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Cell fusion

Cell fusion is the process by which two or more cells merge their plasma membranes, allowing the contents of their cytoplasms to mix and often resulting in the formation of a multinucleated cell called a syncytium.^[1] This phenomenon is fundamental to multicellular organism development, enabling the creation of specialized tissues such as skeletal muscle fibers from the fusion of myoblasts, placental syncytiotrophoblasts from trophoblast cells, and multinucleated osteoclasts for bone resorption.^[1] Beyond development, cell fusion facilitates viral entry into host cells, sperm-egg fertilization, and physiological processes like tissue repair in organs such as the liver and heart, where bone marrow-derived cells can fuse with resident cells to promote regeneration.^[1] In biological contexts, cell fusion expands traditional cell theory by demonstrating that tissues can arise from dynamic mergers rather than solely from proliferation and differentiation of individual cells.^[1] For instance, in skeletal muscle formation, fusion-competent myoblasts repeatedly merge with founder cells to produce large, multinucleated myofibers essential for muscle function and precise patterning, as observed in model organisms like Drosophila.^[2] This process is tightly regulated by intercellular signaling; recent studies have shown that inter-organ communication, such as steroid hormone ecdysone signaling from the amnioserosa in Drosophila embryos, enhances myoblast fusion by activating genes like antisocial (ants) through transcription factors including Twist.^[2] At the molecular level, cell fusion involves distinct steps of membrane adhesion, remodeling, and merger, mediated by specialized fusogenic proteins that overcome energetic barriers between lipid bilayers.^[3] Recent research as of 2025 has further elucidated roles of proteins like galectin-3 in placental fusion and actin dynamics in membrane merger.^[4]^[5] In vertebrates, proteins such as myomaker and myomerger are critical: myomaker initiates cell-cell recognition and adhesion, while myomerger drives the actual membrane fusion, with their expression strictly controlled to ensure specificity in skeletal muscle progenitors.^[3] Dysregulation of these mechanisms has implications in pathology, including potential contributions to cancer progression through hybrid cell formation that enhances malignancy or therapeutic resistance, though the full extent remains under investigation.^[1]

Fundamentals

Definition and Overview

Cell fusion is the biological process in which two or more cells merge their plasma membranes to form a single entity, resulting in a hybrid cell or syncytium characterized by a shared cytoplasm and typically multiple nuclei within a common boundary.^[6] This merger enables the exchange of cellular contents and is a conserved mechanism observed across eukaryotic kingdoms.^[6] Central to cell fusion are several key characteristics, including the localized disruption and resealing of plasma membranes at contact sites, which allows the lipid bilayers to intermingle and form a continuous structure.^[6] Cytoskeletal reorganization, particularly involving actin dynamics, supports membrane curvature and protrusion formation to drive the fusion event. The outcome often includes genetic complementation, where chromosomes from distinct parental cells coexist, or alterations in ploidy, such as the diploidization of gametes during fertilization.^[6] From an evolutionary perspective, cell fusion has significant implications, facilitating fertilization in sexual reproduction to combine genetic material and initiate development, while also enabling the formation of specialized tissues like skeletal muscle and placental structures in multicellular organisms. It promotes adaptability across diverse taxa, including roles in fungal hyphal networks and plant pollen tube guidance, underscoring its ancient origins potentially tied to the emergence of eukaryotic complexity.^[7]^[6] Cell fusion is distinct from related cellular interactions such as adhesion, which mediates surface attachments via proteins like cadherins without cytoplasmic continuity, and endocytosis, an internalization process that engulfs external material into vesicles without merging distinct cell identities.^[6]

Historical Development

The earliest observations of multinucleated cells, indicative of cell fusion processes, date back to the 19th century, when researchers began examining tissue structures under early microscopes. In 1835, Gabriel Valentin described the alignment and apparent fusion of primordial corpuscles during embryonic muscle formation, suggesting that multinucleated muscle fibers arise from the merging of mononucleated precursors.^[8] Similarly, Theodor Schwann, in his foundational work on animal cell structure published in 1839, noted multinucleated configurations in various tissues, contributing to the emerging cell theory while highlighting syncytial-like formations in muscle.^[9] In bone tissue, multinucleated cells were formally identified in 1873 by Albert von Kölliker, who described osteoclasts as large, multi-nucleated structures responsible for bone resorption, sparking debates on their origins through fusion.^[10] A major breakthrough in experimental cell fusion occurred in the 1960s, pioneered by Henry Harris at the University of Oxford. In 1965, Harris and his colleague John F. Watkins demonstrated the artificial fusion of mammalian somatic cells using inactivated Sendai virus, creating stable hybrid cells from human HeLa cells and mouse Ehrlich ascites tumor cells; this work revealed that fused cells could maintain viability and divide, forming heterokaryons and eventually synkaryons.^[11] Their technique, which exploited the virus's hemagglutinin-neuraminidase and fusion proteins to induce membrane merging without infection, laid the groundwork for somatic cell genetics and was instrumental in mapping human chromosomes.^[12] This approach directly enabled the development of hybridoma technology in 1975 by Georges Köhler and César Milstein, who adapted viral fusion to produce monoclonal antibodies from fused spleen and myeloma cells, revolutionizing immunology. During the 1970s and 1980s, researchers advanced non-viral methods for controlled cell fusion, notably through electrofusion techniques developed by Eberhard Neumann and Ulrich Zimmermann. In the late 1970s, Zimmermann's group at the University of Würzburg explored electric field pulses to permeabilize plant protoplast membranes, leading to their initial fusion reports in 1980; this method used dielectric breakdown to bring cells into close contact followed by high-voltage pulses for membrane merger, avoiding biological agents.^[13] Neumann, building on this, refined electrofusion for mammalian cells in the early 1980s, demonstrating efficient hybridization of erythrocytes and other types with precise control over fusion yield and viability, as detailed in his 1982 publications.^[14] These innovations, summarized in Neumann's 1989 edited volume on electroporation and electrofusion, enabled virus-free applications in genetics and biotechnology, marking a shift toward physical manipulation of cellular membranes.^[15] In the 2000s, molecular insights linked cell fusion to evolutionary biology, particularly through the identification of fusogenic proteins in mammalian reproduction. In 2000, Mi et al. discovered syncytin-1, an endogenous retrovirus-derived envelope glycoprotein expressed in placental trophoblasts, which mediates the fusion of cytotrophoblasts into the syncytiotrophoblast layer essential for nutrient exchange and implantation.^[16] This finding, confirmed in subsequent studies, revealed syncytin-1's role in fusogenic activity via its surface unit binding to receptors like SLC1A5/ASCT2, with knockout models showing impaired placentation.^[17] A second protein, syncytin-2, was identified in 2003 from the HERV-FRD provirus, further expanding the syncytin family and highlighting retroviral co-option in eutherian mammal evolution for trophoblast fusion.^[18] These discoveries connected cell fusion to reproductive physiology and suggested broader implications for tissue morphogenesis. Milestones in plant and microbial cell fusion studies emerged prominently in the 1990s, particularly in fungal systems. In Neurospora crassa, N. Louise Glass and colleagues identified genetic loci controlling hyphal fusion during vegetative growth, with key papers in 1990 demonstrating that mating-type idiomorphs (mat a and mat A) regulate anastomosis frequency and compatibility, enabling mycelial network formation for resource sharing. Subsequent 1990s work by Glass's group isolated mutants defective in hyphal fusion, such as ham-1 and ham-2, revealing conserved signaling pathways involving MAP kinases for cell recognition and merger in filamentous fungi.^[19] These studies paralleled advances in plant protoplast fusion, but fungal models provided seminal genetic tools for understanding non-sexual fusion in microbial networks.^[20]

Biological Mechanisms

Natural Fusion Processes

Cell fusion plays a pivotal role in sexual reproduction across eukaryotes, most prominently during fertilization where the sperm and egg merge to form a zygote. In animals, this process involves the plasma membranes of the sperm and egg fusing, allowing the sperm nucleus to enter the egg cytoplasm and initiate embryonic development.^[21] Similarly, in plants, gamete fusion occurs during double fertilization: one sperm fuses with the egg cell to form the zygote, while the second fuses with the central cell to produce the endosperm, ensuring proper seed development. These fusion events restore diploidy and trigger developmental programs essential for offspring formation.^[22] In vertebrate skeletal muscle development, myoblast fusion is crucial for generating multinucleated myofibers that enable muscle contraction and locomotion. During embryogenesis, mononucleated myoblasts align and fuse to form elongated syncytia, which mature into functional muscle fibers supporting body movement.^[23] This process repeats in adult muscle regeneration, where satellite cells fuse with existing fibers to repair damage and maintain tissue integrity.^[24] Osteoclast formation exemplifies fusion's role in physiological remodeling, particularly in bone homeostasis. Monocytes of the macrophage lineage fuse to create large, multinucleated osteoclasts capable of resorbing bone matrix, which is vital for calcium regulation and skeletal adaptation to mechanical stress.^[25] This fusion-dependent multinucleation enhances the cells' resorptive efficiency, balancing bone formation by osteoblasts.^[26] In mammalian pregnancy, trophoblast fusion forms the syncytiotrophoblast layer of the placenta, a multinucleated barrier that facilitates nutrient exchange and hormone production for fetal support. Cytotrophoblast cells continuously fuse into this syncytium, expanding its surface area to meet the growing embryo's demands throughout gestation.^[27] In invertebrates like Drosophila melanogaster, myoblast fusion during embryogenesis constructs the larval musculature: founder cells fuse with fusion-competent myoblasts to form multinucleated muscle precursors, establishing the body wall muscles essential for larval motility.^[24]

Molecular and Cellular Mechanisms

Cell fusion is a tightly regulated process involving sequential biophysical and biochemical steps that enable the merger of two plasma membranes. The process begins with cell-cell adhesion and dehydration, where fusogenic proteins bring opposing membranes into close proximity (approximately 0.5-1 nm), overcoming the repulsive hydration forces between lipid headgroups. This is followed by hemifusion, in which the outer leaflets of the bilayers merge to form a stalk intermediate, allowing lipid mixing but not yet content exchange. Subsequent pore formation occurs through rupture of the hemifusion diaphragm, creating a narrow aqueous channel that expands to enable complete cytoplasmic continuity and mixing. These stages are conserved across eukaryotic systems, from viral entry to developmental syncytia formation.^[6] Central to these stages are fusogenic proteins, or fusogens, that catalyze membrane merger by inserting into bilayers and inducing curvature. In mammals, syncytins—endogenous retroviral envelope-derived proteins such as syncytin-1 and syncytin-2—promote trophoblast cell fusion during placentation, acting through receptor binding (e.g., to ASCT2 for syncytin-1) and heptad repeat-mediated conformational changes that drive hemifusion and pore opening. For skeletal myoblast fusion in vertebrates, myomaker (Tmem8c) promotes cell-cell recognition and adhesion, while myomerger (Tmem8a/Myomixer) induces membrane fusion, working in concert to form multinucleated myofibers.^[28] In Caenorhabditis elegans, EFF-1 (epithelial fusion failure-1) and AFF-1 (anchor cell fusion failure-1) form a family of type I transmembrane fusogens that mediate homotypic fusions in epithelial sheets and other tissues; they undergo cis-dimerization on the same membrane followed by trans-interaction across cells, zippering via conserved cysteine-rich domains to execute the full fusion pathway from hemifusion to cytoplasmic mixing. ADAM (a disintegrin and metalloprotease) family members, including fertilin-α/β and meltrin-α, contribute to fusion in reproductive and myogenic contexts by facilitating adhesion and proteolysis to expose fusogenic motifs, as seen in sperm-egg binding and myoblast alignment.^[17]^[29]^[30] The cytoskeleton provides mechanical support for fusion by driving membrane remodeling and force application. Actin polymerization, nucleated by the Arp2/3 complex and activators like WASP (Wiskott-Aldrich syndrome protein), generates branched networks that form protrusive structures—such as invadopodia-like foci in myoblasts or finger-like projections in epithelial cells—to align membranes and facilitate fusogen engagement. Myosin II dynamics further assist by generating contractile tension that bends membranes toward hemifusion and expands fusion pores, with non-muscle myosin IIA accumulating at fusion sites to resist cortical tension and promote pore stability. These cytoskeletal elements create a positive feedback loop, where initial actin assembly recruits myosins to sustain force generation.^[31]03917-X) Calcium signaling integrates these events by activating downstream effectors that alter membrane composition. Elevated intracellular Ca²⁺ triggers phospholipid scramblases of the TMEM16 family, particularly TMEM16F, which rapidly externalize phosphatidylserine (PS) from the inner to outer leaflet, reducing bilayer asymmetry and lowering the energy for stalk formation in processes like trophoblast syncytialization. This scrambling exposes PS as a recognition signal for fusogens and cytoskeletal regulators, ensuring fusion proceeds in a coordinated manner.^[32] Biophysically, fusion faces high energy barriers from lipid packing and interbilayer repulsion, estimated at 20-50 kT for hemifusion in elastic continuum models. Hydration repulsion, arising from structured water layers between polar headgroups, dominates at separations below 2 nm, but fusogens mitigate this by dehydrating interfaces and imposing splay or tilt deformations that favor negative curvature in the outer leaflets. Pore formation adds another barrier due to line tension around the pore rim, overcome by lateral tension from cytoskeletal pulling. Regulation occurs through inhibitory factors like suppressyn, a placental protein that antagonizes syncytin-mediated fusion by competing for receptor binding, preventing ectopic mergers in epithelial barriers.^[33]

Methods of Inducing Fusion

Physical and Chemical Methods

Physical and chemical methods for inducing cell fusion rely on abiotic techniques to destabilize cell membranes and promote merger in controlled laboratory environments, offering alternatives to biological approaches for generating hybrid cells.^[34] These methods are particularly valuable in research settings for their ability to manipulate cells without introducing viral or enzymatic agents, enabling precise control over fusion events.^[35] Electrofusion involves the application of high-voltage electric pulses to adjacent cells, which induces transient membrane permeabilization and subsequent fusion.^[36] The process typically requires cells to be aligned in a hypo-osmotic medium using a preparatory alignment pulse, followed by a fusion pulse that destabilizes the lipid bilayers.^[37] Key parameters include field strengths of 1-2 kV/cm and pulse durations of 10-100 μs, which ensure membrane charging and pore formation without excessive damage.^[36] This technique, pioneered by Zimmermann in the early 1980s, has been optimized for various cell types, achieving fusion efficiencies up to 35% in mammalian cells under controlled conditions.^[38] Chemical inducers, such as polyethylene glycol (PEG), promote fusion by dehydrating the extracellular space and bridging cell membranes through phase separation effects.^[39] A standard protocol involves treating a pellet of mixed cells with 50% PEG (molecular weight 1450-1550) for approximately 1 minute at 37°C, followed by gradual dilution in serum-free medium to restore osmotic balance.^[40] This method, widely used since the 1970s for hybridoma production, facilitates membrane contact and lipid mixing, with fusion rates enhanced by prior cell aggregation via centrifugation.^[41] PEG's simplicity makes it accessible, though optimization of concentration and exposure time is critical to balance efficiency and viability.^[40] Mechanical methods employ physical force to bring cells into close contact, often using microsurgery or microfluidic devices to overcome membrane repulsion.^[42] In microsurgery, fine glass needles or micromanipulators puncture or compress cells, creating breaches that allow cytoplasmic mixing, as demonstrated in single-cell manipulation studies.^[42] Microfluidic approaches integrate cell pairing through hydrodynamic traps or dielectrophoretic forces, followed by mechanical squeezing or shear to initiate fusion, enabling high-throughput processing of paired cells.^[43] Recent advancements include integrated microfluidic chips that facilitate electrofusion and in situ separation of fused cells, improving efficiency and scalability as of 2025.^[44] These techniques provide spatial precision for targeted fusions, such as in embryo manipulation, but require specialized equipment for reproducible outcomes.^[43] Laser-induced fusion utilizes focused laser beams to generate localized photothermal effects, heating the contact point between cells to form fusion pores without widespread damage.^[45] Femtosecond or nanosecond pulses from infrared or UV lasers, often combined with optical tweezers for positioning, disrupt membrane integrity via multiphoton absorption and thermal expansion.^[46] Typical setups employ powers just above the ablation threshold (e.g., 10-50 mW for femtosecond lasers) to achieve fusion in non-adherent cells, with success rates improving when cells are pre-aligned.^[45] This method excels in single-pair fusions under microscopy, offering real-time visualization of the process.^[46] While these methods provide distinct advantages, such as electrofusion's precision for specific cell pairs and PEG's high efficiency in bulk fusions, limitations include potential cytotoxicity from chemical agents like PEG, which can reduce viability at concentrations above 40%.^[47] Electrofusion and laser techniques offer lower toxicity and better control but demand optimized parameters to avoid irreversible membrane rupture, with mechanical methods facing challenges in scalability due to equipment complexity.^[34] Overall, selection depends on cell type and experimental goals, with hybrid approaches sometimes combining elements for improved yields.^[48]

Biological and Viral Methods

Biological and viral methods for inducing cell fusion leverage natural fusogenic proteins from viruses or endogenous cellular fusogens, enabling controlled hybridization primarily in research and biotechnological contexts. These approaches rely on biotic mediators to promote membrane merger, contrasting with abiotic physical or chemical techniques. Among viral methods, the paramyxovirus Sendai virus (also known as hemagglutinating virus of Japan, HVJ) has been a cornerstone since its discovery as an effective fusogen in the 1950s. Sendai virus induces fusion through the cooperative action of its two envelope glycoproteins: the hemagglutinin-neuraminidase (HN) protein, which binds sialic acid receptors on target cells to facilitate attachment, and the fusion (F) protein, which undergoes a conformational change to drive membrane merger.^[49] Inactivated Sendai virus preparations, typically treated with beta-propiolactone or UV irradiation to prevent replication, are commonly used to hybridize mammalian cells, such as in the production of somatic cell hybrids for genetic studies.^[50] A landmark application of Sendai virus-mediated fusion was the development of hybridoma technology in 1975 by Georges Köhler and César Milstein, who fused murine myeloma cells with spleen B cells to generate immortalized antibody-secreting hybridomas, earning them the 1984 Nobel Prize in Physiology or Medicine.^[51] This method involved exposing mixed cell populations to UV-inactivated Sendai virus at optimized titers, achieving fusion rates sufficient for stable hybrid selection via HAT medium.^[52] Beyond Sendai, other viruses have been adapted for targeted fusion. For instance, the human immunodeficiency virus (HIV-1) envelope glycoproteins gp120 and gp41 mediate receptor-specific fusion; gp120 binds CD4 and co-receptors like CCR5 or CXCR4, triggering gp41's insertion into the target membrane to form a fusion pore.^[53] Engineered HIV Env pseudoviruses or expression vectors expressing gp120/gp41 have been used to induce fusion in CD4+ cell lines for studying viral entry or creating syncytia models.^[54] In insect systems, baculoviruses exploit their GP64 envelope protein for low-pH-dependent fusion; infection of Sf9 or High Five cells with recombinant baculovirus can lead to syncytium formation under acidic conditions, aiding high-yield protein expression by enhancing cell-cell content mixing.^[55] Genetic methods complement viral approaches by directly overexpressing fusogenic proteins to trigger fusion without viral replication risks. Endogenous fusogens such as syncytin-1, a human endogenous retrovirus-derived protein, can be overexpressed via plasmid transfection to induce homotypic or heterotypic fusion in mammalian cells; for example, transient expression in HEK293 cells promotes syncytium formation through interaction with its receptor ASCT2.^[56] Similarly, the C. elegans fusogen EFF-1 (epithelial fusion failure-1), when heterologously expressed in mammalian or insect cells via plasmids, drives cell-cell fusion by forming homodimers that bridge membranes, as demonstrated in studies achieving up to 50% fusion efficiency in transfected populations.^[57] Emerging tools like CRISPR activation (CRISPRa) enable endogenous fusogen upregulation; dCas9 fused to transcriptional activators targets syncytin promoters, increasing expression and fusion in trophoblast-like cell lines without genomic integration.^[58] These genetic strategies allow precise temporal control, often combined with inducible promoters for on-demand fusion. To enhance fusion efficiency, biological agents can promote initial cell-cell contact by clustering adhesion molecules. Lectins, such as concanavalin A, bind glycosylated surface proteins to induce aggregation, thereby increasing the local density of fusogens and amplifying viral or genetic fusion rates in mixed cultures.^[59] Antibodies targeting adhesion molecules, like bispecific constructs against cadherins or integrins, similarly cluster receptors to facilitate membrane apposition prior to fusogen activation, as shown in engineered systems achieving targeted hybridomas.^[60] For specificity and safety, viral doses are titrated—typically 500-2000 hemagglutinating units per 10^6 cells for Sendai—to maximize fusion (20-80% efficiency) while minimizing cytopathic effects like lysis, monitored via trypan blue exclusion or viability assays.^[49] Genetic methods incorporate dose-response via promoter strength or MOI adjustments to prevent excessive syncytia that could impair downstream applications.^[56] Recent chemical-biological hybrids, such as cell-penetrating peptide-conjugated lipids, have shown promise in inducing intercellular interactions and fusion with higher efficiency, offering alternatives to traditional viral methods as of 2024.^[61]

Roles in Multicellular Organisms

Fusion in Animal Development and Physiology

Cell fusion plays a pivotal role in animal development and physiology, enabling the formation of multinucleated structures essential for tissue function and homeostasis. In vertebrates, particularly mammals, fusion events occur during embryogenesis to establish foundational tissues like skeletal muscle and placenta, while in adults, they support maintenance and repair processes such as bone remodeling. These events are tightly regulated by specific molecular cues, contrasting with fusion in plants, which involves cell wall dissolution in sessile contexts.^[62] In skeletal muscle development, mononucleated myoblasts fuse to form multinucleated myotubes, which mature into myofibers containing hundreds to thousands of nuclei per fiber in humans, such as up to 3,000 in biceps brachii fibers. This process is crucial during embryonic myogenesis and postnatal growth, where myoblasts align, adhere via proteins like cadherins, and merge membranes through fusogenic proteins such as myomaker and myomerger. In mammals, myoblast fusion is orchestrated by signaling pathways involving MyoD transcription factors, ensuring proper myofiber elongation and contractility.^[63]^[64]^[24] Bone remodeling relies on the fusion of monocyte-derived macrophages into multinucleated osteoclasts, which resorb bone matrix to maintain calcium homeostasis. This adult physiological process is induced by receptor activator of nuclear factor kappa-B ligand (RANKL) signaling from osteoblasts, which activates transcription factors like NFATc1 to promote fusion-competent states in progenitors. Osteoclasts typically contain 3–20 nuclei, enabling efficient bone degradation through coordinated actin podosome belts. Dysregulation of this fusion can lead to imbalances in bone density, highlighting its role in skeletal integrity.^[26]^[65] In mammalian placentation, cytotrophoblasts fuse into the multinucleated syncytiotrophoblast layer, forming the maternal-fetal interface for nutrient and gas exchange. This embryonic fusion is mediated by syncytins, endogenous retroviral envelope proteins like syncytin-1, which interact with receptors such as ASCT2 to drive membrane merger. Syncytin expression is regulated by transcription factors like GCM1, ensuring continuous renewal of the syncytium throughout gestation. This process is unique to eutherian mammals, supporting viviparous reproduction.^[66]^[18] Fusion events in the nervous system are rare and often involve glial cells, such as microglia fusing with neurons or other glia under stress or injury conditions. In mammals, bone marrow-derived cells can fuse with Purkinje neurons or astrocytes, potentially contributing to limited plasticity, though the functional significance remains debated. During regeneration, such as salamander limb regrowth, glial-like Schwann cells dedifferentiate and proliferate, but these are not primary mechanisms compared to dedifferentiation.^[67]^[68] In the immune system, cell fusion generates hybrid cells, such as dendritic cell-tumor hybrids for enhanced antigen presentation, but such events are limited in vivo and primarily studied in therapeutic contexts. Macrophages can fuse with other immune cells to form multinucleated giant cells during chronic inflammation, improving phagocytosis, yet natural hybrid formation for antigen processing is infrequent outside experimental models. These fusions leverage MHC class I and II presentation from both partners, potentially amplifying T-cell responses.^[69]^[70] Developmental timing of cell fusion varies, with embryonic events dominating in mammals for tissue specification, such as myoblast fusion in somites or trophoblast merger by mid-gestation, while adult fusions sustain physiology, like osteoclast formation in response to mechanical stress. In insects like Drosophila, embryonic myoblast fusion between founder cells and fusion-competent myoblasts occurs rapidly during embryogenesis to form segmental muscles, paralleling mammalian patterns but adapted to metamorphosis-driven growth. These temporal distinctions underscore fusion's adaptability across animal phyla for both formative and reparative roles.^[62]^[24]

Fusion in Plant Cells

In angiosperms, cell fusion is a fundamental aspect of reproduction through double fertilization, where two sperm cells from the pollen tube participate in distinct fusion events within the embryo sac. One sperm cell fuses with the egg cell to form the zygote, which develops into the embryo, while the second sperm cell fuses with the central cell to generate the endosperm, a nutritive tissue essential for seed development.^[71] This process ensures the coordinated development of both embryonic and endosperm tissues, with fusion mediated by specific proteins that facilitate plasma membrane merging despite the presence of cell walls in surrounding tissues.^[72] Somatic cell fusion in plants occurs infrequently in vivo due to the rigid cell walls that act as primary barriers, but it has been observed in specific contexts such as wound healing and grafting. During wound healing, fusion events contribute to callus formation and tissue reconnection, allowing plants to repair damage by merging adjacent cells. In grafting, where a scion is joined to a rootstock, somatic fusion facilitates vascular reconnection and genetic exchange at the junction, as seen in compatible unions like those in tobacco species, promoting long-term integration.^[22] These events are metabolically demanding and often involve localized cell wall remodeling to enable membrane contact.^[73] The rigid plant cell wall poses a significant barrier to fusion, necessitating enzymatic removal for experimental induction, typically through protoplast isolation using cellulase and pectinase to degrade cellulose and pectin components. Protoplasts, the wall-less cells, can then undergo fusion via chemical agents like polyethylene glycol (PEG), which induces membrane destabilization and aggregation, or electrofusion, where electric pulses create temporary pores for merging. Recent advances, such as decorating protoplast membranes with cell-penetrating peptides, have improved fusion efficiency for creating novel hybrids (as of 2025).^[74]^[75]^[76]^[77] These techniques bypass sexual incompatibility, enabling the creation of interspecific hybrids, such as those between Solanum species, by fusing protoplasts from distantly related plants. Outcomes of induced protoplast fusion often include polyploidy, arising from the combination of unreduced genomes, which enhances traits like vigor and stress tolerance in resulting plants. For instance, tetraploid hybrids of Populus tremula × P. tremuloides generated via protoplast fusion exhibit increased biomass production compared to diploids. Similarly, somatic hybrids in potato (Solanum tuberosum) from protoplast fusion display altered chromosome structures and polyploid characteristics, contributing to breeding programs for improved varieties.^[78]^[79] In early plant evolution, endosymbiosis—via engulfment of cyanobacteria by ancestral eukaryotic cells rather than direct cell fusion—facilitated horizontal gene transfer, leading to chloroplast integration and relocation of photosynthetic genes, such as those for chlorophyll synthesis, to the nucleus in lineages like Arabidopsis thaliana and Oryza sativa. Such mechanisms highlight endosymbiosis's contribution to adaptive innovations beyond vertical inheritance.^[80]

Applications and Implications

Therapeutic and Research Applications

Cell fusion has revolutionized therapeutic applications in medicine and biotechnology, particularly through the creation of hybrid cells that combine desirable traits from distinct cell types. One seminal application is the production of monoclonal antibodies via hybridoma technology, where antibody-secreting B cells are fused with immortal myeloma cells using polyethylene glycol, enabling continuous production of specific antibodies. This technique, developed by Georges Köhler and César Milstein, allows for the isolation of hybridomas that secrete antibodies of predefined specificity, transforming diagnostics, therapeutics, and research by providing unlimited supplies of pure antibodies. For their discovery, Köhler and Milstein shared the 1984 Nobel Prize in Physiology or Medicine, recognizing the hybridoma's impact on immunology and beyond.^[81]^[82] In stem cell therapy, cell fusion serves as a powerful tool to study cellular reprogramming and develop universal donor cells. Fusing somatic cells with induced pluripotent stem cells (iPSCs) or embryonic stem cells generates tetraploid hybrids that exhibit pluripotency, offering insights into the molecular mechanisms of reprogramming and enabling the creation of hypoimmunogenic cells for transplantation. This approach has been used to reprogram human fibroblasts into pluripotent states more efficiently than traditional iPSC methods in some models, bypassing limitations in viral transduction and facilitating the production of universal donors by modulating immune recognition factors. Research highlights fusion's role in enhancing reprogramming efficiency, with hybrid cells providing a platform to investigate epigenetic changes and lineage identity shifts.^[83]^[84] Gene therapy leverages cell fusion to deliver corrected genetic material, particularly in models of muscular dystrophy. In Duchenne muscular dystrophy (DMD), fusion of healthy donor myoblasts with patient-derived DMD myoblasts using polyethylene glycol creates chimeric cells that express functional dystrophin, restoring muscle protein integrity and improving contractile function in preclinical mdx mouse models. This chimeric cell therapy, known as Dystrophin Expressing Chimeric (DEC) cells, demonstrates sustained dystrophin production post-transplantation, enhancing muscle repair without eliciting strong immune rejection. Similarly, menstrual blood-derived stromal cells fused with DMD myocytes have shown dystrophin expression in vivo, supporting fusion as a viable strategy for autologous gene correction.^[85]^[86] Vaccine development employs cell fusion to boost immunogenicity, notably by fusing dendritic cells with tumor cells to create hybrid vaccines that present a broad array of tumor antigens. These dendritic cell/tumor fusions process and display whole-tumor antigens via major histocompatibility complex molecules, eliciting robust T-cell responses in preclinical and clinical settings. In multiple myeloma patients, vaccination with autologous dendritic cell/multiple myeloma fusions has proven safe, inducing tumor-specific cytotoxic T lymphocytes and stabilizing disease in a majority of cases during phase I/II trials. Pioneered by Gong and colleagues, this approach enhances cross-presentation of antigens, outperforming peptide-based vaccines in stimulating antitumor immunity.^[87]^[88] In regenerative medicine, controlled cell fusion promotes tissue repair, especially in skeletal muscle and bone. Mesenchymal stem cells (MSCs) fuse with resident myogenic progenitors to contribute to myofiber regeneration, augmenting satellite cell activation and differentiation in injury models. This fusion-mediated process supports muscle homeostasis and repair by integrating stem cell nuclei into damaged fibers, as evidenced in studies where bone marrow-derived cells fuse with myofibers to restore function post-injury. For bone repair, fusion enhances osteoblast-myoblast interactions in tissue-engineered scaffolds, improving mineralization and vascularization. Overall, these applications underscore cell fusion's role in bridging cellular defects for therapeutic regeneration.^[89]^[90] Recent advances post-2020 have expanded cell fusion's utility in drug delivery through engineered fusogenic systems. Fusogenic liposomes, lipid nanoparticles designed to mimic viral fusion proteins, enable direct cytosolic delivery of therapeutics by merging with cell membranes, bypassing endosomal entrapment. These carriers have shown enhanced efficacy in delivering large payloads like mRNA and proteins, with studies demonstrating up to 10-fold improved transfection in hard-to-transfect cells compared to conventional liposomes. Additionally, engineered syncytins—retroviral envelope proteins adapted for therapeutic use—facilitate targeted cell fusion for gene transfer, such as transducing B cells with reduced immunogenicity in vivo models. These innovations, including bioinspired fusogens combined with liposomes, promise safer, more efficient delivery for immunotherapy and beyond.^[91]

Role in Cancer and Disease Progression

Cell fusion plays a detrimental role in tumor progression by generating hybrid cells that acquire enhanced stem-like properties and invasiveness, particularly through fusions between cancer cells and myeloid cells such as macrophages. These tumor-macrophage hybrids exhibit increased heterogeneity, enabling them to evade immune detection and promote aggressive growth. For instance, fusion events between neoplastic cells and leukocytes, including macrophages, contribute to the formation of hybrid cells with altered gene expression profiles that support tumor evolution and malignancy. Such hybrids have been observed to display stem cell-like characteristics, facilitating self-renewal and differentiation potential that drive cancer stem cell formation.^[70]^[92]^[93] In the context of metastasis, cell fusion facilitates epithelial-mesenchymal transition (EMT) and chemoresistance, allowing hybrid cells to invade surrounding tissues and resist therapeutic interventions. Fusion between mesenchymal stem cells (MSCs) and cancer cells, for example, enhances metastatic capacity by inducing EMT, which promotes motility, invasion, and the acquisition of stem-like traits in breast and lung cancers. This process also confers resistance to chemotherapeutic agents, as fused cells in metastatic colon carcinoma demonstrate reduced susceptibility to drugs through altered signaling pathways. Evidence from patient samples supports these mechanisms, with studies identifying fused cells derived from bone marrow in tumor tissues, indicating that bone marrow-derived cells (BMDCs) fuse with circulating cancer cells to generate metastatic hybrids. Human-human fusions between cancer cells and BMDCs have been detected in vivo, linking these events to disease dissemination.^[94]^[95]^[96]^[97] Oncogenic viruses further exacerbate pathological fusion in cancer, as seen with high-risk human papillomavirus (HPV) in cervical cancer, where the E5 protein induces cell fusion as an early initiating event in tumorigenesis. This fusion promotes genomic instability and malignant transformation in infected epithelial cells. Beyond cancer, aberrant cell fusion contributes to disease progression in viral infections, notably through syncytia formation in SARS-CoV-2-infected lungs, where multinucleated pneumocytes persist with viral RNA, exacerbating tissue damage, thrombosis, and inflammation in COVID-19 pathology. In neurodegenerative disorders, cell-cell fusion involving microglia drives aberrant activation and neurotoxic phenotypes, leading to synaptic engulfment and accelerated neuron loss, as observed in models of protein aggregate propagation.^[98]^[99]^[100]^[101] Targeting cell fusion offers therapeutic promise by inhibiting fusogens to prevent hybrid formation and tumor progression. Fusogens such as syncytins, which mediate cancer cell fusion, represent key targets for developing specific inhibitors that block metastasis and drug resistance in various cancers. Preclinical studies have demonstrated that disrupting fusion pathways, including those involving TNF-α and HERV-derived proteins, reduces tumor hybrid viability and enhances treatment efficacy in mouse models. These approaches aim to selectively impair pathological fusions while sparing physiological processes.^[102]^[103]^[96]^[104]

Fusion in Microorganisms

Fungal Cell Fusion

In fungi, cell fusion plays a central role in both sexual reproduction and vegetative growth, enabling genetic exchange and resource distribution within mycelial networks. During mating, compatible hyphae from opposite mating types undergo fusion through localized cell wall dissolution, allowing cytoplasmic and nuclear mixing. This process is prominent in basidiomycetes, where somatic cell fusion initiates mating without requiring specialized structures, leading to the formation of a dikaryotic state.^[105] In ascomycetes, similar fusion events occur between compatible mating types, governed by the MAT locus, which establishes cell-type identity and orchestrates the sexual cycle.00730-9) Hyphal anastomosis represents a key form of vegetative cell fusion in filamentous fungi, where genetically compatible hyphae merge to form interconnected mycelial networks that facilitate nutrient sharing and colony expansion. This process is tightly regulated by vegetative incompatibility (vic) genes, which prevent fusion between unrelated strains to avoid deleterious genetic mixing or viral transmission. In compatible interactions, hyphal tips align, cell walls degrade via localized enzymatic activity, and cytoplasms fuse, promoting heterokaryon formation.^[106] A well-studied example is in Neurospora crassa, where cell fusion pathways involve coordinated MAP kinase signaling cascades, including the MAK-1 and MAK-2 pathways, which regulate cell wall integrity, communication between fusion partners, and activation of scaffold proteins like HAM-5. These pathways ensure reciprocal signaling, where cells alternate between sending and receiving cues to achieve successful fusion.^[107] Evolutionarily, fungal cell fusion underpins parasexual cycles, providing a meiosis-independent mechanism for genetic recombination in many species. Anastomosis leads to heterokaryons, followed by occasional diploid formation and mitotic crossing-over, generating novel genotypes that enhance adaptability without a full sexual cycle. This process has been documented in ascomycetes like Aspergillus nidulans, where it contributes to genetic diversity in asexual populations. Industrially, cell fusion techniques, such as protoplast fusion in yeasts like Saccharomyces cerevisiae, are employed in breeding programs to create hybrid strains with improved traits for bioethanol production, including enhanced xylose utilization and stress tolerance. For instance, intergeneric fusions have yielded strains capable of efficient fermentation from lignocellulosic biomass, boosting ethanol yields under industrial conditions.^[108]^[109]

Fusion in Amoebozoa

In Amoebozoa, a diverse phylum of eukaryotic protists including slime molds and free-living amoebae, cell fusion plays crucial roles in both sexual reproduction and survival strategies under stress. These processes often result in the formation of multinucleated structures, such as giant cells or syncytia, which enhance resource sharing and genetic diversity. Unlike filamentous fungal fusions, amoebozoan fusion typically involves amoeboid movement and engulfment, driven by dynamic cytoskeletal rearrangements.^[110] Sexual reproduction in cellular slime molds like Dictyostelium discoideum prominently features gamete fusion during macrocyst formation, a process triggered under dark, submerged, and nutrient-limited conditions. Cells of opposite mating types, such as NC-4 (mating type I) and V12 (mating type II), undergo sexual differentiation into fusion-competent gametes, followed by rapid cell fusion within 30 minutes of contact, leading to giant zygote cells that ingest surrounding amoebae and develop a protective cellulose wall around the macrocyst. This fusion is mediated by cell surface glycoproteins, including gp138 (encoded by multiple genes like GP138A and GP138B), which are GPI-anchored proteins essential for initial adhesion between compatible partners; mutants lacking gp138 exhibit severely impaired fusion. Another key player, LagC (encoded by macA), a large transmembrane glycoprotein with adhesion domains, is indispensable for gamete interactions and is upregulated in fusion-competent cells. Post-fusion, actin-driven processes facilitate the engulfment of additional cells, contributing to the multinucleated structure.^[111]^[112]^[113]^[114] In contrast, predatory fusion occurs in plasmodial slime molds such as Physarum polycephalum, where uninucleate amoebae coalesce during feeding to form expansive, multinucleated syncytia known as plasmodia. This coalescence involves homotypic fusion of compatible amoebae or plasmodial fragments, regulated by genetic compatibility at multiple loci (e.g., four dominant loci controlling somatic fusion), preventing incompatible mergers that could lead to post-fusion incompatibility or cell death. The resulting plasmodium enables efficient nutrient foraging across substrates via cytoplasmic streaming, powered by actin-myosin contractions. Molecularly, initial adhesion relies on GPI-anchored surface proteins, similar to sexual fusion, while actin polymerization drives membrane protrusion and engulfment during coalescence.^[115]^[116]^[110] Ecologically, cell fusion in Amoebozoa confers adaptive advantages in fluctuating environments, particularly during starvation, by promoting multinucleate structures that distribute resources and genetic material among cells. In D. discoideum, macrocyst formation allows dormant survival through harsh conditions, with fusion enabling genetic recombination for diversity. Similarly, P. polycephalum plasmodia aggregate biomass to withstand nutrient scarcity, enhancing predatory efficiency on bacteria and fungi. Random fusions during encystation in amoebae like Entamoeba invadens further aid nutrient sharing under stress.^[110]^[111] Amoebozoans serve as valuable research models for studying cytokinesis failure as a pathway to fusion-like multinuclearity. In Acanthamoeba castellanii, delayed cytokinesis under non-adherent conditions produces giant multinucleate cells, mimicking fusion outcomes and revealing regulatory overlaps in cell division machinery. E. invadens encystation models demonstrate how stress-induced fusion or cytokinesis arrest forms giant cells, providing insights into eukaryotic membrane dynamics and nuclear coordination absent in simpler bacterial systems. These models highlight conserved actin roles in both processes.^[117]^[110]

Bacterial Cell Fusion

Bacterial cell fusion, defined as the merger of cytoplasms between two or more prokaryotic cells, is exceedingly rare due to the rigid peptidoglycan cell wall that prevents membrane contact and mixing. Unlike eukaryotic cells, where fusion facilitates syncytium formation and genetic exchange, bacteria primarily rely on horizontal gene transfer mechanisms like conjugation, transformation, and transduction for genetic sharing without full cytoplasmic merger. True fusion events, when observed, are typically partial or occur in wall-deficient (L-form) states induced by stress, leading to multinucleated structures that enhance survival or gene dissemination.^[118] In certain actinomycetes, environmental stresses such as hyperosmotic conditions can trigger the formation of wall-deficient cells that exhibit partial fusion-like behaviors, resulting in multinucleated giant cells. For instance, in filamentous actinomycetes such as Kitasatospora viridifaciens, hyperosmotic stress induces the formation of wall-deficient S-cells that can resume filamentous growth upon stress relief, representing a survival strategy enabling coordinated gene expression and resource sharing in harsh environments without complete eukaryotic-style fusion.^[119] Bacterial conjugation serves as a pseudo-fusion process, involving direct cell-to-cell contact via a type IV secretion system but without merging cytoplasms. In Escherichia coli harboring F-plasmids, the process is mediated by Tra proteins, which assemble a pilus to bridge donor and recipient cells, facilitating unidirectional transfer of single-stranded DNA while maintaining separate cytoplasmic compartments. This mechanism, first described in the 1950s, allows efficient dissemination of plasmids carrying antibiotic resistance or virulence genes but does not involve membrane fusion or cytoplasmic exchange, distinguishing it from true cell fusion. In biofilms, partial cell fusion can occur through localized cell wall remodeling, particularly in Gram-positive bacteria like Staphylococcus aureus, where autolysins degrade peptidoglycan to facilitate matrix embedding and close cell-cell associations. During biofilm development, S. aureus undergoes dynamic wall remodeling, with increased expression of hydrolases leading to weakened septa and occasional cytoplasmic bridging between adjacent cells, enhancing community cohesion and gene sharing for collective resistance. This remodeling is pH-dependent and contributes to the structural integrity of the biofilm matrix, though it rarely results in full fusion.^[120] Environmental stresses, such as exposure to antibiotics, can induce bacterial cell fusion as an adaptive response to promote resistance gene sharing. In wall-less L-form variants of antibiotic-producing bacteria like Kitasatospora viridifaciens, fusion can be induced, with efficiency increased up to 3-fold using specific lipopeptides, generating heterokaryons that combine genetic traits for enhanced antibiotic production or resistance. These fused cells exhibit hybrid phenotypes, such as elevated secondary metabolite yields, underscoring fusion's role in rapid evolution under selective pressure.^[118] In synthetic biology, bacterial cell fusion has been engineered to create hybrid cells for biotechnology applications, often using fusogenic agents to overcome cell wall barriers. For example, in E. coli protoplasts, polyethylene glycol (PEG) induces membrane merger, yielding viable heterokaryons with combined genomes for metabolic engineering.^[121] Similarly, in Kitasatospora viridifaciens L-forms, cell-specific fusogenic peptides enable controlled fusion, producing cells with modified antibiotic profiles and demonstrating potential for generating genetic diversity in microbial consortia.^[118]

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