Human blood cell similar to embryonic and nerve cells can extend thin and very long extensions having the same diameter along the entire length called cytonemes. Cytonemes were shown to connect blood cells over a distance of several cell diameters and transport membrane proteins, lipids and ions from one of connected cells to another one, thus executing long range intercellular communications. Formation and breakage of cytonemes upon neutrophil rolling along the vessel walls regulate rolling velocity and control neutrophil adhesion to the endothelium. Direct interaction of neutrophils with platelets over a distance seems to be of great importance in thrombosis. Cytonemes of B cells, peripheral NK cells, monocytes and dendritic cells can play a critical role in long range cellular signalling upon antigen presentation and formation of immune response.
Blood cells secret and accept signalling molecules to communicate with other cells over a distance. Recent investigations demonstrate that cells can directly interact with cells over a distance of several cell diameters using very long and very thin filopodia. Such filopodia were observed firstly in a variety of embryonic cells.1-7 Along with thin filopodia, a number of synonyms are used to call very thin intercellular connectives, such as membrane tethers, tubulovesicular extensions or thread-like projections, tunnelling nanotubes or nanotubular highways. Based on a connectives thickness, authors unite sometimes together under the same term very thin taper and thread-like filopodia, which differ in origin, behaviour and functions.
The term cytoneme was firstly used to describe “slightly beaded” thread-like filopodia with a diameter of approximately 0.2 μm projected by Drosophila wing imaginal disc cells.6 Cytonemes in the present work can be determined as tubular or tubulovesicular cellular filopodia with uniform diameter along the entire length. Diameter of cytonemes can vary from 0.035 to 0.4 μm and more, but always has the same size at their basal, middle and distal parts. The main peculiarities of cytonemes are their length (several cell diameters), high rate of development (1 μm/min-40 μm/s), flexibility and motility (for cytonemes with free tips).
Cytonemes of Embryonic Cells
Cytonemes of blood cells resemble in size, behaviour and functions thin dynamic filopodia of sea urchin primary mesenchyme cells (PMCs). These filopodia seem to serve as cellular probing and adhesive organelles and play a role in signaling and patterning at gastrulation.1,5 During gastrulation of the sea urchin embryo PMCs migrate from the vegetal pole to a site below the equator of the embryo where they form a ring-like structure and begin producing the larval skeleton. As these cells migrate, they extend and retract dynamic thin filopodia which interact with the basal lamina which lines the blastocoel and with underlying ectoderm. For normal skeleton development PMCs have been shown to obtain extensive positional information from ectoderm. Thin, dynamic and rapidly elongating filopodia of PMCs seem to probe the inner surface of the outer epithelial cells and establish cell-cell contacts with them. Bulges, sometimes moving along filopodia to the PMCs cell bodies, could represent transport of signaling substances from filopodia tips.5 Cells of ectoderma also have a capability to develop similar filopodia.5
Isolated PMCs are also capable of growing thin, elongated, active filopodia upon adhesion to extracellular matrix or fibronectin in the presence of deposits of extracellular material prepared from mesenchyme blastula.2-5 These in vitro filopodia closely resemble the filopodia seen in vivo and exhibit several apparent functions: as sensory organelles, as anchoring appendages and as intercellular connectives. Filopodia can extend at a rate 1 μm/min from cells migrating in vitro, or as rapidly as 10-25 μm/min in vivo and can reach 30-80 μm in length. The filopodia diameter varies from 0.2 to 0.4 μm.1-5
Similar cellular extensions were observed in insect embryonic cells. To develop wing imaginal disc cells in Drosophila need information from signaling center associated with the anterioir/posterior (A/P) and dorsal/ventral (D/V) compartment borders. This information can be delivered by cytonemes—long, polarized cellular extensions that were found to extend from outlining disc epithelial cells to the signaling A/P and D/V centres.6,7 Decapentaplegic (Dpp) signaling was shown to determine appearance and orientation of cytonemes. The average length of A/P and D/V oriented cytonemes was 20 μm and 9 μm respectively. Dpp receptor, Thick-veins (Tkv), revealed as Tkv-GFP was found in the plasma membrane of expressing cells and in punctae that move along cytonemes in both anterograde and retrograde directions at a rate 5-7 μm/s.7
Cytonemes in cultured wing disc cells can be induced in vitro in response to tissue fragments containing the anterior/posterior boundary. The rate of cytonemes development can overcome 15 μm/min and cytonemes can reach 700 μm in length. Their diameter does not exceed 0.2 μm.6
During Drosophila oogenesis, a small cluster of border cells migrate over 120 μm along the central surface of the nurse cells to oocyte.8 Posterior germ cells extend cell processes similar to cytonemes that might help them to communicate with the border cells. The germ cell processes are considerably larger in diameter (1-2 μm), probably reflecting the proportionately larger size of germ cells compared with disc epithelial cells.
Cytonemes of Human Blood Cells
Human leukocytes can produce very long and thin membrane structures resembling cytonemes of embryonic cells: ultralong membrane tethers that were found to attach neutrophils (polymorphonuclear leukocytes) to platelets under physiological flow,9-11 tubulovesicular extensions, connecting neutrophils to other neutrophils, erythrocytes and objects for phagocytosis;12,13 thread-like projections of activated B cells;14 membrane nanotubes connecting peripheral blood NK cells, macrophages and cells of EBV-transformed human B cell line;15 tunnelling nanotubules in myeloid lineage dendritic cells and monocytes.16
Ultralong membrane tethers developed from neutrophil cell bodies were shown to connect human neutrophils to spread platelets or immobilizes P-selectin under shear stress.9-11 Adhesive receptors of neutrophils belong to integrin and selectin families. Circulating leukocytes have a round cell shape and roll along the vessel walls, temporarily adhering to endothelial cells by selectins. L-selectin and PSGL-1 (P-selectin glycoprotein ligand-1, common for L-, E- and P-selectins) on neutrophils, E- and P-selectin on the endothelium mediate rolling of neutrophils. L-selectin and PSGL-1 are shown to be clustered on the tips of neutrophil microvillus.17-19
Formation of long membrane tethers in human neutrophils was observed by high speed, high resolution videomicroscopy of flowing neutrophils interacting with spread platelets.9 Thin membrane tethers with the average length 6 μm were pulled from the neutrophil bodies at the average rate of 6-40 μm/s after capture by spread platelets as the wall shear rate was 100-250 s-1.9 Antibodies against P-selectin or PSGL-1, but not anti-CD18 (common β subunit of β2 integrin) antibodies, blocked tether formation. The average tether lifetime was consistent with P-selectin/PSGL-1 bond dynamics under shear stress. It was supposed that formation of thin membrane tethers could occur as a result of binding of PSGL-1 located on the neutrophil microvillus tips to platelet P-selectin and following microvillus elongation under shear stress.9 Such long range contact interactions of neutrophils to platelets could play a critical role in thrombosis.
When neutrophils were perfused over P-selectin surfaces at a wall shear rate 150 s-1, they rolled over the surface and formed thin membrane tethers similar to those observed upon interactions with platelets.9-11 Tethers reached 40 μm and more in length with the average length 8.9 μm. The characteristic jerking motion of the neutrophil over P-selectin coexisted with tether growth, whereas tether breakage caused an acute jump in the rolling velocity. Neutrophil seem to stabilize rolling velocity by rapidly adjusting tether number in response to changes in wall shear stress.10,11 Tether number was rapidly increased as wall shear stress rose and decreased as wall shear stress declined.
Similar mechanism can stabilize neutrophil rolling velocity in blood vessels. Tether formation in circulation could occur due to binding of L-selectin and PGPL-1 clustered on the neutrophil microvillus tips to E- and P-selectin on endothelial cells, lining vessel walls, and following microvillus elongation under shear stress.
Scanning electron microscopy revealed cytonemes formation in human neutrophils upon adhesion to fibronectin-coated substrata, when cell spreading was blocked. Long microvillus-like highly dynamic tubulovesicular extensions developed from the cell bodies of neutrophils, plated to fibronectin-coated substrata in Na+-free extracellular medium or in the presence of drugs, capable of blocking neutrophil spreading, like the rather unspecific phospholipase A2 inhibitor 4-bromophenacyl bromide (BPB), presumed inhibitors of vacuolar-type ATPases N-ethylmaleimide (NEM) and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD-Cl) and cytochalasin D.11 Those extensions, attached cells to substrata in β1-, β2-integrin-independent, but L-selectin-dependent manner and connected neutrophils to each other.12,13 Tubulovesicular extensions can reach 10-80 μm in length during 20 minutes and displayed uniform diameter along the entire length. A variety of cytonemes connecting neutrophils are represented on Figure 1.
In contrast to selectin, β2-integrin Mac-1 (CD11b/CD18) that mediates firm adhesion of neutrophils is mainly located on the membrane of the cell bodies.17 Integrin-mediated adhesion of neutrophils to the vessel walls occurs upon metabolic disorders such as diabetes or ischemia and following reperfusion and leads to the capillary closure and endothelium injury by attached neutrophils. Leukocyte-endothelium interactions are tightly regulated by a number of mediators, including nitric oxide (NO) constitutively produced by both, neutrophils and endothelial cells. NO is shown to reduce β2-integrin-dependent leukocyte adhesion to endothelium, thus protecting vessel walls from the injury induced by adherent leukocytes. At the same time NO did not affect selectin-dependent rolling of leukocytes.20,21
How NO affect leukocyte adhesion remains to be elucidated. NO was shown to induce formation of tubulovesicular extensions in human neutrophils.13 Development of multiple very long and highly dynamic tubulovesicular extensions, executing cell adhesive interactions over a distance through L-selectin, could reduce involvement of β2-integrin located on the cell bodies in cell-cell interactions. NO could alter integrin-dependent adhesion of neutrophils to endothelial cells for selectin dependent rolling along endothelium due to development of cytonemes.
Phagocytosis of micro organisms is the main neutrophil function. Leukocytes are also known to scavenge old erythrocytes from the blood stream by phagocytosis. Tubulovesicular extensions demonstrated a property to stick and coil around serum opsonized zymosan particles and erythrocytes (Fig. 2). Development of extensions increases the contact area of the cells thus stimulating finding and catching of objects for phagocytosis.13
In lymphocytes engagement of B-cell antigen receptor (BCR) was shown to induce formation of cytoneme-like extensions.14 Cytonemes induced by IgM (surrogate for antigen) were observed in primary splenic lymphocyte and Bal 17 cells. Cytonemes had a thickness of 0.2-0.4 μm and lengths reaching up 10 cell diameters (= 80 μm) during 30 min. The induction of cytonemes on B cells suggests that that they may participate in long-distance communication between the antigen-stimulated B cells and other immune cells in the lymphoid organs such as follicular dendritic cells and T cells. The time course of appearance of long, stable cytonemes is consistent with a possible role in presentation of antigen taken up via the BCR to helper T cells.14
Membrane nanotubes were found also to connect human peripheral blood NK cells, macrophages and EBV-transformed B cells.15 Nanotubes seem to be pulled from the cell bodies during disassembly of the immunological synapse, as cells move apart. Nanotubes grew with a speed 0.2 μm/s, lasted over 15 min and reached 140 μm in length. Nanotubes were capable of transporting membrane GPI-anchored proteins, along the surface of the tube, from one of connected cells onto the surface of another cell. GFP-tagged (green fluorescent protein-tagged) cell surface class I MHC proteins expressed in one of the connected cells was found on the nanotubes membrane.15 The data demonstrate a role of nanotubules in cell signalling communication over distance upon formation of immune response.
A fluorescently labelled antibody against class I MHC were used to visualize tunnelling nanotubules in myeloid-lineage dendritic cells and monocytes by confocal microscopy.16 A network of tunnelling nanotubules (TNT) with the average diameter 35 nm were shown to transmit calcium fluxes stimulated by chemical or mechanical stimuli between interconnected cells. Microinjected fluid phase marker Lucifer yellow was demonstrated to be transported between cells through tunnelling nanotubules.16 Nanotubules are suggested to execute long range communication of immune cells, including antigen presentation.
Formation of cytonemes-like long and thin filopodia can be induced in a variety of eukaryotic cells due to transfection of B144/LST1 gene.22 The structures are dynamically rearranging and sometimes connect one cell with another over a distance of 300 μm. B144/LST1 is a gene encoded in human major histocompatibility complex. It is highly expressed in vitro and in vivo in dendritic cells of the immune system. Dendritic cells are professional antigen-presenting cells and have the problem of finding the occasional T cell whose receptor structure is present to recognize the antigen the dendritic cell is presenting. The occurrence of dynamic long cellular extensions offers a possible means for increasing the efficiency of this process.
Formation and Properties of Cytonemes Connecting Blood Cells
Human neutrophils or sea urchin PMCs upon adhesion to fibronectin-coated substrata were shown to develop long dynamic filopodia with unattached tips. These filopodia can probe the environment and establish contacts with the neighbouring cells.5,12 Appearance of multiple dynamic filopodia with unattached tips and their capability to stick to the neighbouring neutrophils, erythrocytes or zymosan particles supports this suggestion (Figs. 1, 2).
Electron microscopy studies revealed two types of cytonemes, connecting neutrophils - strait tubular and flexible tubulovesicular extensions (Fig. 1).12 Strait extensions could be derived from flexible tubulovesicular extensions due to applied tension after attachment of the tips. But strait filopodia or membrane tether can be pulled from the cell bodies after binding of selectin receptors, as it described for neutrophil-spread platelets interactions under shear stress.9 Similar membrane tether can be pulled from neutrophil cell bodies by micropipette manipulation, including suction of latex beads coated with antibodies to proteins on the neutrophil membrane surface.23,24
Cytonemes contained a number of bulges along their length (Fig. 1; see also refs. 5-7, 9, 12, 13, 22). A constant retrograde and/or anterograde motion of these bulges, observed by optic or confocal microscopy, is supposed to represent cytoplasm or lipid flow representing cell-cell communication. The rate of bulges movement coincides with the rate of cytoneme growth. As a size of cytonemes is near the limit of resolution for optical microscopy, it is impossible to distinguish bulged movement along cytonemes from cytonemes (containing bulges) movement between connected cells. Movement of cytonemes, consisting of tubular and vesicular fragments, between cells could look like bulges movement along cytonemes.
Tunnelling nanotubes of myeloid lineage were found to transport calcium ions and small molecules between cells.16 As it was shown for GPI-anchored green fluorescent protein, cell surface proteins also can be transported along the surface of the tube, from one of connected cells onto the surface of another cell.15 Cytonemes movement as a unit can execute transport of signalling membrane proteins and lipids, as well as cytoplasm ions and solutes, between interconnected cells.
Cytonemes were shown to grow unhindered in the presence of the microtubule-destabilizing agents nocodazole or colchicines and found to be tubuline-negative.2,12,22 There is no agreement on a role of actin filaments in cytonemes. As was revealed by rodamine-phalloidin staining thin filopodia of PMCs and long cell filopodia of cells transfected with B144/LST1 contained actin.5,6,22 To examine the involvement of actin cytoskeleton in the formation and maintenance of B cell cytonemes, an actin-GFP fusion protein was expressed in Bal 17 cells. BCR cross-linking resulted in the induction of cytonemes with punctuate staining for actin-GFP along the length of extension.13 All these data are often used to confirm that cytonemes are actin-driven protrusions.
Cytonemes are easily destroyed during fixation. Additional treatment with detergent is required for rodamine-phalloidin staining. In experiments with neutrophils treatment with a very low concentration of detergent eliminated all cytonemes from the cell bodies. It indicated the absence of filamentous actin resistible to detergents, in cytonemes. Moreover, disruption of actin filaments with cytochalasin D induced formation of cytonemes-like dynamic filopodia in neutrophils.12 Treatment with latrunculin A was shown to relieve pulling of membrane tethers from the neutrophil bodies by micropipette suction of latex beads coated with antibodies to proteins on the neutrophil membrane surface.24 .Those results indicate that actin filaments do not drive, but rather hinder development of cytonemes or membrane tethers.
To summarize all data on actin cytoskeleton together we can suppose, that cytonemes contain monomeric G-actin unable to drive cytonemes formation, but not filamentous F-actin. G-actin is diffusely distributed in cytoplasm and punctuate staining at that can reflect vesicular structure of cytonemes.
Cytoneme formation seems not depend on cytoskeleton. Model experiments, demonstrating formation of lipid nanotubes resembling cytonemes in size and rate of development in protein-free system can confirm this suggestion. Very long tubular membrane tethers with diameter 200-400 nm in length were observed to connect two daughter liposomes, which were formed upon mechanical fission of multilammelular liposomes (5-20 μm in diameter) of different lipid composition. Mechanical pushing of one of the daughter liposome at a rate of about 5-15 μm/s leaded to elongation of tubes to several hundreds of micrometers.25
Materials (particles, small liposomes) may be transported between two nanotube-connected daughter liposomes by creating a difference in the surface tension of the membrane, for example by microinjection of buffer solution in one liposome. The similar mechanism of stimulation of intracellular transport through tunneling nanotubules was described for the cells of myeloid leneage.16 Mechanical modulation of membrane tension triggered dendritic cells and monocytes to flux calcium through tunneling nanotubules to other cells at distance of hundreds microns away.17
One can suppose that electrolytes and water transport, regulating membrane tension, could provide a driving force for cytonemes formation. Na+-free medium is the most effective inductors of cytonemes in neutrophils.12 Na+-free medium could inhibit multiple electrogenic cotransporters and antiporters, using Na+ gradient to drive the uphill transport of solute and water into cells, thus inducing extrusion of cytonemes.
Origin and Degradation of Cytonemes
The intracellular origin of the membrane in cytonemes and its traffic pathways remain to be elucidated. Neutrophils or PMCs have diameter 7-8 μm but can extend a number of cytonemes reaching sometimes 80-700 μm. A rate of cytoneme growth can reach 40 μm/s.9 To built numerous and long membrane extracellular structures, additional membrane have to be quickly delivered from intracellular pools and inserted into the plasma membrane. Early endosomes, endoplasmic reticulum, lysosomes and secretory granules can supply plasmalemma with additional membrane for spreading, phagocytosis or surface wound repairing.26-30 Tubulovesicular structures of endosomes, lysosomes and trans Golgi network in some cases can fuse into apparently continuous interconnected tubular structures in the cells.31 Similar integral reorganization of the cellular membrane pool seems to occur upon cytoneme extensions.
As PMCs migrate, they extend and retract thin filopodia which appear to interact with the basal lamina and underlying ectoderm.2-4 Retraction of cytonemes in blood cells was not observed. In neutrophils formation of tubulovesicular extensions was shown to be an alternative for neutrophil spreading.12 Neutrophils, having developed numerous extensions, became normally spread in few minutes after Na+ ions addition or in 30 min after removing of the chemical inhibitors of spreading by washing.
Tubulovesicular extension of neutrophils can be observed in 15-40 min after neutrophil adhesion to fibronectin in the Na+-free medium or in the presence of inhibitors of spreading.12 Further incubation leaded to degradation of extensions by shedding (Fig. 3, left panel), swelling and lysis.12,13 Inspection of the P-selectin-coated surface after neutrophil rolling on the surface under shear stress also demonstrated the existence of shed tethers overcoming 100 μm in length with a beaded appearance.9 Heparitinase I was shown to accelerate degradation of extensions, thus leading to appearance of specific holes on the neutrophil cell bodies (Fig. 3F, right panel).13 Such holes on the neutrophil cell surface resemble in size and appearance porosome – a structure universally present in secretory cells, from the exocrine pancreas to the neurons, where membrane-bound secretory vesicles transiently dock and fuse to expel vesicular contents.32
Neutrophil tubulovesicular extensions could represent protrusions of exocytotic membrane trafficking, which fuse with the plasma membrane of neutrophils upon spreading, supporting it with additional membrane and adhesive receptors. Inhibition of fusion of tubulovesicular extensions with plasma membrane can lead to extrusion of exocytotic carriers from the cell bodies. The presence of the holes on cell bodies after shedding and disruption of cytonemes leads to suggestion that cytonemes can be protruded through these structures. Those holes in the cell bodies can represent the common opening for “compound exocytosis” of tubular and vesicular exocytotic carriers described for neutrophils.33
Formation of cytonemes seems to be a wide spread phenomenon, observed in embryonic, nerve and blood cells. But studies of cytonemes are very complicated. Cytonemes are too small to be observed by optic microscopy. They are easily destroyed upon fixation for electron microscopy. Immunostaining of cytonemes has troubles with fixation and detergent treatments. Due to these difficulties recent investigations demonstrate mainly existence and possible functions of cytonemes in cells of different types. Mechanisms of cytonemes formation and intracellular sources of membranes for building of cytonemes remain to be elucidated. A manner of intercellular signalling between cells mediated by cytonemes also needs further studies.
This work was supported by Grants of Russian Foundation of Basic Research 03-04-49270 and 04-04-48495.
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Svetlana Ivanovna Galkina,* Anatoly Georgievich Bogdanov, Georgy Natanovich Davidovich, and Galina Fedorovna Sud'ina.
Landes Bioscience, Austin (TX)
Galkina SI, Bogdanov AG, Davidovich GN, et al. Cytonemes as Cell-Cell Channels in Human Blood Cells. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.