Lymphatic vessels are present in most organs of the vertebrate body and serve in the uptake of macromolecules and excess fluid from interstitial space. Until recently both the eye and the brain had been considered to be immune privileged and devoid of lymphatics. This notion has been challenged by the discovery of the Schlemm’s canal, a lymphatic-like vessel in the eye (Aspelund et al., 2014; Park et al., 2014; Ramos et al., 2007; Thomson et al., 2014), and by the identification of a lymphatic vascular network in the meningeal dura mater of the mouse brain (Aspelund et al., 2015; Louveau et al., 2015). While the concept of paravascular solute clearance from the brain into peripheral lymphatics had been proposed in previous decades (Cserr and Ostrach, 1974; Yamada et al., 1991), recent research into a sleep-dependent exchange between cerebral interstitial fluid and cerebrospinal fluid via astro-glial channels has revived interest in the concept. Coined the ‘glymphatic’ mechanism, this process would side-step the need for solutes in the brain to pass through the blood-brain endothelial barrier (Iliff et al., 2012; Xie et al., 2013). However, precisely how the cerebral interstitium and cerebrospinal fluid interconnect, as well as if and how the dural lymph vasculature participates in these perivascular clearance mechanisms remains enigmatic. Knowledge of how the energy intensive brain clears macromolecules and waste from its interstitial space will be critical to better understand not only the normal regulation of brain physiology and behaviour but also how pathological conditions such as neurodegenerative diseases may be affected by improper clearance mechanisms (Iliff et al., 2015; Tarasoff-Conway et al., 2015; Wostyn et al., 2015). Moreover, although this system requires a complex interaction among blood endothelium, lymphatic structures and the brain, neither the developmental nor the evolutionary ontology of this system has been described.

The lymphatic vasculature of the peripheral nervous system consists of capillaries, which allow uptake of substances through specialized junctions, and larger collecting vessels, which transport the content of the vessel in a unidirectional manner towards the jugular vein, where lymph is finally funnelled into the vena cava. Lymphatic endothelial cells (LECs) have a molecular signature distinct from blood endothelial cells (BECs), including the expression of Prox1, Lyve1, and Podoplanin. Zebrafish transgenic reporter lines for prox1a, flt4 (van Impel et al., 2014) and lyve1 (Okuda et al., 2012) have allowed in vivo imaging of lymphangiogenic events in the trunk and the facial region of early embryos. There is a significant degree of conservation for lymphatic development on the genetic level between fish and mice, with mutants in the ccbe1/vegfc/vegfr3 signalling axis all resulting in phenotypes lacking lymphatic structures (Hogan et al., 2009a, 2009b; Bos et al., 2011; Karkkainen et al., 2004; Le Guen et al., 2014). In addition, both zebrafish prox1a maternal-zygotic mutants and Prox1 mutant mice show lymphatic phenotypes (Wigle and Oliver, 1999; Koltowska et al., 2015). Whether zebrafish have brain lymphatics like mice has not been reported.

Here, we examine the development of brain lymphatics in the zebrafish embryo and find a pool of cells on the surface of the brain that display hallmark characteristics of LECs and yet do not form an endothelial sheet. These cells are positive for prox1a, lyve1, and vegfr3 but express only low levels of the blood endothelial marker kdr-like. During later stages of development these cells populate the meningeal structures of the larval and adult brain. Functional assays based on tracer injections show that these cells take up exogenous substances similar to macrophages, and we provide evidence for an endocytic mechanism dependent on the mannose receptor (MR, Cluster of Differentiation 206, CD206) (Martinez-Pomares, 2012). However, unlike macrophages these cells are not of myelopoietic origin, suggesting that they constitute a unique cell type. The identification of brain lymphatic endothelial cells in an optically and experimentally tractable animal model complements existing efforts in the mouse to better understand the cellular components of a brain lymphatic system, their development, and their functionality.

While investigating the possible presence of lymphatic vessels in the embryonic and adult zebrafish brain, we have identified a unique population of cells that exhibit many hallmark characteristics of LECs and which we named brain lymphatic endothelial cells, or BLECs. These cells appear to be only loosely connected and do not form endothelial monolayers. Their ability to take up exogenous substances is reminiscent of macrophage and dendritic cell activity (Steinman et al., 1976; Platt et al., 2010), while their proximity to blood vessels suggest a possible perivascular cell lineage (Sweeney et al., 2016). However, there are a number of criteria which makes these cells unlikely to belong to either of these latter lineages.

BLECs sprout from a specific vessel, the CVP, at 56hpf. Concomitant with sprouting, they downregulate the BEC marker kdr-l while, conversely, flt4 becomes up-regulated. This expression profile is common for lymphatic ECs (Bussmann et al., 2010). Consistent with this notion, the LEC markers prox1a (van Impel et al., 2014; Koltowska et al., 2015) and lyve1 (Okuda et al., 2012) are up-regulated in these cells as soon as they sprout from the CVP. Since lymphangiogenesis is exquisitely sensitive to Vegfc/Vegfr3 signaling (Hogan et al., 2009b; Karkkainen et al., 2004), the complete loss of these LECs in the brain of ccbe1 (Figure 2G–K) and vegfc mutants (data not shown) also argues for a lymphatic lineage (Hogan et al., 2009a). The sensitivity to Vegfc signaling, the expression of vascular markers, and the direct endothelial origin from the CVP all exclude pericytes or other non-vascular perivascular cells. Ultrastructural analysis further argues against pericytes, as basement membranes shared with ECs were not found in the case of BLECs.

This newly identified population of cells therefore shares many features with LECs while never aggregating to form lumenized vessels (Figure 5G–K). In this respect BLECs are different from venous-derived parachordal lymphangioblasts in the zebrafish embryonic trunk, which experience an intermediate, single cell phase but then go on to form the thoracic duct and the dorsal longitudinal lymphatic vessel (Hogan et al., 2009a; Padberg et al., 2017). There are few other examples of endothelial cells not belonging to a contiguous epithelium, most notably liver sinusoidal endothelial cells (LSCEs) (Braet and Wisse, 2002).

Intriguingly, the high capacity endocytosis and degradation of extracellular material observed in LSCEs is also dependent on the mannose receptor (MR), Mrc1, in mice (Elvevold et al., 2008). High Mrc1 expression is also a distinguishing feature of perivascular macrophages (pvMΦ) (Elvevold et al., 2008), which strongly resemble BLECs in their morphology and close localization to blood vessels in the murine CNS. However, unlike BLECs, pvMΦ derive from hematopoietic precursors (Goldmann et al., 2016), and sprouting of macrophages directly from an endothelial source has not been described (Epelman et al., 2014). In addition, we monitored CNS resident macrophages by their expression of the reliable zebrafish macrophage marker mpeg1 (Ellett et al., 2011), and this expression was extremely low in lyve1 expressing BLECs (Figure 3B) but strong and robust in adjacent tissue resident macrophages (Figure 3A’). Furthermore, BLECs remained intact when the myelopoietic lineage was deleted (Figure 3). In mice, macrophages express Lyve1 during early embryonic stages but expression does not persist in the adult (Bos et al., 2011), while we observe lyve1 expression in BLECs of adult fish (data not shown). Hence, although BLECs resemble pvMΦ in morphology and function we could not find further supporting evidence for these cells to be part of the macrophage lineage. Even though the expression of flt4 and prox1a and the virtual absence of mpeg1 expression is a strong indicator for a lymphatic fate, marker expression in and of itself has to be considered with some caution when categorizing cells. Therefore, we consider the direct derivation from an endothelial structure (CVP, Figure 1B–C) and the presence of BLECs in pU.1 morphants to be the strongest evidence that BLECs indeed belong to an endothelial and not to a macrophage lineage.

Further, we followed the distribution of BLECs over time, through larval and adult stages. BLECs often are in close proximity to blood vessels, possibly also suggesting a functional interconnectivity. Indeed, BLECs were recently found to express pro-angiogenic factors such as vegfab and egfl7 (Bower et al., 2017; Venero Galanternik et al., 2017) required by blood vessels in the brain. Furthermore, genetic and laser-ablation mediated depletion of BLECs results in a concomitant reduction of blood vessels, and recovery of BLECs precedes regeneration of blood vessels in the affected areas during larval stages (Bower et al., 2017). Anatomically, BLECs cover many, but not all, surfaces of the brain, and display distinct morphological characteristics depending on which region of the brain they occupy. For example, the dorsal surface of the adult telencephalon completely lacks BLECs despite having many blood vessels deeper in the brain. This likely reflects the everted brain development in teleosts, the consequences of which make the dorsal telencephalon a ventricular surface. Functional studies in these late stages after skull formation are difficult but will be required to examine whether morphological differences reflect possible functional distinctions across brain regions.

A particularly intriguing feature of BLECs in the optic tectum and other parts of the brain is the presence of many large, spherical and electron dense vacuoles or granules in adult fish (Figures 5G,H and 6). These are likely a direct indication of endocytic or phagocytic activity of BLECs and are reminiscent of acidic vacuoles seen in platelets (Hernandez-Ruiz et al., 2007) but also secretory granules seen in mast cells (Wernersson and Pejler, 2014). The presence of large inclusions suggests that BLECs are possibly similar to Mato-cells in rodents (Mato et al., 1984), which reside in the perivascular space between the basal lamina of blood vessels and the glia limitans of the neuropil, the so-called Virchow-Robin space. Due to the high content of fluorescent, endocytic granules, Mato cells are also referred to as fluorescent granular perithelial cells (FGP) cells (Mato et al., 1985). However, Mato/FGP cells are typically described to contain a more heterogeneous population of randomly clustered, electron dense and light inclusions that often become foamy and darker with age and under pathological conditions (Mato et al., 2009, Mato et al., 1997). In some images (Figure 6A) we observe cells with heterogeneous inclusions typical of FGP cells, but which appear distinct from BLEC cells. We therefore favor the notion that BLECs and FGP cells are distinct cell populations.

The presence of large spherical vacuoles caused us to investigate whether BLECs can clear macromolecules during embryonic stages until 5dpf. We found that BLECs rapidly take up exogenous molecules into small cytoplasmic vesicles. These vesicles also readily accumulate the pH-sensitive dye pHr, suggesting intracellular localization to low pH lysosomes (Figure 7H). In addition, our photoconversion data using Kaede protein suggest a dynamic process of uptake and clearance of internalized cargo (Figure 7I–J). Taken together, we conclude that BLECs remove extracellular molecules by continuous internalization and subsequent degradation in lysosomes. As mentioned earlier, this process resembles the activity of macrophages or dendritic cells, which selectively internalize substances through receptor-mediated endocytosis (RME) (Roche and Furuta, 2015). Indeed, the selectivity for small and intermediate size macromolecules indicates specific uptake through RME in BLECs (Figure 7C–E), likely involving the MR, which is expressed in BLECs but was not detected in neighboring blood vessels (Figure 8—figure supplement 2) (Taylor et al., 2005). After cargo binding and internalization, the MR unloads bound cargo for degradation in lysosomes. Since the MR continuously recycles between the cytosol and the PM, it enables rapid uptake of exogenous molecules (Martinez-Pomares, 2012). BLECs show hallmarks of MR-mediated uptake including the endocytosis of fluorescently labelled dextran (Figure 7D) and sensitivity to the inhibition of dynamin, a small GTPase essential for RME in eukaryotic cells (Martinez-Pomares, 2012; McMahon and Boucrot, 2011) (Figure 8C). Finally, RME is a saturable process and we show complete inhibition of pHr uptake after administration of the competitive agonist mannan (Sallusto et al., 1995) (Figure 8E), but not after administration of galactose (Figure 8—figure supplement 2). Therefore, we suggest MR-dependent RME as a major entry portal for glycoproteins and polysaccharides into BLECs. To our knowledge, this is the first study to describe the intracellular uptake and clearance of macromolecules by individual LECs.

In mice, MR functions in the maintenance of macromolecule homeostasis in the blood and MR loss-of-function results in reduced clearance of Lutropin (LH) (Mi et al., 2002), denatured collagens (Malovic et al., 2007) and serum glycoproteins including most lysosomal hydrolases (Lee et al., 2002). The latter are upregulated during inflammation and their MR-mediated removal may therefore prevent excess tissue damage. Although not addressed experimentally, MR expressing LSCEs likely represent the cell type involved in the removal of serum glycoproteins, analogous to the clearance of collagens by LSCEs (Malovic et al., 2007). An intriguing hypothesis is that BLECs may play a functionally similar role in the maintenance of cerebrospinal fluid (CSF) homeostasis through MR-mediated removal of potentially noxious molecules such as lysosomal enzymes. Indeed tracer injected into the CSF rapidly accumulates in BLECs (Figure 7—figure supplement 3, Video 5). Such a mechanism may be important in disease involving increased deposition of lysosomal enzymes into the CSF, which in humans is a hallmark of bacterial meningitis (Beratis et al., 1997). MR-mediated endocytosis by macrophages and dendritic cells has also been involved with pathogen recognition and antigen presentation during adaptive immunity. However, although surface glycoproteins from various pathogens internalize through MR, the analysis of MR null mice did not reveal increased sensitivity to infection (Taylor et al., 2005). Further, our data suggest that brain resident mpeg1 positive macrophages do not express mrc1a, which was restricted to BLECs in the meninges (Figure 8—figure supplement 1) and we did not observe apparent tracer uptake in cells other than BLECs in their immediate surroundings. Similarly, MR was not found to be involved in FITC uptake by zebrafish kidney phagocytes (Hohn et al., 2009). Therefore, it is plausible that BLECs in zebrafish may exert functional roles in macromolecule uptake and pathogen recognition normally carried out by macrophages and dendritic cells in mammals.

Our data show that even in the presence of mannan, IgG-647 can adhere to the cell surface of BLECs (Figure 8E,F,H,I). This may be explained by the involvement of a second receptor with similar ligand binding properties as the MR that requires binding to the MR for internalization. For instance, macrophages, sinusoidal ECs and human skin LECs express the stabilin class of scavenger receptors for endocytosis and degradation of various non-self antigens (Kzhyshkowska et al., 2006), and stabilin1 is expressed in lymphatic endothelial cells in zebrafish (Hogan et al., 2009a). Moreover, another PRR, Toll-like receptor 2 (TLR2) forms a complex with MR on the cell surface in response to pathogen interaction in alveolar macrophages (Tachado et al., 2007). Interestingly, human LECs isolated from different tissues differentially express various TLRs including TLR2 (Garrafa et al., 2011).

Another remaining question is whether BLECs are involved in phagocytosis of invading pathogens. The large vacuoles in BLECs, which we observed only in adult fish but not in larval stages, may also represent phagosomes rather than endocytic vesicles (Figure 5G). Interestingly, phagocytosis has been shown to be independent of MR activity in mouse macrophages (Lee et al., 2003). Therefore, certainty about the receptors involved in macromolecule uptake in BLECs as well as in how far these cells assume the classical role of macrophages or dendritic cells awaits further investigation.

In future studies, it will also be important to determine whether zebrafish BLECs participate in glymphatic-paravascular clearance of solutes and waste products from the energy intensive brain, as has been a proposed function for murine meningeal lymphatics (Aspelund et al., 2015; Louveau et al., 2015). In rodents, multiple routes of solute clearance from the brain have been proposed to run either along arterial routes in paravascular compartments (Rennels et al., 1985; Iliff et al., 2013) or more specifically along peri-vascular basement membranes of capillaries and arteries (Weller et al., 2008). It remains to be elucidated how these routes are interconnected, and how they interact with the lymphatic vasculature of the rodent meninges (Aspelund et al., 2015; Louveau et al., 2015). If BLECs are functionally related to rodent LECs, the optical transparency of the zebrafish promises to allow for direct observation of these processes in vivo. Moreover, there is growing evidence that dysfunction of these clearance mechanisms may trigger or exacerbate neurodegenerative disease. For example, amyloid beta (Aβ) has been shown to aggregate and move along basement membranes of capillaries and arteries in the brain (Weller et al., 2008), and Cerebral Amyloid Angiopathy can occur when this pathway is disrupted (Preston et al., 2003; Weller et al., 2009). Other risk factors for Alzheimer’s Disease and dementia, including the cholesterol transporter isoform ApoE4 (Liu et al., 2013), age-related deterioration of arterial integrity and disruption of elasticity (Weller et al., 2009), or changes to CSF production (Silverberg et al., 2001, Silverberg et al., 2003), have been implicated in the disruption of perivascular clearance, specifically including Aβ clearance (Hawkes et al., 2012). Dysfunctional solute clearance from the CSF surrounding the optic nerve has also been suggested to alter interocular pressure contributing to the onset of glaucoma (Wostyn et al., 2015). Interestingly, sleep and anesthesia also directly impact clearance by opening paravascular compartments and increasing tracer influx form the CSF into the brain (Xie et al., 2013), indicating that sleep disruption may play a critical role in the development and exacerbation of neurodegenrative pathologies (Musiek and Holtzman, 2016). How zebrafish brain states and aging influence BLEC macromolecule uptake will be important questions for future studies, paving the way for small molecule screens for regulators of this clinically relevant process (Rihel et al., 2010).

We demonstrate here an endothelial cell population that emerges from a venous blood vessel in the zebrafish embryonic brain and exhibits many critical hallmarks of lymphatic identity, such as prox1a, lyve1 and vegfr3 expression. These cells share properties with, but appear to be distinct from, macrophages and combine structural and molecular features of endothelial cells with functional characteristics of macrophages and microglial cells. Intriguingly, these brain lymphatic endothelial cells persist through larval and adult stages and are situated in the adult meninges, in close proximity to blood vessels. A comparison of zebrafish BLECs with murine meningeal LECs should provide interesting features of conserved and divergent molecular signatures, cellular functions and physiological relevance. As the mammalian glymphatic-paravascular clearance mechanism has recently received significant attention and recognition as a vascular entity involved in physiological and pathophysiological conditions such as behavior, sleep, waste removal, Alzheimer’s disease, and others, the identification of BLECs provides an additional system to experimentally address how lymphatic endothelial cells contribute to brain function.

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Author details

1. Max van Lessen

   1. Institute of Cardiovascular Organogenesis and Regeneration, WWU Münster, Münster, Germany
   2. Faculty of Medicine, WWU Münster, Münster, Germany
   3. Cells-in-Motion Cluster of Excellence, WWU Münster, Münster, Germany

   Contribution

   MvL, Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

2. Shannon Shibata-Germanos

   Department of Cell and Developmental Biology, University College London, London, United Kingdom

   Contribution

   SS-G, Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-4250-7497

3. Andreas van Impel

   1. Institute of Cardiovascular Organogenesis and Regeneration, WWU Münster, Münster, Germany
   2. Faculty of Medicine, WWU Münster, Münster, Germany
   3. Cells-in-Motion Cluster of Excellence, WWU Münster, Münster, Germany

   Contribution

   AvI, Formal analysis, Investigation, Visualization, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-4737-3547

4. Thomas A Hawkins

   Department of Cell and Developmental Biology, University College London, London, United Kingdom

   Contribution

   TAH, Conceptualization, Formal analysis, Investigation, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

5. Jason Rihel

   Department of Cell and Developmental Biology, University College London, London, United Kingdom

   Contribution

   JR, Conceptualization, Supervision, Funding acquisition, Investigation, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-4067-2066

6. Stefan Schulte-Merker

   1. Institute of Cardiovascular Organogenesis and Regeneration, WWU Münster, Münster, Germany
   2. Faculty of Medicine, WWU Münster, Münster, Germany
   3. Cells-in-Motion Cluster of Excellence, WWU Münster, Münster, Germany

   Contribution

   SS-M, Conceptualization, Formal analysis, Supervision, Funding acquisition, Validation, Methodology, Writing—original draft, Writing—review and editing

   For correspondence

   schultes@ukmuenster.de

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-3617-8807

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