Blood and immune cells derive from hematopoietic stem cells (HSCs) that were classically thought to be a homogeneous population generating a defined hierarchy of progenitors (Seita and Weissman, 2010; Yokota, 2019). Recent studies reveal that mammalian HSCs and progenitor populations have dynamic cell surface marker phenotype and proliferative ability and varying in vivo differentiation potential in response to external cues (Ema et al., 2014; Crisan and Dzierzak, 2016; Haas et al., 2018). Studying aspects of intrapopulation heterogeneity and its implication in conditions of immune stress will improve our understanding of native and emergency hematopoiesis. Owing to the conserved signaling pathways and transcriptional factors that regulate hematopoiesis, Drosophila melanogaster has emerged as a powerful model to study blood cell development and the innate cellular immune response (Banerjee et al., 2019).

Like vertebrates, Drosophila hematopoiesis occurs in spatially and temporally distinct phases (Tepass et al., 1994; Evans et al., 2003; Holz et al., 2003; Krzemien et al., 2010). The embryonic wave of hematopoiesis primarily gives rise to macrophage-like phagocytic circulating and sessile hemocytes. A second wave of hematopoiesis takes place in a specialized larval hematopoietic organ, the lymph gland, located dorsally along the anterior cardiac tube (Lanot et al., 2001; Mandal et al., 2004; Grigorian and Hartenstein, 2013; Rugendorff et al., 1994). In third instar larvae, the mature lymph gland is composed of a pair of anterior or primary lobes in segment T3/A1, followed by two to three pairs of lobes referred to as the secondary, tertiary, and quaternary lobes – collectively called the posterior lobes (Banerjee et al., 2019). Based on morphology and molecular marker analysis, primary lobes are compartmentalized into distinct zones. The posterior signaling center (PSC), a small group of cells at the posterior tip of the primary lobes, specifically expresses Antennapedia (Antp) and acts as a signaling niche. The medullary zone (MZ), close to the cardiac tube, consists of multi-potent progenitors and is identified by expression of Drosophila E-cadherin (DE-cad), the complement-like protein Tep4 and reporters for the JAK-STAT pathway receptor Domeless (Dome). The peripheral cortical zone (CZ) consists of differentiated blood cells that are mainly phagocytic plasmatocytes identified by Nimrod C1 (NimC1/P1) expression and a few crystal cells that express Lozenge (Lz) and the prophenoloxidases (ProPO). In addition, intermediate progenitors (IZ) reside in the region between the MZ and the CZ; they are identified by the expression of dome reporter and early differentiation markers like Hemolectin (Hml) or Peroxidasin (Pxn) but lack the expression of late markers like P1 for plasmatocytes and Lz for crystal cells (Banerjee et al., 2019; Jung et al., 2005).

The presence of blood cell progenitors in the anterior lobes prompted intense investigations to unravel how their fate is controlled. During normal development, anterior progenitor (AP) proliferation, quiescence, and differentiation are finely orchestrated by the interplay of various pathways. Notably AP maintenance is controlled by activation of the Hedgehog and ADGF-A pathways in the MZ in response to signaling from the PSC and the CZ respectively (Mandal et al., 2007; Baldeosingh et al., 2018; Mondal et al., 2011). Moreover, within the MZ, reactive oxygen species (ROS) levels, Wingless signaling, and Collier expression regulate AP differentiation (Owusu-Ansah and Banerjee, 2009; Sinenko et al., 2009; Benmimoun et al., 2015). Besides, AP fate is controlled by systemic cues and external stresses such as immune challenge (Krzemien et al., 2010; Khadilkar et al., 2017b). In particular, deposition of egg from the parasitoid wasp Leptopilina boulardi (L. boulardi) in the hemocoel triggers AP differentiation into lamellocytes and premature histolysis of the primary lobes (Lanot et al., 2001; Crozatier et al., 2004; Louradour et al., 2017; Benmimoun et al., 2015; Bazzi et al., 2018; Letourneau et al., 2016; Small et al., 2014). ROS-mediated activation of EGFR and Toll/NF-kB signaling pathways in the PSC and the consecutive downregulation of the JAK-STAT pathway in the AP are essential for this cellular immune response (Makki et al., 2010; Louradour et al., 2017).

In contrast with the anterior lobes, little is known about the posterior progenitors (PP) present in the posterior lobes (Banerjee et al., 2019). The general view is that these lobes essentially harbor progenitors as initially suggested by the higher expression of DE-cadherin and the lack of expression of mature blood cell markers (Jung et al., 2005). Yet only few studies on progenitor differentiation in the primary lobe report on phenotypes in the secondary lobes (Owusu-Ansah and Banerjee, 2009; Dragojlovic-Munther and Martinez-Agosto, 2013; Khadilkar et al., 2017b; Hao and Jin, 2017; Zhang and Cadigan, 2017; Kulkarni et al., 2011; Benmimoun et al., 2015). These studies revealed that posterior lobes could also differentiate in genetic contexts where there is extensive premature differentiation in primary lobes; however, a thorough analysis of the posterior lymph gland lobes is lacking. In addition, depletion of asrij, arf1, or garz and overexpression of arf1GAP, all show more severe phenotypes of hyperproliferation and premature differentiation in the posterior lobes compared to the primary lobes (Kulkarni et al., 2011; Khadilkar et al., 2014). On the other hand, Stat92E mutation causes premature progenitor differentiation in the primary lobes but not in the posterior lobes (Krzemień et al., 2007), suggesting important differences in regulation and function of these lobes as well as inherent differences within the progenitor pool. Along that line, a recent single-cell RNA sequencing analysis of the lymph gland has identified novel hemocyte sub-populations and suggests a higher degree of blood cell progenitor heterogeneity than previously thought (Cho et al., 2020). However, the posterior lobes were excluded from this study and positional information is not retained in such single-cell sequencing analysis. A systematic mapping of lymph gland progenitors in vivo is not available, and we thus lack detailed lobe-wise information about these progenitors. The small size and contiguous nature of the Drosophila hematopoietic organ allows simultaneous comprehensive assessment of progenitors across lobes, which is essential for understanding the dynamics of progenitor heterogeneity and function in response to local and systemic cues. Such analysis is currently not feasible in vertebrate hematopoiesis. Here we combined in situ expression analysis of the entire lymph gland with differential RNA sequencing analysis of the anterior and the posterior lobes to map expression of known blood cell markers and to identify new progenitor markers. Furthermore, by assessing the response to immune challenge, we reveal the functional heterogeneity of the lymph gland progenitors and we propose that differential regulation of the JAK-STAT pathway underlies the maintenance of PP in response to wasp infestation.

The Drosophila lymph gland has been used as a powerful system to study blood cell progenitor maintenance. However, intra-population heterogeneity has not been explored previously. Here we introduce the lymph gland as a model to analyze progenitor heterogeneity at the level of the complete hematopoietic organ by phenotypic marker expression, proliferative capacity, and differentiation potential. We show that posterior lobes acquire cells during the third instar stage of development. The exponential increase in the size of the posterior lobes is accompanied by increased cell proliferation and mitotic activity from the mid-third instar to the wandering larval stages. At the wandering larval stage posterior lobes consist of a significant population of progenitors and are essentially devoid of differentiated cells. PP express progenitor markers like Tep4, dome, DE-cad in the secondary lobes and in some cells of the tertiary lobe but very few cells expressing differentiation markers such as Pxn, P1/NimC1, or ProPO are present. Furthermore, while most cells of the posterior lobes express low levels of col like the APs, part of the tertiary lobes express high levels of col, like the PSC in the anterior lobes. However, we did not observe expression of other PSC markers such as Antp or hh, suggesting that there is no clear homologue of the PSC/niche in these lobes. While several autonomous factors and local signals emanating from the PSC have been implicated in progenitor maintenance in the anterior lobes (Banerjee et al., 2019), how progenitor fate is maintained in the posterior lobes remains largely unknown and certainly deserves further investigation. The identification of genes overexpressed in the PP, such as the transcription factors Apt or the ligand Net-B, paves the way for such investigations.

AP are responsive to systemic cues/long range signals present in the hemolymph. For instance, they are sensitive to nutrient deprivation and olfactory cues, which regulate specific signaling pathways in the anterior lobes under physiological conditions (Benmimoun et al., 2012; Shim et al., 2012; Tokusumi et al., 2012; Shim et al., 2013). Olfactory-immune crosstalk also helps in priming larvae to respond rapidly in conditions of immune stress (Madhwal et al., 2020). It would be all the more interesting to study whether the same processes operate in PP as we revealed clear differences between AP and PP response to systemic cues elicited by immune challenges. Our finding that 5-HT1B and 5-HT1A, which code for serotonin receptors, are expressed at higher levels in the posterior lobes suggests that progenitor fate or function could be controlled by serotonin circulating through the hemolymph or produced by neighboring cells. Indeed, besides its function as a neurotransmitter, serotonin acts as a peripheral hormone and has an immunomodulatory effect on blood cells (Herr et al., 2017). Notably, mice deficient for the serotonin receptor 5-HT2B show altered bone marrow composition, with increased granulocyte precursors and reduced immature endothelial precursors (Launay et al., 2012). Moreover, phagocytosis is severely impaired in Drosophila mutants for serotonin receptors 5-HT1B and 5-HT2B (Qi et al., 2016).

Although our transcriptome analysis revealed a strong over-representation of genes associated with ECM organization (such as the laminins LanB1/B2/A, Collagen 4A1, Viking, Tiggrin, Glutactin, or Papilin) among those overexpressed in the primary lobes, the HSPG Dlp and the ECM receptor Dg were overexpressed in the PP. Dlp was shown to regulate PSC size by regulating the response to the Decapentaplegic (Dpp) signaling pathway (Pennetier et al., 2012), but its function in the prohemocytes is unknown. Dg binds ECM proteins like Perlecan, whose mutation causes reduced lymph gland growth and premature differentiation of the AP in the primary lobes (Grigorian et al., 2013). Similarly, the ECM protein Tiggrin was found to control the progression of intermediate progenitors to mature plasmatocytes (Zhang and Cadigan, 2017). Grigorian et al., 2011 also suggested that hemocytes digest only a small part of the ECM to facilitate their dispersal and most of the ECM is left intact during metamorphosis. Systemic as well as local signals regulating ECM secretion and adhesiveness play an important role in vertebrate bone marrow to regulate blood cell quiescence, maintenance, or egress (Klamer and Voermans, 2014; Gattazzo et al., 2014; Zhang et al., 2019; Khadilkar et al., 2020). However, in-depth analysis of the widely dispersed vertebrate hematopoietic compartment is technically challenging. A deeper understanding of the differential expression of ECM components in the Drosophila lymph gland and how they regulate signaling in and maintenance of progenitors could reveal evolutionary conserved mechanisms that help understand bone marrow hematopoiesis.

Our results bring new insights into the origin and fate of the posterior lobes during development. Posterior lobes flank the dorsal vessel in the abdominal segments (Jung et al., 2005; Banerjee et al., 2019); however, there is no literature regarding the ontogeny of the posterior lobes. In the embryo the homeotic gene Ubx provides positional cues to restrict the formation of the primary lobes to the thoracic segments (Mandal et al., 2004). Yet, our transcriptome show that Ubx is strongly expressed in the PP and we observe that Ubx is specifically expressed in the tertiary lobes of third instar larval lymph glands. Moreover, lineage tracing analysis with Ubx(M3)-Gal4 strongly suggests that all the cells of the posterior lobes (and none of the anterior lobes) are derived from the Ubx⁺ anlage, that is, the embryonic abdominal segments A1–A5 (Lo et al., 2002). It would be interesting to study the role of Ubx and the more posterior Hox Abdominal-A (Abd-A) or Abdominal-B (Abd-B) (which are not expressed in the AP or PP) in providing positional cues for seeding the posterior lobes. Likewise several Hox, including Ubx ortholog HoxA7, have been implicated in HSPC development in mammals (Collins and Thompson, 2018). Whether they contribute to the emergence of distinct pools of blood cell progenitors during development is still unknown.

Lymph gland lobes histolyze at the onset of metamorphosis (Lanot et al., 2001; Grigorian et al., 2011; Makhijani et al., 2011; Gold and Brückner, 2015). A previous study focused on the anterior lobes showed that secondary lobes express Pxn at 4 hr APF but disperse before terminal differentiation (Grigorian et al., 2011). We observe that in all the posterior lobes, cells that persist till 10 or 15 hr APF still express progenitor markers and do not undergo terminal differentiation. Pupal and adult blood cells derive from the embryonic and lymph gland lineages (Holz et al., 2003). We speculate that under normal conditions PP act as a reserve/long-term pool of progenitors that could have specific functions in larval and/or pupal and adult stages. Along that line, it was proposed that undifferentiated blood cells derived from col-expressing posterior lobe hemocytes persist in the adult (Ghosh et al., 2015), but a recent study challenged these conclusions and found no evidence for active hematopoiesis during adulthood (Sanchez Bosch et al., 2019). However, a detailed lineage tracing analysis for understanding the contribution of AP and PP to pupal and adult stages has not been possible. It is anticipated that the present identification of new progenitor markers and of a Gal4 driver specifically expressed in the posterior lobes should help characterize the fate of lymph gland progenitors in the pupal and adult stages.

Importantly, we show here that the PP exhibit a distinct behavior as compared to AP and our data support the hypothesis that differential regulation of the JAK-STAT pathway underlies this functional compartmentalization. In response to wasp parasitism downregulation of JAK-STAT signaling is required for the differentiation of lamellocytes in the primary lobes (Makki et al., 2010; Louradour et al., 2017). Our analysis of the lymph gland in its entirety indicates that PP exhibit higher level of JAK-STAT signaling than the anterior lobes and further activate the pathway in response to wasp parasitism. Moreover, the maintenance of high level of STAT92E activity in the PP appears to be required to prevent lamellocyte differentiation in these cells. Interestingly, wasp infestation was also shown to cause JAK-STAT signaling activation in the larval somatic muscle, which is essential for mounting an efficient immune response (Yang et al., 2015). Thus, wasp infestation seems to lead to differential regulation of the JAK-STAT pathway in multiple target organs. Notably, sustained JAK-STAT signaling in the PP, by contributing to the expression of complement like factor Tep1, could further activate the humoral arm of immunity. Along that line, our observation that sustained STAT92E activation in PP is important for fly survival following wasp infestation also underlines the biological relevance of PP differential regulation.

Notably, we monitored Toll/NF-kB and Notch signaling to test whether these pathways are involved in regulating differential immune response across the anteroposterior axis. Indeed Toll/NF-kB activation and Notch repression were implicated in lamellocyte production in the anterior lobes (Gueguen et al., 2013; Hao and Jin, 2017; Louradour et al., 2017; Small et al., 2014). However, we found that Toll signaling was induced both in the anterior and in the posterior lobes in response to wasp parasitism, and Notch signaling was barely active in the posterior lobes in control as well as infected larvae. Thus, the differential response of AP and PP is unlikely to involve these two pathways. Yet, activation of the Toll reporter Drs-GFP in the PP in response to wasp infection further supports the idea that they could contribute to the humoral immune response. Indeed, Toll/NF-kB signaling is widely implicated in the regulation of AMP production in response to infections (Lemaitre and Hoffmann, 2007).

Along the same lines, it is interesting to note that while infestation by the specialist wasp L. boulardi induces melanization and lamellocyte differentiation, venom from the generalist L. heterotoma is more immune suppressive and causes hemocyte lysis (Schlenke et al., 2007). Toll and JAK/STAT pathway genes are some of the most highly expressed genes in the anti-parasite immune response to L. boulardi leading to Tep1 upregulation, which is not seen in L. heterotoma infested flies. However, upstream signals that bring about this regulation are not known. The virulence of the parasitoid and the immune response of the host define which species prevails. Several studies show that parasitoid wasps exert a selective pressure on Drosophila larvae in order to overcome infection (Kraaijeveld et al., 2001; Leitão et al., 2020; McGonigle et al., 2017). Exposing Drosophila larvae to L. boulardi and selecting flies that survive parasitism over generations lead to constitutive upregulation of immune-inducible genes (including Drs) in such selected populations (Leitão et al., 2020). It would be interesting to know whether PP contribute to the heightened immune response in such resistant Drosophila populations.

The PSC is critically required for lamellocyte production in the anterior lobes (Benmimoun et al., 2015; Crozatier et al., 2004) and PSC-derived systemic signals are also essential for the differentiation of lamellocytes in the circulating blood cells (Sinenko et al., 2011). Similar systemic signals emanating from the PSC or relayed by circulating blood cells could contribute to PP response to wasp parasitism as we observed that PSC ablation abrogated cell–cell coalescence in the posterior lobes. In addition to the PSC, signals derived from the differentiated blood cells in the CZ contribute to AP homeostasis (Mondal et al., 2011). Hence, further investigations will be required to elucidate whether systemic signals emanating from the PSC, the CZ, or the circulating hemocytes could influence PP fate in physiological or immune conditions.

Although the decrease in latran expression that we observe in the PP following wasp parasitism could strengthen JAK-STAT signaling, how this pathway is activated in the PP remains unclear. Integration of external stimuli to produce an appropriate response is essential for maintaining blood cell homeostasis and survival. While wasp parasitism causes a decrease in upd3 expression in the lymph gland (Makki et al., 2010) and our own results, it also triggers Upd3 and Upd2 upregulation in circulating hemocytes, which leads to JAK-STAT signaling activation in the larval muscles (Yang et al., 2015) and could contribute to JAK-STAT activation in PP. Besides, Dlp is known to promote JAK-STAT activation by binding Upd cytokines (Zhang et al., 2013) and it is expressed at high levels in the PP. Dlp could thus help sequester Upd2 and/or Upd3 from the hemolymph and promote JAK-STAT signaling in the PP. More generally, enhanced expression of the ECM components, like the HSPG Dlp, in the posterior lobes may help integrate long-range cytokine signals leading to local activation of pathways in response to immune stress. Furthermore, the role of signals such as serotonin or developmental events remains to be investigated.

In summary, we show that the Drosophila larval hematopoietic organ, the lymph gland, has a heterogeneous pool of progenitors whose maintenance is spatially and temporally regulated and we reveal a previously unexpected role for JAK-STAT signaling in maintaining the PPs in the presence of immune challenge (Figure 8). Our analysis underscores the linear arrangement and genesis of lymph gland lobes with the youngest and most immature progenitors at the posterior end. Further we identify additional reagents to drive gene expression in specific subsets of progenitors. This provides unique opportunities for visualization and sophisticated developmental analysis of blood progenitor specification and differentiation within the same animal. The Drosophila lymph gland could serve as a potent model to understand blood cell progenitor heterogeneity and our findings pave the way for future investigation aimed at understanding the spatio-temporal regulation of progenitor fate in normal and pathological situations in vivo. Wasp infestation provides refined and relevant interventions, akin to a sensitized genetic background, to highlight the context-dependent roles of signaling and progenitors. Using infestation as a tool we could uncover differences in the progenitor response to systemic signals and evolutionarily conserved signaling pathways that regulate these. Understanding such interactions between the immune system and its stimuli could inform developmental analysis and our work sets the stage for future studies to decipher these.

Figure 8

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RNA-seq data has been deposited in GEO under the accession number GSE152416. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 3, 4, 5, 6, 7 and Figure 1—figure supplement 1, 2, Figure 4—figure supplement 1, 2, Figure 5—figure supplement 1, 2, Figure 7—figure supplement 1.

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Author details

1. Diana Rodrigues

   1. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
   2. National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
   3. Shanmugha Arts, Science, Technology & Research Academy, Tamil Nadu, India

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2395-4328

2. Yoan Renaud

   University of Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France

   Contribution

   Data curation, Formal analysis, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4036-8315

3. K VijayRaghavan

   1. National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
   2. Shanmugha Arts, Science, Technology & Research Academy, Tamil Nadu, India

   Contribution

   Resources, Supervision, Writing - review and editing

   Competing interests

   Senior editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-4705-5629

4. Lucas Waltzer

   University of Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   lucas.waltzer@uca.fr

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5361-727X

5. Maneesha S Inamdar

   Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   inamdar@jncasr.ac.in

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8243-2821

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