Cellular and molecular actors of myeloid cell fusion: podosomes and tunneling nanotubes call the tune

Abstract

Different types of multinucleated giant cells (MGCs) of myeloid origin have been described; osteoclasts are the most extensively studied because of their importance in bone homeostasis. MGCs are formed by cell-to-cell fusion, and most types have been observed in pathological conditions, especially in infectious and non-infectious chronic inflammatory contexts. The precise role of the different MGCs and the mechanisms that govern their formation remain poorly understood, likely due to their heterogeneity. First, we will introduce the main populations of MGCs derived from the monocyte/macrophage lineage. We will then discuss the known molecular actors mediating the early stages of fusion, focusing on cell-surface receptors involved in the cell-to-cell adhesion steps that ultimately lead to multinucleation. Given that cell-to-cell fusion is a complex and well-coordinated process, we will also describe what is currently known about the evolution of F-actin-based structures involved in macrophage fusion, i.e., podosomes, zipper-like structures, and tunneling nanotubes (TNT). Finally, the localization and potential role of the key fusion mediators related to the formation of these F-actin structures will be discussed. This review intends to present the current status of knowledge of the molecular and cellular mechanisms supporting multinucleation of myeloid cells, highlighting the gaps still existing, and contributing to the proposition of potential disease-specific MGC markers and/or therapeutic targets.

Monocyte–Macrophage Lineage Cell Fusion

“…Depending on applied criteria, cell fusion can be divided into homotypic (fusion of the same cell types) versus heterotypic (different cell type fusion), and synkaryotic (homotypic or heterotypic nuclei merge creating mononuclear syncytium) versus heterokaryotic (homotypic or heterotypic multinucleated syncytium) ( Figure 2 A; [ 30 , 31 , 32 , 33 ]). Some cases fall between strict categories when fusing cells are of the same origin but at a different phase of differentiation [ 34 , 35 , 36 ]. Additionally, the origin of syncytia can differ.…”

“…The only fusogen implicated in the fusion of myeloid cells is Syncytin. Syncytin 1 and 2 in humans and Syncytin A and B in mice derived from retroviral syncytin gene integrated during evolution into the mammalian genome [ 34 , 46 , 47 ]. Syncytin binds to its receptor Sodium-Dependent Neutral Amino Acid Transporter Type 2 (ASCT-2); [ 34 , 46 ].…”

“…Cells of monocyte–macrophage lineage are highly syncyciogenic (fusogenic) under physiological and pathological conditions, forming syncytial multinucleated giant cells (MGCs). Examples of homotypic syncytia derived from monocyte–macrophage lineage cell fusion are osteoclasts (OCs), MGCs associated with areas of infection/inflammation called granulomas [ 48 ], and foreign body-induced giant cells (FBGCs) [ 34 ]. Additionally, monocyte–macrophages can fuse with cells of different origins, such as hepatocytes [ 49 ], T cells [ 50 ], and various circulating and tissue-resident tumor cells [ 51 , 52 , 53 ], resulting in heterotypic syncytia.…”

“…Fusopods contain bands of actin filaments, and their formation is regulated by Rac-1 [ 93 ], Wiskott–Aldrich syndrome protein (WASp) family, and Arp2/3 complex, which nucleate and branch actin filaments [ 42 , 102 , 103 ]. Some studies of myeloid cell fusion indicate that tunneling nanotubes (TNTs), which contain actin filaments and/or microtubules [ 79 ], can also function as fusopodes [ 34 ].…”

Baohuoside I Inhibits Osteoclastogenesis and Protects Against Ovariectomy-Induced Bone Loss

“…Apart from differentiation, cell–cell fusion is also an important step in osteoclast maturation. Being controlled mainly by M-CSF and RANKL, the monocytic precursors can fuse into osteoclasts ( Dufrançais et al, 2021 ). During osteoclast differentiation, the macrophage colony-stimulating factor (M-CSF or CSF-1) and receptor activator of NF-kB ligand (RANKL) are deemed the two most important cytokines for osteoclast maturation and survival ( Boyle et al, 2003 ).…”