scholarly journals Metabolic control of cellular immune-competency by odors in Drosophila

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sukanya Madhwal ◽  
Mingyu Shin ◽  
Ankita Kapoor ◽  
Manisha Goyal ◽  
Manish K Joshi ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Model Systems ◽  
Specific Cell ◽  
Hematopoietic Progenitor ◽  
Immune Priming ◽  
Animal Development ◽  
Cellular Immune ◽  
Immune Potential ◽  
The Impact

Studies in different animal model systems have revealed the impact of odors on immune cells, however, any understanding on why and how odors control cellular immunity remained unclear. We find that Drosophila employ an olfactory-immune cross-talk to tune a specific cell type, the lamellocytes, from hematopoietic-progenitor cells. We show that neuronally released GABA derived upon olfactory stimulation, is utilized by blood-progenitor cells as a metabolite and through its catabolism, these cells stabilize Sima/HIFα protein. Sima capacitates blood-progenitor cells with the ability to initiate lamellocyte differentiation. This systemic axis becomes relevant for larvae dwelling in wasp-infested environments where chances of infection are high. By co-opting the olfactory route, the pre-conditioned animals elevate their systemic GABA levels leading to the up-regulation of blood-progenitor cell Sima expression. This elevates their immune-potential and primes them to respond rapidly when infected with parasitic wasps. The present work highlights the importance of the olfaction in immunity and shows how odor detection during animal development is utilized to establish a long-range axis in the control of blood-progenitor competency and immune-priming.

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1544-1548 ◽  
Author(s):  
Natalija Buza-Vidas ◽  
Petter Woll ◽  
Anne Hultquist ◽  
Sara Duarte ◽  
Michael Lutteropp ◽  
...  
Keyword(s):  
Cell Surface ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Hematopoietic Progenitor ◽  
Cell Compartment ◽  
Multipotent Progenitors ◽  
Flt3 Mutations ◽  
Flt3 Expression

Abstract Lymphoid-primed multipotent progenitors with down-regulated megakaryocyte-erythroid (MkE) potential are restricted to cells with high levels of cell-surface FLT3 expression, whereas HSCs and MkE progenitors lack detectable cell-surface FLT3. These findings are compatible with FLT3 cell-surface expression not being detectable in the fully multipotent stem/progenitor cell compartment in mice. If so, this process could be distinct from human hematopoiesis, in which FLT3 already is expressed in multipotent stem/progenitor cells. The expression pattern of Flt3 (mRNA) and FLT3 (protein) in multipotent progenitors is of considerable relevance for mouse models in which prognostically important Flt3 mutations are expressed under control of the endogenous mouse Flt3 promoter. Herein, we demonstrate that mouse Flt3 expression initiates in fully multipotent progenitors because in addition to lymphoid and granulocyte-monocyte progenitors, FLT3− Mk- and E-restricted downstream progenitors are also highly labeled when Flt3-Cre fate mapping is applied.

scholarly journals Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3197-3207 ◽  
Author(s):  
Kirsteen J. Campbell ◽  
Mary L. Bath ◽  
Marian L. Turner ◽  
Cassandra J. Vandenberg ◽  
Philippe Bouillet ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Fetal Liver ◽  
Cytotoxic Agents ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Fetal Liver Cells ◽  
Follicular Lymphomas ◽  
The Impact

Abstract Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.

scholarly journals Effects of recombinant alpha and gamma interferons on the in vitro growth of circulating hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM) from patients with myelofibrosis with myeloid metaplasia

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 1014-1019 ◽  
Author(s):  
C Carlo-Stella ◽  
M Cazzola ◽  
A Gasner ◽  
G Barosi ◽  
L Dezza ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Hematopoietic Progenitor Cells ◽  
Definitive Treatment ◽  
Hematopoietic Progenitor Cell ◽  
In Vitro Growth ◽  
Hematopoietic Progenitor ◽  
Myeloid Metaplasia ◽  
Myelofibrosis With Myeloid Metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder due to clonal expansion of a pluripotent hematopoietic progenitor cell with secondary marrow fibrosis. No definitive treatment has as yet been devised for this condition, which shows a marked variability in clinical course. To evaluate whether excessive hematopoietic progenitor cell proliferation could be controlled by recombinant human interferon alpha (rIFN-alpha) and gamma (rIFN-gamma), we studied the effects of these agents on the in vitro growth of pluripotent and lineage-restricted circulating hematopoietic progenitor cells in 18 patients with MMM. A significant increase in the growth (mean +/- 1 SEM) per milliliter of peripheral blood of CFU-GEMM (594 +/- 253), CFU-Mk (1,033 +/- 410), BFU-E (4,799 +/- 2,020) and CFU- GM (5,438 +/- 2,505) was found in patients as compared with normal controls. Both rIFN-alpha and rIFN-gamma (10 to 10(4) U/mL) produced a significant dose-dependent suppression of CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM growth. Concentrations of rIFN-alpha and rIFN-gamma causing 50% inhibition of colony formation were 37 and 163 U/mL for CFU-GEMM, 16 and 69 U/mL for CFU-Mk, 53 and 146 U/mL for BFU-E, and 36 and 187 U/mL for CFU-GM, respectively. A marked synergistic effect was found between rIFN-alpha and rIFN-gamma: combination of the two agents produced inhibitory effects greater than or equivalent to those of 10- to 100- fold higher concentrations of single agents. These studies (a) confirm that circulating hematopoietic progenitors are markedly increased in MMM, (b) indicate that these presumably abnormal progenitors are normally responsive to rIFNs in vitro, and (c) show that IFNs act in a synergistic manner when used in combination. Because rIFN-gamma can downregulate collagen synthesis in vivo, this lymphokine could be particularly useful in the treatment of patients with MMM.

Functional Correction of Fanconi Anemia Group A Hematopoietic Cells by Retroviral Gene Transfer

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3296-3303 ◽  
Author(s):  
Kai-Ling Fu ◽  
Jerome R. Lo Ten Foe ◽  
Hans Joenje ◽  
Kathleen W. Rao ◽  
Johnson M. Liu ◽  
...  
Keyword(s):  
Cell Growth ◽  
Progenitor Cells ◽  
Fanconi Anemia ◽  
Progenitor Cell ◽  
Hematopoietic Cells ◽  
Retroviral Vectors ◽  
Retroviral Vector ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Increased Risk

Abstract Fanconi anemia (FA) is an autosomal recessive genetic disorder characterized by a variety of physical anomalies, bone marrow failure, and an increased risk for malignancy. FA cells exhibit chromosomal instability and are hypersensitive to DNA cross-linking agents such as mitomycin C (MMC). FA is a clinically heterogeneous disorder and can be functionally divided into at least five different complementation groups (A-E). We previously described the use of a retroviral vector expressing the FAC cDNA in the complementation of mutant hematopoietic cells from FA-C patients. This vector is currently being tested in a clinical trial of ex vivo hematopoietic progenitor cell transduction. The FA-A group accounts for over 65% of all FA cases, and the FAA cDNA was recently identified by both expression and positional cloning techniques. We report here the transduction and phenotypic correction of lymphoblastoid cell lines from four unrelated FA-A patients, using two amphotropic FAA retroviral vectors. Expression of the FAA transgene was adequate to normalize cell growth, cell-cycle kinetics, and chromosomal breakage in the presence of MMC. We then analyzed the effect of retroviral vector transduction on hematopoietic progenitor cell growth. After FAA transduction of mutant progenitor cells, either colony number or colony size increased in the presence of MMC. In addition, FAA but not FAC retroviral transduction markedly improved colony growth of progenitor cells derived from an unclassified FA patient. FAA retroviral vectors should be useful for both complementation studies and clinical trials of gene transduction.

scholarly journals Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin− cells via modulation of the bone marrow microenvironment

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 4934-4943 ◽  
Author(s):  
Asaf Spiegel ◽  
Eyal Zcharia ◽  
Yaron Vagima ◽  
Tomer Itkin ◽  
Alexander Kalinkovich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Cathepsin K ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Cell Mobilization ◽  
Tumor Growth And Metastasis

Abstract Heparanase is involved in tumor growth and metastasis. Because of its unique cleavage of heparan sulfate, which binds cytokines, chemokines and proteases, we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis. We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca-1+/c-Kit+/Lin− cells in the bone marrow (BM) of mice overexpressing heparanase (hpa-Tg). This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment, manifested in increased SDF-1 turnover. Furthermore, heparanase overexpression in mice was accompanied by reduced protease activity of MMP-9, elastase, and cathepsin K, which regulate stem and progenitor cell mobilization. Moreover, increased retention of the progenitor cells also resulted from up-regulated levels of stem cell factor (SCF) in the BM, in particular in the stem cell–rich endosteum and endothelial regions. Increased SCF-induced adhesion of primitive Sca-1+/c-Kit+/Lin− cells to osteoblasts was also the result of elevation of the receptor c-Kit. Regulation of these phenomena is mediated by hyperphosphorylation of c-Myc in hematopoietic progenitors of hpa-Tg mice or after exogenous heparanase addition to wildtype BM cells in vitro. Altogether, our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells.

scholarly journals Targeted gene transfer to human hematopoietic progenitor cell lines through the c-kit receptor

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 472-478 ◽  
Author(s):  
P Schwarzenberger ◽  
SE Spence ◽  
JM Gooya ◽  
D Michiel ◽  
DT Curiel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Progenitor Cell ◽  
Gene Transfection ◽  
Luciferase Reporter ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Covalently Linked

In this report, we describe a novel gene therapy approach for hematopoietic stem/progenitor cells using a specific receptor-mediated gene transfection procedure to target c-kit+ cell lines. The vector consists of plasmid DNA containing a luciferase reporter gene that is condensed by electrostatic forces with polylysine (PL) covalently linked to streptavidin (binds biotinylated ligand) and PL covalently linked to adenovirus (AD; to achieve endosomal lysis) with the final addition of biotinylated steel factor (SLF-biotin). Targeted transfection of growth factor-dependent hematopoietic progenitor cell lines that express c-kit showed specific luciferase gene expression over cell lines that did not express c-kit. This effect was dependent on the dose of SLF-biotin and was competed by excess SLF or with monoclonal antibodies that recognize c-kit and block the binding of SLF to its receptor. Maximum transfection efficiency (> 90%) requires a 2- hour incubation period of the vector with the cells, and maximum gene expression occurred 30 hours later. Removal of the endosomalytic agent, AD, from the vector resulted in the loss of gene expression. Vector targeting was versatile and could be changed by the addition of other biotinylated ligands. In principle, this vector should be broadly applicable to deliver genes to hematopoietic stem/progenitor cells in vitro and in vivo.

Optimal Proliferation of a Hematopoietic Progenitor Cell Line Requires Either Costimulation With Stem Cell Factor or Increase of Receptor Expression That Can Be Replaced by Overexpression of Bcl-2

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2569-2577 ◽  
Author(s):  
Huei-Mei Huang ◽  
Jian-Chiuan Li ◽  
Yueh-Chun Hsieh ◽  
Hsin-Fang Yang-Yen ◽  
Jeffrey Jong-Young Yen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Line ◽  
Progenitor Cells ◽  
Stem Cell Factor ◽  
Progenitor Cell ◽  
Stem Cell Differentiation ◽  
Hematopoietic Progenitor Cell ◽  
Hematopoietic Progenitor ◽  
Progenitor Cell Line

Abstract In vitro proliferation of hematopoietic stem cells requires costimulation by multiple regulatory factors whereas expansion of lineage-committed progenitor cells generated by stem cells usually requires only a single factor. The distinct requirement of factors for proliferation coincides with the differential temporal expression of the subunits of cytokine receptors during early stem cell differentiation. In this study, we explored the underlying mechanism of the requirement of costimulation in a hematopoietic progenitor cell line TF-1. We found that granulocyte-macrophage colony-stimulating factor (GM-CSF) optimally activated proliferation of TF-1 cells regardless of the presence or absence of stem cell factor (SCF). However, interleukin-5 (IL-5) alone sustained survival of TF-1 cells and required costimulation of SCF for optimal proliferation. The synergistic effect of SCF was partly due to its anti-apoptosis activity. Overexpression of the IL-5 receptor  subunit (IL5R) in TF-1 cells by genetic selection or retroviral infection also resumed optimal proliferation due to correction of the defect in apoptosis suppression. Exogenous expression of an oncogenic anti-apoptosis protein, Bcl-2, conferred on TF-1 cells an IL-5–dependent phenotype. In summary, our data suggested SCF costimulation is only necessary when the expression level of IL5R is low and apoptosis suppression is defective in the signal transduction of IL-5. Expression of Bcl-2 proteins released the growth restriction of the progenitor cells and may be implicated in leukemia formation.

Comparison between Progenitor Cells from Mobilized Peripheral Blood (PB) in Healthy Donors and Non-Hodgkin’s Lymphoma (NHL) Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5002-5002
Author(s):  
Eva M. Villaron ◽  
Julia Almeida ◽  
Natalia Lopez-Holgado ◽  
Fermin M. Sanchez-Guijo ◽  
Mercedes Alberca ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Peripheral Blood ◽  
Progenitor Cell ◽  
Functional Assays ◽  
Healthy Donors ◽  
Cd34 Cells ◽  
Cell Subpopulations ◽  
The Impact ◽  
Pbsc Mobilization

Abstract INTRODUCTION: Peripheral blood stem cell (PBSC) mobilization is impaired in patients receiving chemotherapy but, as far as we know there is no data about the impact of chemotherapy on different PB progenitor cell subpopulations. AIM: to ascertain whether or not immature or committed progenitor cell are affected by chemotherapy prior PBSC mobilization in NHL patients. MATERIAL AND METHODS: a total of 27 PB samples from NHL patients and 36 PB samples from healthy donors were studied. Immunophenotypic analysis of CD34+ cell subpopulations was performed using the following four colour combinations of monoclonal antibodies (FITC/PE/PC5/APC): CD90/CD133/CD38/CD34 and CD71/CD13/CD45/CD34. In order to study committed progenitor cells “in vitro”, standard colony-forming assays were used and, in order to investigate the behaviour of the uncommitted progenitors Delta Assays of plastic adherent progenitor cells (PΔ) were performed. RESULTS: The comparison between NHL patients and healthy donors is shown in Table 1. The relationship between data obtained by flow cytometry and cultures was statistically significant (p<0.05, r>0.568) for all the progenitors analysed. Table 1: Results of Immunophenotypic and Functional Assays LNH patients Healthy donors p Data expressed as median (range). 1. Percentage among CD34+ cells. 2. Number of CFU/10 5 planted cells. 3. Number of CFU/10 6 planted cells % CD34 0.16(0.04–3.65) 0.57(0.11–1.81) 0.013 Immunophenotypic Data Erithroid 1 0.05(0.01–0.60) 0.14(0.02–0.42) 0.098 Myelo–monocytic 1 0.11(0.02–2.41) 0.37(0.07–1.18) 0.014 Immature 1 0.01(0.00–0.63) 0.05(0.01–0.19) 0.014 CFU-GM 2 70(4–440) 90(0–904) 0.327 Clonogenic and Delta Assays data BFU-E 2 62(6–172) 85(0–240) 0.046 CFU-Mix 2 18(0–124) 42(0–140) 0.018 CFU Δ3 356(0–3509) 953(90–8320) 0.033 CONCLUSIONS: We can conclude that in NHL, mobilized committed and above all immature progenitors are impaired when compared with healthy subjects, both analysed by immunological and functional assays. Only granulomonocytic progenitors analysed by a functional approach seemed to be preserved.

Aldehyde Dehydrogenase-Positive Hematopoetic Progenitor Cells in Peripheral Blood and Progenitor Cell Apheresis Products: Characterization and Correlation with Kinetics of Engraftment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1076-1076
Author(s):  
Martin Hildebrandt ◽  
Markus Schuler ◽  
Kirstin Rautenberg ◽  
Christian Gerecke ◽  
Wolf-Dieter Ludwig
Keyword(s):  
Progenitor Cells ◽  
Peripheral Blood ◽  
Progenitor Cell ◽  
Cell Lymphoma ◽  
High Dose Chemotherapy ◽  
Hematopoietic Progenitor Cells ◽  
High Dose ◽  
Hematopoietic Progenitor ◽  
Mantle Cell ◽  
Kinetics Of

Abstract Hematopoietic progenitor cells are rich in aldehyde dehydrogenase (ALDH) activity, allowing their identification using fluorogenic substrates (Aldefluor®, StemCo Biomedical, Durham, North Carolina) and Fluorescence-activated cell sorting (FACS). We compared the numbers of ALDH+ cells in peripheral blood and progenitor cell harvests with the numbers of CD34-positive cells. Furthermore, we compared the numbers of ALDH+ cells with the kinetics of hematopoietic engraftment following high-dose chemotherapy (HDCT) and transplantation of autologous stem cell harvests (SCT). 25 Patients (Multiple Myeloma, n=10, Hodgkin’s disease, n=3, mantle cell lymphoma, n=3, follicular lymphoma, n=2, T-cell lymphoma, n=3, Burkitt-like lymphoma, n=3) were included in treatment protocols involving high-dose chemotherapy, and received mobilization chemotherapy and G-CSF (10 μg/kg/d s.c.). The numbers of CD34-positive cells were determined daily, and peripheral blood progenitor cell apheresis was initiated when adequate. PBPC collections were performed on an AS 104 cell separator (Fresenius AG, St. Wendel, Germany). Samples of peripheral blood and of progenitor cell harvests were routinely tested for the numbers of CD34-positive cells and ALDH+ cells. The enrichment of CD34-positive cells was calculated and compared to the numbers of ALDH+ cells. 20 patients (Multiple Myeloma, n=10, Hodgkin’s disease, n=3, mantle cell lymphoma, n=3, follicular lymphoma, n=2, T-cell lymphoma, n=2) proceeded to HDCT followed by reinfusion of progenitor cell harvests. The enrichment of ALDH+ cells in the course of apheresis exceeded the enrichment of CD34-positive cells slightly (18,3fold +/−12,8 vs. 15,7fold +/−10,2). The percentage of CD34-negative cells among ALDH+ cells was comparable in peripheral blood and in the harvest, whereas the population of CD34-positive, ALDH−negative cells varied substantially in the peripheral blood (CD34−/ ALDH+: 7,53% +/−5,2% (pB) vs. 6,52% +/−3,9 (harvest); CD34+/ALDH−: 24,6% +/−12,3% (pB) vs. 11,9% +/−9,3% (harvest). Following HDCT and SCT, the numbers of ALDH+ cells and of CD34+ cells in the peripheral blood on the day of apheresis and in the harvests were compared with the reconstitution of the peripheral blood count. In a regression analysis, the number of ALDH+ cells in the peripheral blood on the day of apheresis (p=0,005), the number of ALDH+ cells transfused (p=0,01) and the number of CD34-positive cells transfused (p=0,012) were independent predictors of early recovery of the leukocyte counts. CD34-positive and ALDH+ cells appear to comprise partially different subsets of hematopoietic progenitor cells. The quantitation of ALDH+ cells may allow a more reliable prediction of the numbers of early hematopoietic progenitor cells than the assessment of CD34-positive cells and thus may be of predictive value for the recovery of leukocytes following SCT.

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