scholarly journals Drosophila as a Model to Study Cellular Communication Between the Hematopoietic Niche and Blood Progenitors Under Homeostatic Conditions and in Response to an Immune Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Ismaël Morin-Poulard ◽  
Yushun Tian ◽  
Nathalie Vanzo ◽  
Michèle Crozatier
Keyword(s):  
Blood Cell ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Lymph Gland ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Hematopoietic Organ ◽  
Immune Stress

In adult mammals, blood cells are formed from hematopoietic stem progenitor cells, which are controlled by a complex cellular microenvironment called “niche”. Drosophila melanogaster is a powerful model organism to decipher the mechanisms controlling hematopoiesis, due both to its limited number of blood cell lineages and to the conservation of genes and signaling pathways throughout bilaterian evolution. Insect blood cells or hemocytes are similar to the mammalian myeloid lineage that ensures innate immunity functions. Like in vertebrates, two waves of hematopoiesis occur in Drosophila. The first wave takes place during embryogenesis. The second wave occurs at larval stages, where two distinct hematopoietic sites are identified: subcuticular hematopoietic pockets and a specialized hematopoietic organ called the lymph gland. In both sites, hematopoiesis is regulated by distinct niches. In hematopoietic pockets, sensory neurons of the peripheral nervous system provide a microenvironment that promotes embryonic hemocyte expansion and differentiation. In the lymph gland blood cells are produced from hematopoietic progenitors. A small cluster of cells called Posterior Signaling Centre (PSC) and the vascular system, along which the lymph gland develops, act collectively as a niche, under homeostatic conditions, to control the balance between maintenance and differentiation of lymph gland progenitors. In response to an immune stress such as wasp parasitism, lymph gland hematopoiesis is drastically modified and shifts towards emergency hematopoiesis, leading to increased progenitor proliferation and their differentiation into lamellocyte, a specific blood cell type which will neutralize the parasite. The PSC is essential to control this emergency response. In this review, we summarize Drosophila cellular and molecular mechanisms involved in the communication between the niche and hematopoietic progenitors, both under homeostatic and stress conditions. Finally, we discuss similarities between mechanisms by which niches regulate hematopoietic stem/progenitor cells in Drosophila and mammals.

scholarly journals The vascular niche controls Drosophila hematopoiesis via fibroblast growth factor signaling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Manon Destalminil-Letourneau ◽  
Ismaël Morin-Poulard ◽  
Yushun Tian ◽  
Nathalie Vanzo ◽  
Michele Crozatier
Keyword(s):  
Blood Cell ◽  
Vascular System ◽  
Lymph Gland ◽  
Growth Factor Signaling ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Fibroblast Growth Factor Signaling ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Signaling Center

In adult mammals, hematopoiesis, the production of blood cells from hematopoietic stem and progenitor cells (HSPCs), is tightly regulated by extrinsic signals from the microenvironment called ‘niche’. Bone marrow HSPCs are heterogeneous and controlled by both endosteal and vascular niches. The Drosophila hematopoietic lymph gland is located along the cardiac tube which corresponds to the vascular system. In the lymph gland, the niche called Posterior Signaling Center controls only a subset of the heterogeneous hematopoietic progenitor population indicating that additional signals are necessary. Here we report that the vascular system acts as a second niche to control lymph gland homeostasis. The FGF ligand Branchless produced by vascular cells activates the FGF pathway in hematopoietic progenitors. By regulating intracellular calcium levels, FGF signaling maintains progenitor pools and prevents blood cell differentiation. This study reveals that two niches contribute to the control ofDrosophila blood cell homeostasis through their differential regulation of progenitors.

scholarly journals The vascular niche controls Drosophila hematopoiesis via Fibroblast Growth Factor signaling

2020 ◽  
Author(s):  
Manon Destalminil-Letourneau ◽  
Ismaël Morin-Poulard ◽  
Yushun Tian ◽  
Nathalie Vanzo ◽  
Michèle Crozatier
Keyword(s):  
Blood Cell ◽  
Vascular System ◽  
Lymph Gland ◽  
Growth Factor Signaling ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Fibroblast Growth Factor Signaling ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Signaling Center

AbstractIn adult mammals, hematopoiesis, the production of blood cells from hematopoietic stem and progenitor cells (HSPCs), is tightly regulated by extrinsic signals from the microenvironment called “niche”. Bone marrow HSPCs are heterogeneous and controlled by both endosteal and vascular niches. The Drosophila hematopoietic lymph gland is located along the cardiac tube which corresponds to the vascular system. In the lymph gland, the niche called Posterior Signaling Center controls only a subset of the heterogeneous hematopoietic progenitor population indicating that additional signals are necessary. Here we report that the vascular system acts as a second niche to control lymph gland homeostasis. The FGF ligand Branchless produced by vascular cells activates the FGF pathway in hematopoietic progenitors. By regulating intracellular calcium levels, FGF signaling maintains progenitor pools and prevents blood cell differentiation. This study reveals that two niches contribute to the control of Drosophila blood cell homeostasis through their differential regulation of progenitors.

scholarly journals Headcase is a Repressor of Lamellocyte Fate in Drosophila melanogaster

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 173 ◽  
Author(s):  
Gergely I. B. Varga ◽  
Gábor Csordás ◽  
Gyöngyi Cinege ◽  
Ferenc Jankovics ◽  
Rita Sinka ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Cell Differentiation ◽  
Blood Cell ◽  
Cell Fate ◽  
Blood Cells ◽  
Mutational Analysis ◽  
Genetic Interaction ◽  
Lymph Gland ◽  
Loss Of Function ◽  
Hematopoietic Stem

Due to the evolutionary conservation of the regulation of hematopoiesis, Drosophila provides an excellent model organism to study blood cell differentiation and hematopoietic stem cell (HSC) maintenance. The larvae of Drosophila melanogaster respond to immune induction with the production of special effector blood cells, the lamellocytes, which encapsulate and subsequently kill the invader. Lamellocytes differentiate as a result of a concerted action of all three hematopoietic compartments of the larva: the lymph gland, the circulating hemocytes, and the sessile tissue. Within the lymph gland, the communication of the functional zones, the maintenance of HSC fate, and the differentiation of effector blood cells are regulated by a complex network of signaling pathways. Applying gene conversion, mutational analysis, and a candidate based genetic interaction screen, we investigated the role of Headcase (Hdc), the homolog of the tumor suppressor HECA in the hematopoiesis of Drosophila. We found that naive loss-of-function hdc mutant larvae produce lamellocytes, showing that Hdc has a repressive role in effector blood cell differentiation. We demonstrate that hdc genetically interacts with the Hedgehog and the Decapentaplegic pathways in the hematopoietic niche of the lymph gland. By adding further details to the model of blood cell fate regulation in the lymph gland of the larva, our findings contribute to the better understanding of HSC maintenance.

scholarly journals Reactive oxygen species-dependent Toll/NF-κB activation in the Drosophila hematopoietic niche confers resistance to wasp parasitism

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Isabelle Louradour ◽  
Anurag Sharma ◽  
Ismael Morin-Poulard ◽  
Manon Letourneau ◽  
Alain Vincent ◽  
...  
Keyword(s):  
Regulatory Network ◽  
Lymph Gland ◽  
Cell Renewal ◽  
Egfr Signaling ◽  
Hematopoietic Stem ◽  
Hematopoietic Organ ◽  
Immune Stress ◽  
Pathway Activation ◽  
Co Activation ◽  
Open Question

Hematopoietic stem/progenitor cells in the adult mammalian bone marrow ensure blood cell renewal. Their cellular microenvironment, called ‘niche’, regulates hematopoiesis both under homeostatic and immune stress conditions. In the Drosophila hematopoietic organ, the lymph gland, the posterior signaling center (PSC) acts as a niche to regulate the hematopoietic response to immune stress such as wasp parasitism. This response relies on the differentiation of lamellocytes, a cryptic cell type, dedicated to pathogen encapsulation and killing. Here, we establish that Toll/NF-κB pathway activation in the PSC in response to wasp parasitism non-cell autonomously induces the lymph gland immune response. Our data further establish a regulatory network where co-activation of Toll/NF-κB and EGFR signaling by ROS levels in the PSC/niche controls lymph gland hematopoiesis under parasitism. Whether a similar regulatory network operates in mammals to control emergency hematopoiesis is an open question.

scholarly journals Stochastic Modeling of Hematopoietic Stem and Progenitor Cell Barcoding Data from Rhesus Macaques Challenges the Classic Model of Hematopoiesis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2643-2643
Author(s):  
Jason Xu ◽  
Samson J. Koelle ◽  
Peter Guttorp ◽  
Chuanfeng Wu ◽  
Cynthia E. Dunbar ◽  
...  
Keyword(s):  
Blood Cell ◽  
Nk Cells ◽  
Statistical Method ◽  
Rhesus Macaque ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Cell Lineages

Abstract The classical model of hematopoiesis states that differentiation proceeds from hematopoietic stem cells (HSC) to mature blood cells via specified multipotent and bipotent progenitors, such as the common myeloid progenitor (CMP), common lymphoid progenitor (CLP), erythrocyte-megakaryoctye progenitor and granulocyte-monocyte progenitor. However, recent studies question this assumption and suggest that these intermediates are neither required nor prevalent. As an example, analyses of binarized data from murine barcoding experiments (Perie et al, Cell Reports, 2014) raise the possibility that hematopoiesis progresses via a random loss of potentials rather than discrete steps. Additionally, Notta et al (Science, 2015) showed that oligopotent progenitor cells form only a negligible component in the hierarchy by studying the distribution of progenitors in human marrow, leading them to infer that HSC and earliest multipotent progenitors differentiate directly into unipotent cells. Although these data challenge fundamental beliefs, the quantitative contributions of HSC and progenitors to cell lineages could not be tracked in individual mice or persons over time. We developed a statistical method to infer the rates and probabilities of cell fate decisions in a class of stochastic branching models and used this to analyze sequence data from a rhesus macaque transplanted with lentivirally barcoded CD34+ HSC and progenitor cells. The macaque's blood granulocytes (Gr), monocytes (Mo), B cells, T cells, and NK cells were tracked over 30 months. Our quantitative framework is based on computing correlations between pairs of observable mature blood cell types across all independently barcoded lineages. The method also accounts for experimental uncertainties intrinsic to blood sampling, cell purification and PCR amplification. Specifically, our approach relies on a loss function estimator that minimizes residuals between empirical pairwise correlations across barcode lineages and analytical model-based correlations derived generally for continuous-time multi-type branching processes. We integrate over sampling distributions accounting for noise in experimental protocol and CBC counts. Candidate models represent possible hematopoietic structures and allow an arbitrary number of progenitor and mature cell types descended from each HSC. We identify best-fitting fate decision rates and initial marking levels with corresponding confidence intervals via nonlinear least squares and can assess whether a given model is statistically consistent with the data. This is the first statistical method to our knowledge for fitting stochastic models of hematopoiesis to lineage barcoding time-series, and together with the rhesus macaque data, enables quantitative analysis of in vivo dynamics in a large animal model. Using this new approach, we confirmed the major finding in Wu et al. (Cell Stem Cell, 2014) of a distinct NK cell ontogeny, i.e., that CD16+ blood NK cells do not overlap in origin with T and B cell lineages. We estimate that 13.9% of HSC and 86.1% of progenitors were initially barcoded, which is consistent with the finding by Wu that the percentage of blood cells expressing GFP stabilized at 13% after 6 months. Additionally, we estimate that HSC self-renew approximately once every 12 weeks, which is consistent with the range estimated in previous primate studies based on telomere studies (Shepherd, Blood, 2007). These initial analyses help validate our method. We then showed that Gr and Mo cells derive from a common precursor in vivo (correlation ρ ≈.9 across time). We also estimated progenitor differentiation rates and showed that Gr and Mo cells are produced up to 10- to 100-fold more rapidly than T, B and NK cells, and that each progenitor committed to the Gr/Mo lineage (i.e., CFUGM) produces thousands of mature cells per day. Importantly, we tested models requiring an ordered differentiation through defined intermediaries and found that they did not suitably fit the data compared to models allowing for non-restricted pathways. Together these analyses challenge the classic model of blood cell differentiation and provide new insights into the structure of hematopoiesis. Disclosures Dunbar: GSK/Novartis: Research Funding.

scholarly journals A parasitoid wasp of Drosophila employs preemptive and reactive strategies to deplete its host’s blood cells

2021 ◽  
Author(s):  
Johnny R. Ramroop ◽  
Mary Ellen Heavner ◽  
Zubaidul H. Razzak ◽  
Shubha Govind
Keyword(s):  
Extracellular Vesicles ◽  
Cellular Immunity ◽  
Blood Cells ◽  
Insect Pests ◽  
Lymph Gland ◽  
Parasite Development ◽  
Parasitoid Wasps ◽  
Parasitic Wasps ◽  
Hematopoietic Organ ◽  
Leptopilina Heterotoma

AbstractThe wasps Leptopilina heterotoma parasitize and ingest their Drosophila hosts. They produce extracellular vesicles (EVs) in the venom that are packed with proteins, some of which perform immune suppressive functions. EV interactions with blood cells of host larvae are linked to hematopoietic depletion, immune suppression, and parasite success. But how EVs disperse within the host, enter and kill hematopoietic cells are not well understood. Using an antibody marker for L. heterotoma EVs, we show that these parasite-derived structures are readily distributed within the hosts’ hemolymphatic system. EVs converge around the tightly clustered cells of the posterior signaling center (PSC) of the larval lymph gland, a small hematopoietic organ in Drosophila. The PSC serves as a source of developmental signals in naïve animals. In wasp-infected animals, the PSC directs the differentiation of lymph gland progenitors into lamellocytes. These lamellocytes are needed to encapsulate the wasp egg and block parasite development. We found that L. heterotoma infection disassembles the PSC and PSC cells disperse into the disintegrating lymph gland lobes. Genetically manipulated PSC-less lymph glands remain non-responsive and largely intact in the face of L. heterotoma infection. We also show that the larval lymph gland progenitors use the endocytic machinery to internalize EVs. Once inside, L. heterotoma EVs damage the Rab7- and LAMP1-positive late endocytic and phagolysosomal compartments. Rab5 maintains hematopoietic and immune quiescence as Rab5 knockdown results in hematopoietic over-proliferation and ectopic lamellocyte differentiation. Thus, both aspects of anti-parasite immunity, i.e., (a) phagocytosis of the wasp’s immune-suppressive EVs, and (b) progenitor differentiation for wasp egg encapsulation reside in the lymph gland. These results help explain why the lymph gland is specifically and precisely targeted for destruction. The parasite’s simultaneous and multipronged approach to block cellular immunity not only eliminates blood cells, but also tactically blocks the genetic programming needed for supplementary hematopoietic differentiation necessary for host success. In addition to its known functions in hematopoiesis, our results highlight a previously unrecognized phagocytic role of the lymph gland in cellular immunity. EV-mediated virulence strategies described for L. heterotoma are likely to be shared by other parasitoid wasps; their understanding can improve the design and development of novel therapeutics and biopesticides as well as help protect biodiversity.Author summaryParasitoid wasps serve as biological control agents of agricultural insect pests and are worthy of study. Many parasitic wasps develop inside their hosts to emerge as free-living adults. To overcome the resistance of their hosts, parasitic wasps use varied and ingenious strategies such as mimicry, evasion, bioactive venom, virus-like particles, viruses, and extracellular vesicles (EVs). We describe the effects of a unique class of EVs containing virulence proteins and produced in the venom of wasps that parasitize fruit flies of Drosophila species. EVs from Leptopilina heterotoma are widely distributed throughout the Drosophila hosts’ circulatory system after infection. They enter and kill macrophages by destroying the very same subcellular machinery that facilitates their uptake. An important protein in this process, Rab5, is needed to maintain the identity of the macrophage; when Rab5 function is reduced, macrophages turn into a different cell type called lamellocytes. Activities in the EVs can eliminate lamellocytes as well. EVs also interfere with the hosts’ genetic program that promotes lamellocyte differentiation needed to block parasite development. Thus, wasps combine specific preemptive and reactive strategies to deplete their hosts of the very cells that would otherwise sequester and kill them. These findings have applied value in agricultural pest control and medical therapeutics.

scholarly journals Murine HSCs contribute actively to native hematopoiesis but with reduced differentiation capacity upon aging

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Petter Säwen ◽  
Mohamed Eldeeb ◽  
Eva Erlandsson ◽  
Trine A Kristiansen ◽  
Cecilia Laterza ◽  
...  
Keyword(s):  
Stem Cell ◽  
Steady State ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Lineage Tracing ◽  
Compensatory Mechanism ◽  
Fetal Origins ◽  
Hematopoietic Stem ◽  
Differentiation Capacity ◽  
Hsc Transplantation

A hallmark of adult hematopoiesis is the continuous replacement of blood cells with limited lifespans. While active hematopoietic stem cell (HSC) contribution to multilineage hematopoiesis is the foundation of clinical HSC transplantation, recent reports have questioned the physiological contribution of HSCs to normal/steady-state adult hematopoiesis. Here, we use inducible lineage tracing from genetically marked adult HSCs and reveal robust HSC-derived multilineage hematopoiesis. This commences via defined progenitor cells, but varies substantially in between different hematopoietic lineages. By contrast, adult HSC contribution to hematopoietic cells with proposed fetal origins is neglible. Finally, we establish that the HSC contribution to multilineage hematopoiesis declines with increasing age. Therefore, while HSCs are active contributors to native adult hematopoiesis, it appears that the numerical increase of HSCs is a physiologically relevant compensatory mechanism to account for their reduced differentiation capacity with age.

scholarly journals Differential Effects of RASA3 Mutations on Hematopoiesis are Profoundly Influenced by Genetic Background and Molecular Variant

2020 ◽  
Author(s):  
Raymond F. Robledo ◽  
Steven L. Ciciotte ◽  
Joel H. Graber ◽  
Yue Zhao ◽  
Amy J. Lambert ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Blood Cells ◽  
Genetic Background ◽  
White Blood Cells ◽  
Independent Effect ◽  
Mouse Strains ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Blood Formation ◽  
Molecular Variant

AbstractStudies of the severely pancytopenic scat mouse model first demonstrated the crucial role of RASA3, a dual RAS and RAP GTPase activating protein (GAP), in hematopoiesis. RASA3 is required for survival in utero; germline deletion is lethal at E12.5-13.5 due to severe hemorrhage and decreased fetal liver erythropoiesis. Conditional deletion in hematopoietic stem and progenitor cells (HSPCs) using Vav-Cre recapitulates the null phenotype demonstrating that RASA3 is required at the stem and progenitor level to maintain blood vessel development and integrity and effective blood production. In adults, bone marrow blood cell production and spleen stress erythropoiesis are suppressed significantly upon induction of RASA3 deficiency, leading to pancytopenia and death within two weeks. Notably, RASA3 missense mutations in mouse models scat (G125V) and hlb381 (H794L) show dramatically different hematopoietic consequences specific to both genetic background and molecular variant. Global transcriptomic studies in scat suggest potential targets to ameliorate disease progression.Author SummaryHematopoiesis is the process by which blood cells are formed. The individual must have a normal complement of red blood cells to prevent anemia, platelets to control bleeding, and white blood cells to maintain immune functions. All blood cells are derived from hematopoietic stem cells that differentiate into progenitor cells that then develop into mature circulating cells. We studied several mouse strains carrying different mutations in RASA3. We show that RASA3 is required at the earliest stages of blood formation, the stem and progenitor cells, and that the complement of genes other than RASA3, or the genetic background of the mutant strain, profoundly alters the overall effect on blood formation. Further, the molecular nature of the mutation in RASA3 also has a profound and independent effect on overall blood formation. One strain, designated scat, suffers cyclic anemia characterized by severe anemic crisis episodes interspersed with remissions where the anemia significantly improves. Comparison of scat crisis and remission hematopoietic stem and progenitor cells reveals striking differences in gene expression. Analyses of these expression differences provide clues to processes that potentially drive improvement of anemia in scat and provide new avenues to pursue in future studies to identify novel therapeutics for anemia.

scholarly journals Cellular and Molecular Mechanisms of Environmental Pollutants on Hematopoiesis

2020 ◽  
Vol 21 (19) ◽  
pp. 6996
Author(s):  
Pablo Scharf ◽  
Milena Fronza Broering ◽  
Gustavo Henrique Oliveira da Rocha ◽  
Sandra Helena Poliselli Farsky
Keyword(s):  
Bone Marrow ◽  
Immune Responses ◽  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Environmental Pollutants ◽  
Hematopoietic Stem ◽  
Vital Functions ◽  
Maturation Stages ◽  
And Function

Hematopoiesis is a complex and intricate process that aims to replenish blood components in a constant fashion. It is orchestrated mostly by hematopoietic progenitor cells (hematopoietic stem cells (HSCs)) that are capable of self-renewal and differentiation. These cells can originate other cell subtypes that are responsible for maintaining vital functions, mediate innate and adaptive immune responses, provide tissues with oxygen, and control coagulation. Hematopoiesis in adults takes place in the bone marrow, which is endowed with an extensive vasculature conferring an intense flow of cells. A myriad of cell subtypes can be found in the bone marrow at different levels of activation, being also under constant action of an extensive amount of diverse chemical mediators and enzymatic systems. Bone marrow platelets, mature erythrocytes and leukocytes are delivered into the bloodstream readily available to meet body demands. Leukocytes circulate and reach different tissues, returning or not returning to the bloodstream. Senescent leukocytes, specially granulocytes, return to the bone marrow to be phagocytized by macrophages, restarting granulopoiesis. The constant high production and delivery of cells into the bloodstream, alongside the fact that blood cells can also circulate between tissues, makes the hematopoietic system a prime target for toxic agents to act upon, making the understanding of the bone marrow microenvironment vital for both toxicological sciences and risk assessment. Environmental and occupational pollutants, therapeutic molecules, drugs of abuse, and even nutritional status can directly affect progenitor cells at their differentiation and maturation stages, altering behavior and function of blood compounds and resulting in impaired immune responses, anemias, leukemias, and blood coagulation disturbances. This review aims to describe the most recently investigated molecular and cellular toxicity mechanisms of current major environmental pollutants on hematopoiesis in the bone marrow.

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