Prostaglandin E2 Modulates Monocytes and Dendritic Cells Specific Progenitor Cell (MDP) Fate by Regulating M-CSF Receptor and Flt3 Receptor Expression.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2636-2636
Author(s):  
Pratibha Singh, ◽  
Jonathan Hoggatt ◽  
Jennifer Speth ◽  
Louis M. Pelus
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Prostaglandin E2 ◽  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Receptor Expression ◽  
Vehicle Treated Control ◽  
Indomethacin Treatment

Abstract Abstract 2636 Prostaglandin E2 (PGE2), the predominant metabolite of arachidonic acid metabolism by cyclooxygenase (COX) enzymes, is an important physiological regulator of hematopoiesis. We have previously shown that PGE2 negatively regulates proliferation of macrophage colony formation (CFU-M) (Pelus et al. JEM 1979), however the mechanism through which PGE2 inhibits monocyte/macrophage generation is not known. Recently we showed that blockade of endogenous PGE2 synthesis in vivo in mice decreased overall dendritic cell (DC) number in lymphoid organs and bone marrow (Singh et al. ASH 2009). Since monocytes and dendritic cells originate in bone marrow from common hematopoietic progenitor cells termed monocyte and DC progenitor cells (MDP), having the phenotype (Lin− cKithi CD115+CX3CR1+ Flt3+), we hypothesized that PGE2 signaling may modulate MDP fate. Treatment of mice with Indomethacin, a dual COX 1 and COX2 inhibitor, for 6 days simultaneously increased bone marrow monocytes and decreased dendritic cells number compared to vehicle treated control mice. To determine whether the observed in vivo change in monocytes and dendritic cells after Indomethacin treatment was due to fate switch of MDP, we cultured FACS sorted MDP cells with Flt3L plus M-CSF, which simultaneously supports both DC and monocyte differentiation, in the absence or presence of Indomethacin for 9 days. Indomethacin reduced DC differentiation by 42±3.8% compared to vehicle control, and concomitantly increased monocyte generation in the same cultures by 25±2.8%. Moreover, as expected, addition of exogenous PGE2 to these cultures reverted the Indomethacin mediated alteration in dendritic cell and monocyte generation from MDP. To confirm whether the reduction in dendritic cells and increase in monocytes generated from MDP upon the blockade of PGE2 was due to preferential differentiation of MDP into monocyte-committed precursors rather than DC-committed precursors, we analyzed specific DC committed precursors (lin−c-kitint M-CSFR+ Flt3+) and monocyte-committed precursors (CD11−CD11b+F4/80intM-CSFR+) generated from MDP in vitro in the presence of Indomethacin. Fewer DC committed precursors were detected in Flt3L plus M-CSF cultures in the presence of Indomethacin, however monocyte precursor cell number increased compared to vehicle treated control. To further investigate whether a change in fate decision of MDP by blockade of PGE2 is due to modulation of Flt3 and M-CSF receptors on MDP, we evaluated Flt3 receptor and M-CSF receptor on bone marrow MDP from Indomethacin treated mice. Flt3 receptor expression on MDP was decreased by 30±5.2% after Indomethacin treatment compared to control, however M-CSF receptor expression on MDP was increased by 51±4.5. In conclusion, our data suggest that PGE2 regulates monocytes and dendritic cell generation by switching the differentiation fate of MDP by modulating M-CSF receptor and Flt3 receptor expression. Disclosures: No relevant conflicts of interest to declare.

Human Conventional and Plasmacytoid Dendritic Cells Can Originate from Both Lymphoid and Myeloid Progenitors in a New Humanized Mouse System.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2273-2273
Author(s):  
Fumihiko Ishikawa ◽  
Tadafumi Iino ◽  
Hiroaki Niiro ◽  
Shuro Yoshida ◽  
Toshihiro Miyamoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cells ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Transcription Profiles ◽  
Human Dendritic Cells ◽  
Myeloid Progenitors

Abstract Dendritic cells play a key role in host defense by presenting exogenous antigens to T cells. Two dendritic cell subsets, conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs), express distinct repertoire of Toll-like-receptors and recognize different antigens. We previously reported that murine cDCs and pDCs differentiate via either the myeloid or the lymphoid pathway (Shigematsu et al. Immunity ). It is, however, still unclear whether human cDCs and pDCs develop from myeloid, lymphoid or both lineages. In order to analyze the in vivo differentiation of human dendritic cells, we employed the newly-developed xenotrasplant assay system which utilizes newborn NOD-scid/IL2rgnull mice (Ishikawa et al., Blood, in press). Transplantation of 104 Lin-CD34+CD38- hematopoietic stem cells into sublethally irradiated newborn NOD-scid/IL2rgnull mice resulted in generation of all hematopoietic and lymphoid components for a long-term via physiological intermediates such as common myeloid progenitors (CMP) and common lymphoid progenitors (CLP). We found that in this system, dendritic cell subcomponents such as hCD11c+hIL3Ralow cDCs and hCD11c-hIL3Rahigh pDCs, efficiently developed in recipients’ bone marrow, spleen and peripheral blood. To elucidate the origin of human mDCs and pDCs, we purified CMP or CLP from the cord blood, and transplanted these cells into sublethally irradiated newborn NOD-scid/IL2rgnull mice via facial vein. At 4-6 weeks post-transplantation, CMP gave rise only to myeloid cells such as erythroid cells, platelets and granulocytes, while CLP exclusively generated T, B and NK cells. Interestingly, in either mouse group injected with CMP or CLP, cDCs and pDCs were easily detected in the spleen and in the bone marrow. Phenotypic and RT-PCR analyses of purified CMP- or CLP-derived DCs revealed that DCs possessed similar phenotypic characteristics, and transcription profiles in TLR families, BDCA antigens and costimulation molecules, irrespective of their lineage origin. Thus, human cDCs and pDCs develop through both myeloid and lymphoid pathways as in case of mouse hematopoiesis. Further characterization of DCs of different lineage origin is currently performed by microarray analyses in order to find genes specifically expressed in each DC subset.

scholarly journals The Neurotransmitter Receptor Gabbr1 Regulates Proliferation and Function of Hematopoietic Stem and Progenitor Cells

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Adedamola Elujoba-Bridenstine ◽  
Lijian Shao ◽  
Katherine Zink ◽  
Laura Sanchez ◽  
Kostandin V. Pajcini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Receptor Expression ◽  
Bone Marrow Niche ◽  
Transplant Recipients ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Null Mutants

Hematopoietic stem and progenitor cells (HSPCs) are multipotent cells which differentiate to maintain and replenish blood lineages throughout life. Due to these characteristics, HSPC transplants represent a cure for patients with a variety of hematological disorders. HSPC function and behavior is tightly regulated by various cell types and factors in the bone marrow niche. The nervous system has been shown to indirectly influence hematopoiesis by innervating the niche; however, we present a direct route of HSPC regulation via expression of neurotransmitter receptors on HSPC surface. We have identified Gamma Aminobutyric acid (GABA) receptor B subunit 1 (Gabbr1), a hitherto unknown hematopoietic player, as a regulator of HSPC function. GABBR1 is known to be expressed on human HSPCs (Steidl et al., Blood 2004), however its function in their regulation remains unknown. Based on published RNA-seq data (Nestorowa et al., Blood 2016), we discovered that Gabbr1 is expressed on a subset of HSPCs. We confirmed this expression using RT-qPCR to assay hematopoietic populations in the bone marrow (BM). Surface receptor expression analysis showed that Gabbr1 protein is expressed on a subset of BM HSPCs. To detect GABA, the ligand for Gabbr1 in the BM microenvironment, we utilized imaging mass spectrometry (IMS). We detected regionally specific GABA signal in the endosteal region of the BM. We further identified B cells as a cellular source of GABA in the BM. To understand the role of Gabbr1 in hematopoiesis, we generated CRISPR-Cas9 Gabbr1 null mutants on a C57/BL6 background suitable for hematopoietic studies and studied their hematopoietic phenotype. We discovered a decrease in the absolute number of Lin-Sca1+cKit+ (LSK) HSPCs, but the long-term hematopoietic stem cells (LT-HSCs) remain unaffected. Further analysis of peripheral blood of Gabbr1 null mutants showed decreased white blood cells due to reduced B220+ cells. This differentiation defect was confirmed in an in vitro differentiation assay where Gabbr1 null HSPCs displayed an impaired ability to produce B cells. We show that Gabbr1 null HSCs show diminished reconstitution ability when transplanted in a competitive setting. Reduced Gabbr1 null HSC reconstitution persisted in secondary transplant recipients indicating a cell autonomous role for Gabbr1 in regulating reconstitution of HSCs in transplant recipients. Our results show a crucial role for Gabbr1 in HSPC regulation and may translate to human health as a rare human SNP within the GABBR1 locus that correlates with altered leukocyte counts has been reported (Astle et al., Cell 2016). Our studies indicate an important role for Gabbr1 in HSPC reconstitution and differentiation into B cell lineages. Disclosures No relevant conflicts of interest to declare.

Synergistic Effect of Flt3L and Rapamycin On Immune Tolerance Induction Via Plasmacytoid Dendritic Cells and Treg.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2209-2209
Author(s):  
Debalina Sarkar ◽  
Gongxian Liao ◽  
Cox Terhorst ◽  
Roland W Herzog
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Synergistic Effect ◽  
Progenitor Cells ◽  
Immune Tolerance ◽  
Prolonged Exposure ◽  
Conflicts Of Interest ◽  
Tolerance Induction ◽  
Coagulation Factor

Abstract Abstract 2209 In vivo induction and expansion of Treg is a powerful tool to limit unwanted immune responses and promote tolerance. For example, we have been successful inducing tolerance to factors VIII and FIX in hemophilic mice when the coagulation factor antigen was administered with the mTOR inhibitor rapamycin (J Thromb Haemost 7:1523 and 9:1524, Front Microbiol 2:244). Rapamycin, a macrocyclic triene antibiotic, is an immunosuppressant used to avoid transplant rejection. It suppresses the mTOR1 (and upon prolonged exposure also mTOR2) signaling pathway. Importantly, while mTOR blockage results in deletion of Teff, Treg can be induced and expanded because they are able to utilize alternative (STAT) signaling pathways. Others have shown that existing Treg can be expanded in vivo upon administration of Fms-like tyrosine kinase ligand-3 (Flt3L), a cytokine that drives generation of dendritic cells (DC) from hematopoietic progenitor cells and DC proliferation. This link between DC homeostasis and Treg is evident from the low Treg numbers found in Flt3L-deficient mice and from prevention of graft vs host disease upon treatment with Flt3L. This raises the question of whether a combined approach of rapamycin administration and Flt3L-induced DC generation would result in an optimal immune tolerance protocol. Interestingly, it has been reported that rapamycin blocks Flt3L-induced differentiation of progenitor cells into DC, indicating that Flt3L signaling in DC occurs through the mTOR pathway. However, we find in mice transgenic for an ovalbumin-specific CD4+ T cell receptor (but deficient in recombinase activating gene, rag-2) that ova peptide antigen administration results in substantially enhanced deletion of Teff and in induction of CD4+CD25+FoxP3+CD62L+GITR+ Treg when combined with these two drugs. This was accomplished by repeated administration (twice per week) of a cocktail of the 3 components. Antigen plus either drug causes Teff deletion, while rapamycin is required for Treg induction (which is further enhanced by Flt3L). Antigen, rapamycin, and Flt3L all impact changes in the numbers and frequencies of DC subsets in the spleen during the regimen. The combination all 3 components most potently directs a substantial (3–5 fold, P<0.001) increase in CD11cloPDCA+ plasmacytoid DC numbers (but not of conventional CD11chiPDCA− DCs). While pDCs are known to provide innate anti-viral responses, they also play an important role in immune tolerance. Consequently, when pDC were partially depleted with anti-PDCA, Treg induction was significantly impaired. Furthermore, the protocol caused an increase in the frequency of Indoleamine-pyrrole 2,3-dioxygenase (IDO)-expressing pDCs (which is known to activate resting Treg for suppressor activity). Finally, FLt3L-induced expansion of Treg (but not of DCs) is less effective in GITR-L −/− mice. Combined, these data demonstrate that i) Flt3L and rapamycin can be used synergistically for induction of T cell tolerance, ii) pDCs can be expanded within a rapamycin regimen, iii) and Fl3tL-induced pDC expansion facilitates Treg induction, which is partially dependent on GITR-L (a co-stimulatory molecule primarily expressed by pDCs that promotes cross talk to Treg by engagement of the GITR receptor). In order to establish relevance of this protocol for treatment of disease, we intravenously injected a F.VIII protein/rapamycin/Flt3L cocktail into hemophilia A mice (C57BL6/129 F8e16 −/−) twice per week for 1 month. Subsequently, mice received 1 month of factor replacement therapy (1 IU human FVIII, IV, once per week). Control mice without prior immune modulatory regiment or that received non-specific immune suppression (rapamycin and Flt3L only) formed high-titer inhibitors against FVIII (70–80 BU), which was significantly suppressed to ∼10 BU (P<0.001, n=5 per group). Importantly, inhibitor titers were only mildly reduced (to ∼40 BU) when Flt3L was omitted from the tolerogenic cocktail, thereby confirming the synergistic effect of flt3L and rapamycin in tolerance induction. This approach combines expansion of regulatory antigen presenting and T cells and should be of broad relevance for cell and organ transplantation as well as for treatment of inherited protein deficiencies and of autoimmune diseases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Blood ◽  
2012 ◽  
Vol 119 (7) ◽  
pp. 1671-1682 ◽  
Author(s):  
Pratibha Singh ◽  
Jonathan Hoggatt ◽  
Peirong Hu ◽  
Jennifer M. Speth ◽  
Seiji Fukuda ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Prostaglandin E2 ◽  
Progenitor Cells ◽  
Survivin Expression ◽  
Regulatory Mechanisms ◽  
Flt3 Ligand ◽  
Regulatory Pathway ◽  
Hematopoietic Progenitor ◽  
Flt3 Expression

Abstract Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E2 (PGE2) is required for optimal Flt3 ligand–mediated DC development and regulates expression of the Flt3 receptor on DC-committed progenitor cells. Inhibition of PGE2 biosynthesis reduces Flt3-mediated activation of STAT3 and expression of the antiapoptotic protein survivin, resulting in increased apoptosis of DC-committed progenitor cells. Reduced DC development caused by diminished PGE2 signaling is reversed by overexpression of Flt3 or survivin in DC progenitors and conversely is mimicked by STAT3 inhibition. PGE2 regulation of DC generation is specifically mediated through the EP1 and EP3 G protein PGE2 receptors. These studies define a novel DC progenitor regulatory pathway in which PGE2 signaling through EP1/EP3 receptors regulates Flt3 expression and downstream STAT3 activation and survivin expression, required for optimal DC progenitor survival and DC development in vivo.

Further Evidence That HO-1 Regulates SDF-1 Expression in the Bone Marrow Microenvironment and That HO-1-Deficient Mice Show a Defect in the SDF-1–CXCR4 Retention Axis of Hematopoietic Stem/Progenitor Cells in Bone Marrow and Thus Are Easy Mobilizers - Studies in HO-1 Mutant Mice, Irradiation Chimeras, and the Effect of in Vivo Pharmacological Inhibition of HO-1

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 344-344
Author(s):  
Marcin Wysoczynski ◽  
Janina Ratajczak ◽  
Gregg Rokosh ◽  
Roberto Bolli ◽  
Mariusz Z Ratajczak
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Crucial Role ◽  
Conflicts Of Interest ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Deficient Mice

Abstract Abstract 344 Background: Stromal derived factor-1 (SDF-1), which binds to the CXCR4 receptor expressed on the surface of hematopoietic stem/progenitor cells (HSPCs), plays an important role in the retention of HSPCs in BM niches. Heme oxygenase (HO-1) is a stress-responsive enzyme that catalyzes the degradation of heme and plays an important function in various physiological and pathophysiological states associated with cellular stress, such as ischemic/reperfusion injury, atherosclerosis, and cancer. Interestingly, it has also been reported that HO-1 regulates the expression of SDF-1 in myocardium (J Mol Cell Cardiol. 2008;45:44–55). Aim of study: Since SDF-1 plays a crucial role in retention and survival of HSPCs in BM, we become interested in whether HO-1 is expressed by BM stromal cells and whether deficiency of HO-1 affects normal hematopoiesis and retention of HSPCs in BM. Experimental approach: To address this issue, we employed several complementary strategies to investigate HO-1–/–, HO-1+/–, and wild type (wt) mouse littermates for i) the expression level of SDF-1 in BM, ii) the number of clonogenic progenitors from major hematopoietic lineages in BM, iii) peripheral blood (PB) cell counts, iv) the chemotactic responsiveness of HSPCs to an SDF-1 gradient as well as to other chemoattractants, including sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and extracellular nucleotiodes (ATP, UTP), iv) the adhesiveness of clonogenic progenitors to immobilized SDF-1 and stroma, v) the number of circulating HSPCs in PB, and vi) the degree of mobilization in response to granulocyte-colony stimulating factor (G-CSF) or AMD3100, assessed by enumerating the number of CD34–SKL cells and clonogeneic progenitors (CFU-GM) circulating in PB. We also exposed mice to the small HO-1 molecular inhibitor tin protoporphyrin IX (SnPP) and studied the effect of this treatment on G-CSF- or AMD3100-induced mobilization of HSPCs. Finally, to prove an environmental HSPC retention defect in HO-1-deficient mice, we created radiation chimeras, wild type mice transplanted with HO-1-deficient BM cells, and, vice versa, HO-1-deficient mice reconstituted with wild type BM cells. Results: Our data indicate that under normal, steady-state conditions, HO-1–/– and HO+/– mice have normal PB cell counts and numbers of circulating CFU-GM, while a lack of HO-1 leads to an increase in the number of erythroid (BFU-E) and megakaryocytic (CFU-GM) progenitors in BM. However, while BMMNCs from HO-1–/– have normal expression of the SDF-1-binding receptor, CXCR4, we observed that the mRNA level for SDF-1 in BM-derived fibroblasts was ∼4 times lower. This corresponded with the observation in vitro that HSPCs from HO-1–/– animals respond more robustly to an SDF-1 gradient, and HO-1–/– animals mobilized a higher number of CD34–SKL cells and CFU-GM progenitors into PB in response to G-CSF and AMD3100. Both G-CSF and AMD3100 mobilization were also significantly enhanced in normal wild type mice after in vivo administration of HO-1 inhibitor. Finally, mobilization studies in irradiation chimeras confirmed the crucial role of the microenvironmental SDF-1-based retention mechanism of HSPCs in BM niches. Conclusions: Our data demonstrate for the first time that HO-1 plays an important and underappreciated role in modulating the SDF-1 level in the BM microenvironment and thus plays a role in retention of HSPCs in BM niches. Furthermore, our recent data showing a mobilization effect by a small non-toxic molecular inhibitor of HO-1 (SnPP), suggest that blockage of HO-1 could be a promising strategy to facilitate mobilization of HSPCs. Further studies are also needed to evaluate the role of HO-1 in homing of HSPCs after transplantation to BM stem cell niches. Disclosures: No relevant conflicts of interest to declare.

Lack of the Transcription Factor NFAT (Nuclear Factor of Activated T cells) c2 in Hematopoietic Progenitor Cells Results in Profound Hematological Abnormalities in Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1296-1296
Author(s):  
Laleh S. Arabanian ◽  
Michael Haase ◽  
Ivonne Habermann ◽  
Malte von Bonin ◽  
Claudia Waskow ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Extramedullary Hematopoiesis ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Hematological Abnormalities

Abstract Abstract 1296 Understanding the transcriptional mechanisms that control hematopoiesis and the interaction between hematopoietic stem cells and the bone marrow microenvironment in vivo is of considerable interest. We have previously shown that aged mice lacking the transcription factor NFATc2 develop bone marrow hypoplasia, anemia, and extramedullary hematopoiesis in spleen and liver. The proliferation and differentiation of NFATc2-deficient hematopoietic progenitor cells (HPC) ex vivo, however, was found to be intact. It remained therefore unclear whether the disturbed hematopoiesis in NFATc2-deficient mice was caused by the hematopoietic or the stroma component of the bone marrow hematopoietic niche. In the current study we dissected the relative contribution of hematopoietic and stroma cells to the phenotype of the NFATc2-deficent mice by transplanting immunomagnetically purified NFATc2-deficient (ko) HPCs to lethally irradiated wildtype (wt) mice, and vice versa. After a posttransplantation period of 6–8 months, peripheral blood, bone marrow as well as spleen and liver of the transplanted animals were analyzed and compared to wt and ko mice transplanted with control cells. Transplantation of NFATc2-deficient HPCs into wt recipients (ko → wt) induced similar hematological abnormalities as those occurring in non-transplanted ko mice or in ko mice transplanted with ko cells (ko → ko). Compared to wt mice transplanted with wt cells (wt → wt), ko → wt mice showed evidence of anemia, thrombocytopenia and a significantly reduced number of hematopoietic cells in their bone marrow. Likewise, ko → wt mice developped clear signs of extramedullary hematopoiesis in spleen and liver, which was not the case in wt → wt control animals. Our data demonstrate for the first time, that NFAT transcription factors directly regulate the intrinsic function of hematopoietic progenitor cells in vivo. The transcriptional targets for NFAT in these cells are yet unknown and are the focus of further investigations. Disclosures: No relevant conflicts of interest to declare.

Novel function for interleukin-7 in dendritic cell development

Blood ◽  
2009 ◽  
Vol 113 (17) ◽  
pp. 3961-3968 ◽  
Author(s):  
Tobias K. Vogt ◽  
Alexander Link ◽  
John Perrin ◽  
Daniela Finke ◽  
Sanjiv A. Luther
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Lymph Nodes ◽  
B Lymphocytes ◽  
Large Fraction ◽  
Interleukin 7 ◽  
Plasmacytoid Dcs ◽  
Bone Marrow Chimeras

Abstract Interleukin-7 (IL-7) is crucial for the development of T and B lymphocytes from common lymphoid progenitors (CLPs) and for the maintenance of mature T lymphocytes. Its in vivo role for dendritic cells (DCs) has been poorly defined. Here, we investigated whether IL-7 is important for the development or maintenance of different DC types. Bone marrow–derived DCs expressed the IL-7 receptor (IL-7R) and survived significantly longer in the presence of IL-7. Migratory DCs (migDCs) isolated from lymph nodes also expressed IL-7R. Surprisingly, IL-7R was not required for their maintenance but indirectly for their development. Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) resident in lymph nodes and spleen were IL-7R−. Using mixed bone marrow chimeras, we observed an intrinsic requirement for IL-7R signals in their development. As the number of CLPs but not myeloid progenitors was reduced in the absence of IL-7 signals, we propose that a large fraction of cDCs and pDCs derives from CLPs and shares not only the lymphoid origin but also the IL-7 requirement with lymphocyte precursors.

Impaired Bone Marrow Microenvironment in Fanconi Anemia Murine Model Is Responsible for the Defective Hematopoietic Stem/ Progenitor Cell Mobilization.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3629-3629
Author(s):  
Yan Li ◽  
Shi Chen ◽  
Yongzheng He ◽  
Xiaohong Li ◽  
Fengchun Yang
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Fanconi Anemia ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Bone Marrow Microenvironment ◽  
Hematopoietic Stem

Abstract Abstract 3629 Poster Board III-565 Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by progressive bone marrow failure (BMF) and acquisition of malignancies. The only cure for BMF is a human leukocyte antigen (HLA)-matched BM transplantation from a family member or autologous stem cells before BMF develops. Therefore, mobilization of hematopoietic stem/progenitor cells (HSPCs) from BM into peripheral blood (PB) for collection has been a prerequisite for the therapy. However, patients with FA show a markedly decreased HSPC mobilization in response to the traditional mobilizing drug G-CSF and the mechanism(s) underlying the defect remains unknown. Mesenchymal stem/progenitor cells (MSPCs) have been known to be the common progenitor of a variety of cellular components in the bone marrow microenvironment. MSPCs express/secrete cytokines, extracellular matrix proteins and cell adhesion molecules, which regulate the homing, migration, proliferation and survival of HSPCs in vitro and in vivo. Recently, we reported that Fancg-/- MSPCs have a defect in hematopoietic supportive activity both in vitro and in vivo (Li et al. Blood, 2009). In the current studies, we show that Fancg-/- MSPCs have significant reduction in HSPC recruitment as compared to WT MSPCs in a transwell assay. Furthermore, Fancg-/- MSPCs have an alteration in the production of multiple cytokines/chemokines. Application of a neutralizing antibody to the cytokine blocked WT MSPC mediated HSPC migration in vitro. Furthermore, administration of the specific cytokine significantly increased HSPC mobilization in the Fancg-/- mice in vivo. These results demonstrated that an impaired BM microenvironment, specifically MSPCs in Fancg-/- mice, is contributory to defective HSPC mobilization. This study provides evidence of alternative clinical therapeutics for the mobilization of HSPCs in FA patients. Disclosures: No relevant conflicts of interest to declare.

Bone Marrow Niches for Skeletal Progenitor Cells and their Inhabitants in Health and Disease

2019 ◽  
Vol 14 (4) ◽  
pp. 305-319 ◽  
Author(s):  
Marietta Herrmann ◽  
Franz Jakob
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Adult Stem Cells ◽  
Current Knowledge ◽  
Cell Populations ◽  
Surface Markers ◽  
Bone Marrow Niches

The bone marrow hosts skeletal progenitor cells which have most widely been referred to as Mesenchymal Stem or Stromal Cells (MSCs), a heterogeneous population of adult stem cells possessing the potential for self-renewal and multilineage differentiation. A consensus agreement on minimal criteria has been suggested to define MSCs in vitro, including adhesion to plastic, expression of typical surface markers and the ability to differentiate towards the adipogenic, osteogenic and chondrogenic lineages but they are critically discussed since the differentiation capability of cells could not always be confirmed by stringent assays in vivo. However, these in vitro characteristics have led to the notion that progenitor cell populations, similar to MSCs in bone marrow, reside in various tissues. MSCs are in the focus of numerous (pre)clinical studies on tissue regeneration and repair.Recent advances in terms of genetic animal models enabled a couple of studies targeting skeletal progenitor cells in vivo. Accordingly, different skeletal progenitor cell populations could be identified by the expression of surface markers including nestin and leptin receptor. While there are still issues with the identity of, and the overlap between different cell populations, these studies suggested that specific microenvironments, referred to as niches, host and maintain skeletal progenitor cells in the bone marrow. Dynamic mutual interactions through biological and physical cues between niche constituting cells and niche inhabitants control dormancy, symmetric and asymmetric cell division and lineage commitment. Niche constituting cells, inhabitant cells and their extracellular matrix are subject to influences of aging and disease e.g. via cellular modulators. Protective niches can be hijacked and abused by metastasizing tumor cells, and may even be adapted via mutual education. Here, we summarize the current knowledge on bone marrow skeletal progenitor cell niches in physiology and pathophysiology. We discuss the plasticity and dynamics of bone marrow niches as well as future perspectives of targeting niches for therapeutic strategies.

scholarly journals Dendritic cells differentiate into osteoclasts in bone marrow microenvironment in vivo

Blood ◽  
2009 ◽  
Vol 113 (1) ◽  
pp. 264-265 ◽  
Author(s):  
Mawadda Alnaeeli ◽  
Yen-Tung A. Teng
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Bone Marrow Microenvironment
Sign in / Sign up

Export Citation Format

Share Document