Adipocytes have many functions in various tissues beyond energy storage, including regulating metabolism, growth, and immunity. However, little is known about their role in wound healing. Here we use live imaging of fat body cells, the equivalent of vertebrate adipocytes in Drosophila, to investigate their potential behaviors and functions following skin wounding. We find that pupal fat body cells are not immotile, as previously presumed, but actively migrate to wounds using an unusual adhesion-independent, actomyosin-driven, peristaltic mode of motility. Once at the wound, fat body cells collaborate with hemocytes, Drosophila macrophages, to clear the wound of cell debris; they also tightly seal the epithelial wound gap and locally release antimicrobial peptides to fight wound infection. Thus, fat body cells are motile cells, enabling them to migrate to wounds to undertake several local functions needed to drive wound repair and prevent infections.

While major efforts have been made over the last few decades to elucidate the roles of the fat body in regulating metabolism, growth, and immunity, its potential role in wound repair has not been studied to date. Using live imaging of pupal epithelial wounds we show for the first time that pupal fat body cells (FBCs) are motile cells that actively migrate to wounds. We find that these giant cells move through the hemolymph toward the wound using an adhesion-independent, actomyosin-driven, peristaltic mode of motility. Once they have reached the wound, FBCs assist hemocytes in clearing the wound of cell debris as well as sealing the epithelial wound gap and locally releasing AMPs to repair the wound and fight infection.

The Drosophila fat body is considered to be equivalent to both the vertebrate adipocytes and liver, and is known to play many diverse systemic roles throughout all insect life stages. It regulates metabolism by actively sensing nutritional conditions and accordingly storing or releasing energy in the form of lipids, glycogen, and protein (). Importantly, fat storage in intracellular lipid droplets, and the mechanisms and key components responsible for stored-fat mobilization in the Drosophila fat body and mammalian adipocytes, appear to be evolutionarily conserved (). In addition to storing energy, the fat body also plays a central role in regulating systemic growth in response to nutrition. Upon sensing dietary amino acids, the fat body secretes several humoral factors, which control systemic growth of the animal (). This is achieved, in part, by the regulated secretion of insulin-like peptides by the insulin-producing cells of the brain (). Furthermore, the fat body is known also to play a crucial role in systemic immunity. Bacterial and fungal infections activate the Toll and IMD pathways in the fat body, resulting in the systemic expression and secretion of several antimicrobial peptides (AMPs), including Attacin ().

There is a growing realization that adipocytes, once believed to act merely as local reservoirs of energy and to provide mechanical and thermal insulation, also have numerous other roles in various tissues in health and disease. These range from systemic metabolic and immune regulation through to key functions in tissue development and cancer progression (). In the context of skin, there is a clear link between initial seeding of adipocyte precursors and subsequent dermal differentiation and hair follicle growth (). However, rather little is known about the potential function of adipocytes in tissue repair. After skin wounding myofibroblasts have been shown to transdifferentiate into adipocytes (). Furthermore, adipocyte precursor cells are known to differentiate into mature adipocytes and these appear to contribute to repair because blocking their differentiation leads to defects in fibroblast migration and matrix deposition (). Other known functions of adipocytes include antimicrobial activities, since Staphylococcus aureus infection of otherwise healthy skin leads to rapid proliferation of dermal adipocytes, and impaired adipogenesis results in increased skin infections ().

Drosophila FBCs have been shown to systemically produce a variety of AMPs following infection with a variety of pathogens (). We wondered whether, since wounding is generally associated with infection, local delivery of AMPs to the wound might be another function of FBCs recruited to wounds. To test this, we wounded pupae expressing a reporter of one of these AMPs, Attacin, and then briefly added RFP-labeled Escherichia coli to the wound prior to live imaging. Our laser wounding usually only results in a very small hole in the cuticle of <0.5 μm in diameter ( Figure S1 D) and so bacteria generally fail to enter the wound but their pathogen-associated molecular patterns (PAMPs) can (schematic in Figure 5 F and data not shown). Wounding in the absence of an infection did not induce an upregulation of Attacin in FBCs. In contrast with this, within 60–90 min of making an infected wound, we saw an upregulation of Attacin in a few epithelial cells near the wound, as well as in the FBCs that plugged the wound and those in close proximity, up to 50 μm away ( Figure 5 F and Movie S10 ). This was clearly a local response by the FBCs since it did not occur in FBCs distant from the wound ( Figure 5 F). This shows that, following wound infection, FBCs are able to detect bacteria at the epithelial breach and locally deliver AMPs. Thus, FBCs, together with hemocytes, appear to play important local functions in combating wound infection: FBCs plug the wound gap, thereby forming a barrier that might prevent entry of bacteria and locally deliver AMPs to fight off pathogens, while hemocytes clear bacteria by phagocytosis.

Next, we wanted to investigate whether, in addition to wound repair, FBCs might play local functions in fighting wound infection. Given the large size of FBCs and their apparent tight association with the wound throughout closure, we wondered whether they might play a role in plugging the wound to prevent entrance of pathogens and leakage of tissue fluids, much as a clot in a vertebrate wound. Light and transmission electron microscopy revealed an extremely tight seal between wound-associated FBCs and the epithelial wound margin ( Figures 5 A–5C ; Movie S2 ), leaving a gap of less than 20 nm (see inset Figure 5 C), which would be too small for bacteria to pass through. In order to understand how these cells are able to achieve such a tight association, we again turned to live imaging of the actin dynamics within these cells as they arrive at the wound site. Expressing fluorescently tagged forms of the actin regulatory proteins Fascin, Fimbrin, and Ena revealed that, although FBCs moved to the wound without the use of lamellipodia or blebbing, once at the wound site, all co-operating cells extended lamellipodial protrusions from their apical surfaces that reached around and out of the wound margin, to form a tight seal ( Figure 5 D; Movies S4 and S5 ). These dynamic lamellipodia remained in a ring formation around the closing wound edge, sealing off the wound from the body cavity of the animal until reepithelialization was complete. Throughout this period, FBCs within the vicinity of the wound produced extensive blebs as if jostling to become more firmly wedged into the wound gap and form an effective plug ( Figure 5 E; Movie S2 , second movie). Interestingly, this plugging of the wound may come with some cost; since expressing dominant-negative Zipper specifically in FBCs to prevent their recruitment to wounds (see earlier) resulted in significantly faster wound reepithelialization ( Figure S4 ). This suggests that the presence of FBCs at the wound site may partially physically obstruct epithelial closure.

Given our finding that FBCs are motile and rapidly migrate to wounds, next we wanted to investigate what local functions they might play during wound healing. Efficient wound repair requires the clearance of wound debris from the wound site, which is known to be, in part, orchestrated by hemocytes through phagocytosis (). Interestingly, we noticed that, when we ablated hemocytes, the majority of cellular debris at the wound (visualized as bright Histone-RFP-labeled nuclei of damaged epithelial cells) was swept aside by the incoming FBCs ( Figures 4 B and 4C; Movie S9 ). In the presence of hemocytes, this clearance of cell debris away from the wound site by FBCs also occurred, albeit to a lesser extent, and was accompanied by engulfment of the debris by hemocytes ( Movie S2 ). We also observed phagocytic cup formation and subsequent engulfment of debris at the wound site by FBCs in 35% of small and 75% of large wounds, which contained wound-recruited FBCs (n = 17 and 12, respectively, Figure 4 D). Thus FBCs, in concert with hemocytes, appear to play an important local function in clearing cell debris during wound repair: FBCs physically clear the wound site of cell debris by displacing it to the wound periphery, where hemocytes, and to a lesser extent FBCs, take up the debris by phagocytosis ( Figure 4 E).

Previous studies have shown that hemocytes, the equivalent of macrophages in Drosophila, are actively drawn to wound sites in embryos and pupae (), much as innate immune cells are drawn to wounds in vertebrates (). Interestingly, larval hemocytes have been shown to collaborate with and even communicate with FBCs through cytokine release in response to bacterial infections, leading to a scenario whereby hemocytes phagocytose bacteria while FBCs produce AMPs systemically, but these AMP levels are significantly reduced in the absence of hemocytes (). To investigate whether hemocytes and FBCs interact with one another during wound healing, we wounded pupae in which both hemocytes and FBCs were labeled with cytosolic GFP and nuclear RFP. Both cell types migrated at approximately the same speed, 2.5–3.5 μm/min ( Movie S7 Figures 4 A and 2 D;), although in general, due to their proximity to the wound and increased numbers, hemocytes often arrived before FBCs ( Figure 4 A). We see the same if these two lineages are labeled with complementary cytosolic GFP and mCherry tags ( Figure S3 and Movie S8 ). Interestingly, most hemocytes were swept aside as the first FBC approached the wound ( Movies S7 and S8 ). To test whether FBC recruitment might be dependent on the presence of hemocytes at the wound, we genetically ablated hemocytes through lineage-specific expression of apoptosis-inducing Reaper for 16 hr before wounding. This loss of hemocytes did not significantly alter the frequency of FBC recruitment to wounds (70% and 60% of wounds with or without hemocyte ablation, n = 11 and 9, respectively; Figures 4 B and 4C; Movie S9 ), suggesting that FBCs are not drawn to wounds by attractant signals released by hemocytes.

(B and C) Time-lapse sequences of wounded srp-GMA+Ubq>Histone-RFP pupae (FBC in green and outlined; epithelial nuclei in red; colored circles highlight some nuclei of necrotic epithelial cells) expressing srp-Gal4+UAS-Reaper+tubGal80ts for 16 hr before wounding at the restrictive temperature to ablate hemocytes. See also Movie S9

In order to test whether motility of FBCs is indeed actomyosin driven, we expressed a dominant-negative version of Zipper (Myosin II heavy chain) tagged with YFP specifically in FBCs. During early pupal development, FBCs normally undergo an extensive remodeling, characterized by the dissociation of the fat body into single cells followed by their redistribution in the body cavity. This redistribution leads to the translocation of some cells into the anterior head capsule, which has previously been suggested to be driven by abdominal muscular contractions (). Interestingly, we found that expression of dominant-negative Zipper-YFP only in FBCs led to a complete failure in FBC redistribution within the body cavity and translocation into the head ( Figure 3 D). Moreover, when we imaged and tracked these cells in the dorsal abdomen we found that their general motility was strongly reduced ( Figures 3 E and 3F; Movie S6 ). This suggests that the developmental process of FBC redistribution and translocation in pupae is not driven passively by muscular body contractions but is instead an active process driven by actomyosin-dependent migration of FBCs. Similarly, expression of dominant-negative Zipper in FBCs completely blocked their ability to migrate to wounds in the ventral thorax (0% recruitment of FBCs to wounds, n = 72 wounds). Together, these data suggest that pupal FBCs are indeed motile cells, which migrate using an adhesion-independent, actomysin-driven peristaltic mode of motility during both their developmental dispersal and their recruitment to wounds.

Given our observation that Drosophila FBCs can actively migrate, we used live imaging of the actin cytoskeleton to understand the mechanism by which these cells power their migration. Most cells, whether in tissue culture or in vivo within tissues, migrate by adhering to, and crawling over, a substratum, often using actin-rich lamellipodia at their leading edges. By contrast, FBCs are not adherent to any epithelial surface; rather, they reside within the hemolymph ( Figure 1 A and Movie S1 ). To our surprise, live imaging of FBCs expressing GMA (GFP fused to the actin-binding domain of moesin) revealed that these cells were constantly undergoing actin-based contractile waves that initiated from the cortex of the cell center and extended to the rear of the cell, propelling them in the opposite direction (i.e., forward) in a peristaltic fashion. These waves occurred constantly within FBCs in unwounded pupae ( Figure 3 A; Movie S3 , first movie) but upon wounding became highly directed with respect to the wound ( Figures 3 B and 3C; Movie S3 , second movie). Using markers of the actin regulatory proteins, Fimbrin, Ena, and Fascin, we saw no sign of the more standard lamellipodial structures, observed for example in Drosophila macrophages (hemocytes), as they migrate to wounds (), as FBCs “swam” toward the wound ( Movies S4 and S5 ). However, once they had reached the wound, FBCs started to form lamellipodia that extended around the wound margin ( Movies S4 and S5 ).

To test whether the recruitment of FBCs to wounds was driven by true directed migration and not just a random walk or passive fluid flow, we tracked individual cells in wounded and unwounded pupae ( Figure 2 A) and measured the directional persistence of the resulting tracks. Further analysis of these tracks showed an increase in the meandering index and a decrease in the angle of migration, together suggesting that wound-recruited FBCs responded to the wounds with high directional persistence ( Figures 2 B and 2C). The movement of FBCs to wounds is not due to passive flow of hemolymph toward the wound; this possibility has previously been ruled out by bead-tracking experiments following epithelial wounding in pupae where we saw no such flow (). Moreover, we see no hemolymph leakage from wounds since laser wounding generally results in cuticular holes of <0.5 μm in diameter ( Figure S1 D). Next, we measured the speed of FBCs and found that they did not accelerate toward the wound; their meandering index was increased but their speed remained the same as in unwounded pupae until they reached the wound, when they decelerated and stopped ( Figure 2 D and Movie S2 , first movie). Once the wound became fully occupied by one or more FBCs, late-arriving cells appeared unable to gain direct access because this space was occupied by earlier-arriving FBCs, but they often remained in the vicinity and circulated at the periphery ( Movie S2 , first movie; Figure S2 A). Interestingly, both wound-recruited and late-arriving FBCs initially showed an increase in their meandering index ( Figure S2 B), suggesting that both cell populations respond equally to wound attractants.

(A–D) Migration tracks of FBCs (A) and quantification of meandering index (B), angle (C), and speed (D) of FBC migration in c564-Gal4+UAS-GFP+Ubq>Histone-RFP unwounded or wounded pupae (n = 20 and 20); only analyzing cells that passed through a circular area of 25-μm radius from center within 30-min time window. See also Figure S2 . Mean ± SEM. ns, p > 0.05;p < 0.001 (Student's t test).

To investigate the potential functions of FBCs during wound healing, we first studied their location and potential behaviors following tissue injury in pupae, since this developmental stage has proven ideal for live imaging of other wound healing events (). We found that 16-hr-old pupae contain large numbers of giant polyploid, dissociated FBCs that populate the body cavity ( Figure 1 A). To study the behaviors of FBCs following tissue injury by live imaging, we used a laser to induce small epithelial wounds in the ventral thorax of pupae, an area sparsely populated by FBCs ( Movie S1 ). Nuclei were labeled with Histone-red fluorescent protein (RFP; bright red, condensed nuclei mark damaged epithelial cells in the wound area, while dimmer red nuclei mark the surrounding healthy epithelial cells; Figure S1 ) and FBCs were labeled with GFP ( Figures 1 B and 1C). Strikingly, we found that FBCs, previously thought to be immotile, were actually highly dynamic, and migrated rapidly toward wounds. Once at the wound site these cells remained tightly associated with the wound until closure, when they detached and actively migrated away ( Figures 1 B and 1C; Movie S2 , first movie). When we compared small, medium, and large wounds (30–60, 60–90, and 90–120 μm in diameter, respectively; Figures 1 D–1F; Movie S2 , second, third, and fourth movies), we found that the frequency of FBC recruitment to wounds ( Figure 1 G), as well as the number of wound-associated FBCs ( Figure 1 H), positively correlated with the size of the wound: for small wounds, a single FBC generally plugged the wound, whereas in larger wounds up to 5 FBCs approached and associated with the wounded area ( Figures 1 D–1F, 1H, and Movie S2 ). The time of FBC arrival at the wound was variable, depending on their initial distance from the wound; some FBCs arrived after 10 min, with the average arrival time being around 1 hr after wounding, irrespective of wound size ( Figure 1 I). Once FBCs started contacting the wound area, they usually remained associated until reepithelialization was complete, resulting in a longer period of FBC-wound association in larger wounds with longer closure times ( Figure 1 I).

(D–H) Time lapse (D–F) and graphs (G and H) showing how FBCs are drawn to small, medium, and large wounds (30–60 μm, 60–90 μm, and 90–120 μm in diameter; n = 32, 12, and 15, respectively) in c564-Gal4+UAS-GFP+Ubq>Histone-RFP pupae (epithelial nuclei in red; FBCs in green and outlined). See also Movie S2 , second, third, and fourth movies.

(B and C) Schematic (B) and time-lapse (C) images to illustrate FBC migration to a wound (projection, C top; Z plane, B and C bottom) in a c564-Gal4+UAS-GFP+Ubq>Histone-RFP pupa (epithelial nuclei in red; FBCs in green and outlined; asterisk labels wound-associated FBCs; arrowheads indicate wound margins). See also Movie S2 , first movie, and Figure S1

Discussion

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Horsley V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Our data show that FBCs, Drosophila adipocytes, are recruited to wounds in pupae where they have multiple local roles in wound healing. The observation that FBCs are motile cells that actively migrate to wounds is unexpected and has not previously been made for adipocytes in any other organism. However, our findings raise the interesting question as to whether vertebrate adipocytes might also have the capacity to migrate. In that regard, a recent mammalian wound study found that adipocytes repopulate murine wounds, and suggested that some may have migrated from distant sites (). It will be fascinating to discover whether some sub-populations of vertebrate adipocytes are indeed motile and whether they utilize similar migratory strategies to those highlighted in Drosophila FBCs.

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et al. Cortical contractility triggers a stochastic switch to fast amoeboid cell motility. The mode of motility we observe for FBCs moving through the hemolymph to wounds is unusual, since it does not appear to involve the use of standard lamellipodia or blebs, utilized by most known migrating cells as they crawl in an adhesion-dependent fashion over substrates and through a milieu of extracellular matrix. Adhesion-independent migration has recently emerged as an alternative migration mode that has now been described for several other types of cells, including ameba, lymphocytes, and some cancer cells (). Four models have been proposed for adhesion-independent migration: force transmission driven by “chimneying” between two opposing substrate faces, the intercalation of lateral cell protrusions with gaps in the substrate, non-specific friction between cell and substrate, and swimming by noncyclic cell shape deformations (). Only the last of these is entirely independent of any interactions with (or close proximity to) a solid substrate and hence best describes our observation of the migration of FBCs through hemolymph to wounds, since we do not see significant interactions of these cells with any substrate or other cells as they migrate. Similar to FBCs, several other cell types have been reported to migrate by swimming, when they are required to move through viscous fluid: amebae and neutrophils have been shown to swim when in viscous solution () and lymphocytes are known to migrate using contraction waves when in suspension (). However, the exact mechanism by which these swimming cells generate internal forces and how these forces are transduced to the extracellular environment to generate forward movement is still unknown. A recent study has shed some light on how internal forces are generated during another type of adhesion-independent migration; it showed that the migration of Walker carcinoma cells in confinement is driven by cyclical rearward flow of cortical actin that is coupled to the substrate through friction. This migration depends on the contractility of cortical actin at the rear of the cells (). Moreover, rearward flow of cortical actin has also been described for the oscillatory behavior of detached cells and cell fragments (), as well as for the stable-bleb cell migration of zebrafish germ layer progenitor cells (). This is strikingly similar to the rearward peristaltic actin waves we observe in FBCs migrating to wounds, suggesting that this could be the mechanism of force generation in FBCs also.

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Paluch E.K. Force transmission during adhesion-independent migration. However, it still remains unclear how such an intracellular force might be transduced to the extracellular environment to drive forward movement of FBCs. It has previously been presumed that, while swimming works for large multicellular organisms, it cannot operate at the microscopic cell level, where viscous forces are many orders of magnitude higher than inertial forces (i.e., at low Reynold's number;) and hence geometrically reciprocal cell shape changes may not generate propulsive forces (). However, this view has been challenged and may only be true for simple Newtonian fluids, like water (), which the hemolymph that FBCs swim through is clearly not. Moreover, swimming in a non-Newtonian fluid is thought to be possible if the cell shape changes of migrating cells are nonreciprocal, which might be true for FBCs migrating to wounds. It is also possible that FBCs, in addition to swimming, make use of other mechanisms to migrate. The hemolymph is relatively densely packed with cells including hemocytes and other FBCs (see Figure 1 A), and FBCs are adjacent to the epithelium and muscle, depending on the location in the body. Although we have not observed contacts, it is possible that the close proximity of FBCs with other cells and tissues en route to a wound might enable them to occasionally generate additional frictional forces like the ones reported for non-adherent Walker cells migrating in a confined microfluidics channel (), which may also contribute to their swimming motility.

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Gallo R.L. Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Our study shows that FBCs play multiple local roles in driving wound repair and preventing wound infection. We wonder whether some of these local functions might also partially extrapolate to the vertebrate wound scenario. Drosophila FBCs have long been known to systemically produce a variety of AMPs following infection () and our study reveals that, during wound infection, FBCs migrate to wounds to release AMPs locally. A recent study has shown that mouse adipocytes are able to produce AMPs following bacterial skin infections (). Hence, it would be interesting to examine whether mammalian adipocytes, like Drosophila FBCs, play a local role during wound healing in delivering AMPs to fight wound infection.

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Geissmann F. Macrophage-derived upd3 cytokine causes impaired glucose homeostasis and reduced lifespan in Drosophila fed a lipid-rich diet. Given our finding that hemocytes and FBCs collaborate during the wound repair process to clear cell debris and fight infection, it is tempting to speculate that these two cell types communicate with each other during vertebrate wound healing also. Interestingly, in recent years several mammalian studies have uncovered complex interactions between adipocytes and macrophages in white adipose tissue (WAT), with important implications for tissue regeneration and disease (). One example is obesity-induced inflammation and insulin resistance, where, upon overnutrition, the adipocytes in visceral WAT are thought to release chemokines to stimulate macrophage recruitment into fat tissue, leading to smoldering inflammation and subsequently insulin resistance (). This is believed to be due to proinflammatory macrophages releasing cytokines that attenuate insulin signaling in various cell types, including adipocytes (). In support of these mammalian reports, a recent study in the fly showed that animals fed a lipid-rich diet display reduced insulin sensitivity and lifespan, and both of these effects are mediated by hemocytes ().

Thus interactions between adipocytes and immune cells appear to be key in many diseases, including type 2 diabetes, and we believe that important insights into these links may be provided by future studies of the functional relationship and communication between FBCs and hemocytes during pupal wound repair in flies.

Our studies in Drosophila pupae flag up novel behaviors and functions for FBCs in Drosophila and open up genetic opportunities to further our understanding of the important roles played by adipocytes in repair and regeneration.