Monocyte-Macrophage Lineage Cell Fusion

Abstract

Cell fusion (fusogenesis) occurs in natural and pathological conditions in prokaryotes and eukaryotes. Cells of monocyte-macrophage lineage are highly fusogenic. They create syncytial multinucleated giant cells (MGCs) such as osteoclasts (OCs), MGCs associated with the areas of infection/inflammation, and foreign body-induced giant cells (FBGCs). The fusion of monocytes/macrophages with tumor cells may promote cancer metastasis. We describe types and examples of monocyte-macrophage lineage cell fusion and the role of actin-based structures in cell fusion.

Keywords: cell fusion; cell protrusions; giant cells; hematopoietic stem cells; macrophage; monocyte; osteoclast; podosomes; syncytium; tumor-associated macrophages; viral fusion.

Figure 1

Differentiation of hematopoietic stem cells (HSCs). Multipotent and unbiased hematopoietic stem cells (HSCs) are derived from bone marrow. Depending on the niche they occupy in bone marrow and/or expression of certain genes, they become biased in their differentiation potential toward a specific cell lineage, such as osteoclast-biased (Os-Bi), myeloid-biased (My-Bi), platelet biased (Pl-Bi), and lymphoid-biased (Ly-Bi). Some HSCs have balanced differentiation potential and can develop into osteoclast, myeloid, platelet, and lymphoid lineage precursors. Os-Bi HSCs develop into preosteoclasts which, after fusion, create multinucleated osteoclasts. Osteoclasts can also derive from mature monocytes or macrophages. The My-Bi HSCs differentiate into neutrophils, eosinophils, basophils, erythrocytes, and monocytes forming dendritic cells and macrophages. Pl-Bi HSCs develop into megakaryocytes, which subsequently produce platelets. Megakaryocytes can also develop from My-Bi HSCs. Ly-Bi develop into T cells, NK cells, and B cells producing plasma cells.

Figure 2

Types and origin of syncytia. (A) Syncytium derived from the fusion of identical cells is called homotypic syncytium. Homotypic fusion of cell cytoplasms creates homotypic heterokaryotic syncytium with multiple nuclei. Homotypic fusion of cell cytoplasms and nuclei creates homotypic synkaryotic syncytium. Syncytium derived from the fusion of different cell types is called heterotypic syncytium. Heterotypic fusion of only cell cytoplasms creates heterotypic heterokaryotic syncytium with multiple nuclei of different origins. Heterotypic fusion of cell cytoplasms and nuclei creates heterotypic synkaryotic syncytium. (B) Origin of syncytia during development. In some instances, progenitor cell divides multiple times with partial cytokinesis forming a group (called nest or cyst) of descendant cells connected by cytoplasmic bridges. Eventually, these cells either separate into individual cells (for example, in frog or mammalian oogenesis) or fuse to form multinuclear syncytium (for example, nurse cell syncytium in insect telotrophic ovary). In other instances, for example, during early embryogenesis in Drosophila, the nucleus of the progenitor cell divides multiple times, creating a multinuclear cell (syncytium), which eventually cellularizes into individual cells.

Figure 3

Osteoclast formation. There is a balance between bone-forming and bone-resorbing activities in normal conditions. The bone-resorbing cells’ osteoclasts form through the fusion of preosteoclasts, which are derived from monocytes/macrophages and/or osteoclast-biased hematopoietic stem cells (HSC). Osteoblasts and stromal cells in the bone produce a receptor activator of nuclear factor-kappa-Β ligand (RANKL), which belongs to a tumor necrosis factor family of proteins. RANKL binds to its receptor RANK expressed on the surface of preosteoclasts and osteoclasts, promoting fusion and formation of syncytial multinuclear osteoclasts. After further activation by various cytokines, mature osteoclasts acquire a bone-resorbing activity. Osteoblast and stromal cells also produce osteoprotegerin (OPC) that prevents excessive bone resorption by binding to and depleting RANKL. Thus, RANKL/OPC ratio determines bone resorption or bone formation.

Figure 4

Virally induced fusion. (A) Fusion of the virus with the host cell membrane. Fusion of virus with the host cell membrane. Virus envelope contains fusion protein, which is recognized by receptors on the host cell membrane. After binding to its receptor, viral fusion protein unfolds, causing membrane scission and allowing the viral genome to enter the host cell. (B) Virally induced fusion of host cells. An infected cell expresses viral fusion protein on its surface. Fusion protein binds to its receptor on the surface of the noninfected cells promoting cell fusion. Resulting multinuclear syncytium replicates the viral genome, becoming the virus’s reservoir and facilitating the virus’s further spreading.

Figure 5

Actin-based structures in cell adhesion and fusion. (A) After establishing a fusion area between fusing partners, the cell-initiating fusion extends different size actin-based (red lines) protrusions at its edge. (B) Podosomes (stars), consisting of actin center (red) and peripheral adhesion proteins (blue), of the fusion-initiating cell migrate from the cell interior to the pre-fusion area. (C) One of the protrusions (usually the longest) acts as a fusopod-initiating fusion and creates the fusion pore. (D) Reorganization of actin filaments expands fusion pore, allowing migration of podosomes from donor to fusion partner (Modified from Faust et al., Ref. [42]). (E) Zipper-like structures (ZLSs) at the surface of adhering MGCs formed in response to foreign materials. Membranes of adjacent cells adhere via adhesion proteins (gray ovals). Podosomes (red and blue stars) fuse into giant actin globules (red) surrounded by adhesion proteins (blue) and attached by smaller actin globules to the membrane. Actin globules are evenly spaced (resembling the zipper) along the membrane (modified from Balbyev et al., Ref. [105]). (F) Image of mouse macrophage showing podosomes (yellow). The nucleus (blue) is stained with DAPI. Actin is stained red with Rhodamine-Phalloidin; podosomes look yellow because of the high actin concentration and image overexposure. The magnification bar is equal to 10 μm.