that the 30-kD protein is linked to the membrane skeleton via an integral membrane protein both in erythroblasts and macrophages. Furthermore, our results show that the cell:cell interactions mediated by the 30-kD protein are calcium-independent and could be specifically inhibited by heparin. We conclude that the association of erythroblasts with macrophages promotes erythroid proliferation and maturation leading to erythroblast enucleation and that a 30-kD heparin-binding protein present on the surface of macrophages and erythroblasts is involved in this contact. This protein is capable of binding homotypic and heterotypic cells.

The role of high‐mobility group protein box 1 in lung cancer

“…Additionally, earlier studies demonstrated that membrane-associated HMGB1 is required for murine erythroleukemia cell differentiation and erythroid proliferation and maturation. 38,39…”

“…15,33,36 Membrane HMGB1 Involves in neurite outgrowth, platelet activation, cell differentiation, erythroid maturation, adhesion, and innate immunity. [37][38][39][40][41][42] interact and constitute a tripod that triggers NF-κB pathway. 14,43 RAGE, a transmembrane protein, is a member of the immunoglobulin superfamily, which was the first identified receptor for HMGB1.…”

“…Mediates HMGB1-induced cell migration, proliferation, autophagy, injury, inflammation, and immunity through activating various signaling pathways like caspase-9/-3, p44/p42, NF-κB, Erk1/2, p38, and SAP/ JNK MAPK. 22,28,30,38,[46][47][48][49][50][51] TLRs TLR4 could mediate anti-cancer immunity during radio-or chemotherapy. Knockout of TLR4 decreases HMGB1-induced tissue injury, angiogenesis, inflammation, immunity responses, cell migration and adhesion.…”

Decreased stability of erythroblastic islands in integrin β3-deficient mice

“…Proliferating and differentiating erythroblasts require a specialized microenvironment termed erythroblastic island (EI) (Mohandas and Prenant 1978;Allen and Dexter 1982;Hanspal and Hanspal 1994), normally (for review see, e.g., An and Mohandas 2011;Manwani and Bieker 2008;Mohandas and Chasis 2010) composed of a F4/80 expressing central macrophage surrounded by about 5-30 cells from nucleated proerythroblasts (ProE) through multilobulated reticulocytes (Lee et al 1988). During differentiation orthochromatic erythroblasts extrude their nucleus that is subsequently engulfed by the central macrophage, a mechanism crucially requiring macrophage erythroblast interactions (Mohandas and Chasis 2010).…”

“…During differentiation orthochromatic erythroblasts extrude their nucleus that is subsequently engulfed by the central macrophage, a mechanism crucially requiring macrophage erythroblast interactions (Mohandas and Chasis 2010). Moreover, this interaction enhances proliferation of erythroblasts by speeding up the G0/G1 phase to complete more cell divisions per time unit and, thus, generating more reticulocytes (Hanspal and Hanspal 1994). In addition, erythroblast-erythroblast interactions regulate survival of erythroblasts through Fas-FasL interaction (Liu et al 2006).…”