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Nature Mar 2021Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of...
Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors. LEPR cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin, distinguishes peri-arteriolar LEPR cells poised to undergo osteogenesis from peri-sinusoidal LEPR cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPRosteolectin cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin cells depleted osteolectin cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing.
Topics: Adipose Tissue; Aging; Animals; Arterioles; Bone Marrow Cells; Bone and Bones; Female; Hematopoietic Cell Growth Factors; Lectins, C-Type; Lymphocytes; Lymphopoiesis; Male; Mice; Osteogenesis; Receptors, Leptin; Stem Cell Factor; Stem Cell Niche; Stromal Cells
PubMed: 33627868
DOI: 10.1038/s41586-021-03298-5 -
International Journal of Cell Cloning Mar 1989Studies of the growth regulation, differentiation and transformation of myeloid cells have been greatly facilitated by the availability of a variety of hematopoietic... (Review)
Review
Studies of the growth regulation, differentiation and transformation of myeloid cells have been greatly facilitated by the availability of a variety of hematopoietic growth factor-dependent cell lines. These cell lines have been isolated from long-term bone marrow cultures and myeloid tumors using interleukin 3 (IL-3) as a growth factor. Using growth factor-dependent cells, it has been shown that growth regulation by IL-3 involves binding to a high-affinity receptor of 140 Kd and activation of tyrosine phosphorylation. IL-3 binding is associated with a number of cellular responses which are required for maintenance of viability, including induction of transcription of the c-myc and ornithine decarboxylase (ODC) genes. In addition, IL-3 regulates the expression of transcription of the gamma T cell receptor locus. The properties of the IL-3-dependent lines are consistent with the hypothesis that they are transformed in their ability to terminally differentiate. In some of the cell lines, this transformation may terminally differentiate. In other of the cell lines, this transformation may be due to the altered expression of the c-myb gene. In other cell lines, transformation is associated with the activation of the expression of a novel gene, termed Evi-1, of the zinc finger family of transcriptional factors. Comparable transformation of erythroid lineage cells is speculated to be due to the activation of the expression of another novel gene termed spi-1. These studies have emphasized the value of well-characterized hematopoietic growth factor-dependent cell lines in advancing our understanding in the basic biology of myeloid cells.
Topics: Animals; Cell Line; Growth Substances; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Interleukin-3; Tumor Cells, Cultured
PubMed: 2656885
DOI: 10.1002/stem.5530070202 -
The Yale Journal of Biology and Medicine 1990Normal hematopoiesis is a well-regulated process in which the generation of mature blood elements occurs from a primitive pluripotent stem cell in an ordered sequence of... (Review)
Review
Normal hematopoiesis is a well-regulated process in which the generation of mature blood elements occurs from a primitive pluripotent stem cell in an ordered sequence of maturation and proliferation. Regulation occurs at the level of the structured microenvironment (stroma), via cell-cell interactions and by way of the generation of specific hormones and cytokines: erythropoietin, interleukin 3, granulocyte-monocyte colony-stimulating factor (GM-CSF), monocyte-macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin 5, interleukin 4, and other less well-defined factors, including the megakaryocyte growth factors. Understanding of this complex process has revealed insights into the pathophysiology of human disease and provided a theoretical framework for the therapeutic use of bone marrow transplantation and potential gene transfer therapy. Furthermore, ongoing clinical trials suggest that the hematopoietic growth factors may represent a significant new group of therapeutic reagents for patients with hematological and oncologic disease.
Topics: Cell Differentiation; Forecasting; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Receptors, Colony-Stimulating Factor
PubMed: 2293498
DOI: No ID Found -
Frontiers in Immunology 2018Sepsis is a complex syndrome characterized by simultaneous activation of pro- and anti-inflammatory processes. After an inflammatory phase, patients present signs of... (Review)
Review
Sepsis is a complex syndrome characterized by simultaneous activation of pro- and anti-inflammatory processes. After an inflammatory phase, patients present signs of immunosuppression and possibly persistent inflammation. Hematopoietic growth factors (HGFs) are glycoproteins that cause immune cells to mature and/or proliferate. HGFs also have a profound effect on cell functions and behavior. HGFs play crucial role in sepsis pathophysiology and were tested in several clinical trials without success to date. This review summarizes the role played by HGFs during sepsis and their potential therapeutic role in the Management of sepsis-related immune disturbances.
Topics: Animals; Clinical Trials as Topic; Disease Models, Animal; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Immunotherapy; Inflammation; Interleukins; Mice; Rats; Sepsis
PubMed: 29977234
DOI: 10.3389/fimmu.2018.01015 -
CA: a Cancer Journal For Clinicians 1996Over the past ten years, the availability of pharmacologic quantities of hematopoietic growth factors has opened many avenues of study in basic science and clinical... (Review)
Review
Over the past ten years, the availability of pharmacologic quantities of hematopoietic growth factors has opened many avenues of study in basic science and clinical investigation. Numerous studies performed to date have demonstrated significant benefits from the use of these cytokines. The side effect profiles, particularly for "later acting" growth factors, indicate that they are generally well tolerated by most patients. The table summarizes the potential indications for hematopoietic growth factor use as discussed in this article, as justified by current evidence of benefit, harm, and cost effectiveness resulting from their use in various clinical settings. It has been clearly demonstrated in standard-dose chemotherapy regimens that these agents shorten the duration of myelosuppression, reduce the incidence of significant infection, can shorten hospital stay, and reduce antibiotic use for most patients, although the cost/benefit ratio for growth factors such as G-CSF makes this a cost-effective approach only for regimens with a high (40 percent or more) incidence of febrile neutropenia. Limited indirect evidence supports the use of growth factors in patients with a prior episode of fever and neutropenia. The suppressive approach to growth factor use could potentially benefit patients with documented infection or clinical deterioration, but it has not otherwise been shown to be a particularly effective or cost-effective approach. Administration of hematopoietic growth factors has been instrumental in facilitating both autologous and allogeneic peripheral progenitor cell mobilization and techniques such as ex vivo expansion. There is an increasing body of data supporting the use of high-dose chemotherapy regimens with progenitor cell rescue for a number of malignancies and limited data supporting the benefits of maintaining dose-intensity for certain malignancies in standard-dose settings. Although of continuing concern, clinically significant evidence of disease stimulation and recurrence has not been unequivocally demonstrated in studies to date. A comprehensive set of evidence-based guidelines has recently been published by the American Society of Clinical Oncology. As often is the case, current studies have perhaps generated more questions than answers. Future investigation will undoubtedly focus on use of hematopoietic growth factors in conjunction with other techniques, such as outpatient-based treatment of febrile neutropenia, CD34-positive stem cell selection in autologous transplantation, selective manipulation of T-cell subsets (to decrease the incidence of severe graft-versus-host disease) in allogeneic transplantation, and high-dose therapy with stem cell transplantation.
Topics: Anemia; Animals; Erythropoietin; GPI-Linked Proteins; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Leukemia; Lymphoma; Membrane Glycoproteins; Mesothelin; Multiple Myeloma; Neoplasms; Proteins
PubMed: 8646546
DOI: 10.3322/canjclin.46.3.165 -
Blood Jun 1994Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the...
Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all-trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.
Topics: Cell Differentiation; Cells, Cultured; Hematopoietic Cell Growth Factors; Humans; Leukemia, Promyelocytic, Acute; Tretinoin
PubMed: 8193361
DOI: No ID Found -
Haematologica May 2009Immunosuppressive therapy is the treatment for aplastic anemia patients ineligible for transplantation. The role of hematopoietic growth factors as adjunct to treatment... (Meta-Analysis)
Meta-Analysis Review
Immunosuppressive therapy is the treatment for aplastic anemia patients ineligible for transplantation. The role of hematopoietic growth factors as adjunct to treatment in these patients is unclear. We conducted a systematic review and meta-analysis of randomized controlled trials comparing treatment with immunosuppressive therapy and hematopoietic growth factors to immunosuppressive therapy alone in patients with aplastic anemia. Two reviewers appraised the quality of trials and extracted data. For each trial, results were expressed as relative risks with 95% confidence intervals (CI) for dichotomous data. The addition of hematopoietic growth factors yielded no difference in overall mortality at 100 days, one year and five years [relative risks 1.33 (95% CI 0.56-3.18), relative risks 0.90 (95% CI 0.50-1.63) and relative risks 0.89 (95% CI 0.55-1.46), respectively]. There was no difference in overall hematologic response and in the occurrence of infections. HGF significantly decreased the risk for relapse, relative risks 0.45 (95% CI 0.30-0.68, 3 trials). Hematopoietic growth factors were not associated with higher occurrence of myelodysplastic syndrome and acute myeloid leukemia or paroxysmal nocturnal hemoglobinuria. The addition of hematopoietic growth factors does not affect mortality, response rate or infections occurrence. Therefore, it should not be recommended routinely as an adjunct to the immunosuppressive therapy for patients with aplastic anemia.
Topics: Anemia, Aplastic; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Survival Analysis; Survival Rate; Treatment Outcome
PubMed: 19336743
DOI: 10.3324/haematol.2008.002170 -
Blood Oct 2001Because interleukin-18 (IL-18) is similar to IL-1 and is known to be involved in the hematopoietic progenitor cell growth, the effect of IL-18 on circulating cell...
Because interleukin-18 (IL-18) is similar to IL-1 and is known to be involved in the hematopoietic progenitor cell growth, the effect of IL-18 on circulating cell populations was examined. Repeated administration of IL-18 induced significant amounts of neutrophilia in mice. In parallel, high levels of interferon-gamma (IFN-gamma), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were detected in the serum of these mice. Interestingly, the cytokine profiles as well as the cell populations in circulation altered around 2 weeks after the beginning of IL-18 administration. A weak but definite eosinophilia was observed concurrently with the appearance of serum IL-5. Consistent with these observations, IL-18 induced secretion of IFN-gamma, GM-CSF, and IL-6 from splenocytes in culture. IL-18 also induced low levels of IL-5 in the splenocyte culture, which was inhibited by IL-12. However, markedly high levels of IL-5 were secreted into the culture medium when splenocytes from IFN-gamma-deficient mice were stimulated by IL-18. CD4(+) T cells strongly responded to IL-18 to secrete IL-5 and GM-CSF. IL-18 stimulated secretion of IL-6 and expression of G-CSF mRNA in splenic adherent cells. Expression of IL-18 receptors was detected in CD4(+) T cells and splenic adherent cells (macrophages). These results show that IL-18 stimulates CD4(+) T cells and macrophages to secrete IL-5, GM-CSF, IL-6, and granulocyte-colony stimulating factor in the absence of IL-12, which in turn induces hematopoietic cell proliferation causing neutrophilia and eosinophilia in mice.
Topics: Animals; Cytokines; Drug Interactions; Female; Granulocytes; Hematopoietic Cell Growth Factors; Interferon-gamma; Interleukin-18; Leukocyte Count; Mice; Mice, Inbred BALB C; Mice, Knockout; Spleen; T-Lymphocytes
PubMed: 11567996
DOI: 10.1182/blood.v98.7.2101 -
International Journal of Cell Cloning Sep 1991Hematopoietic stem cells (HSCs) are distinguished from other hematopoietic progenitors in bone marrow by their unique ability to undergo multilineage differentiation and... (Review)
Review
Hematopoietic stem cells (HSCs) are distinguished from other hematopoietic progenitors in bone marrow by their unique ability to undergo multilineage differentiation and self-renewal. Two mouse mutations, dominant spotting (W) and steel (Sl), have pleiotropic effects on hematopoiesis, gametogenesis, and melanoblast development. These two mutations have been shown to be intrinsic (W) and microenvironmental (Sl) defects. Recently, molecular studies revealed that the W and Sl loci encode the c-kit receptor and steel factor (SLF), respectively. The c-kit receptor is expressed on HSCs and hematopoietic progenitors, while SLF is produced by stromal cells. SLF acts on hematopoietic progenitors synergistically with other growth factors. Here we review the effect of these mutations on mouse hematopoiesis, and show that SLF acts on HSCs and other myeloerythroid progenitors, but that it, in our hands, does not play a critical role in HSC generation or self-renewal. Rather, SLF is the most potent co-mitogen (with IL-1, IL-3, IL-6, G-CSF, GM-CSF, or M-CSF) found that acts on these cells, but the effect of such treatments is the rather specific and massive expansion of myeloerythropoiesis, not lymphopoiesis, and perhaps at the expense of HSC self-renewal.
Topics: Animals; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Mice; Mutation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; Stem Cell Factor
PubMed: 1720154
DOI: 10.1002/stem.1991.5530090503 -
Blood Jun 1994The cell-surface receptor c-kit and its cognate ligand stem-cell factor (SCF) or steel factor (SLF) are important for the maintenance of hematopoiesis both in vitro and...
The cell-surface receptor c-kit and its cognate ligand stem-cell factor (SCF) or steel factor (SLF) are important for the maintenance of hematopoiesis both in vitro and in vivo. Transforming growth factor-beta (TGF-beta) has been shown to be a potent inhibitor of SLF-mediated synergistic growth of murine Lin-Sca-1+ progenitor cells, as well as more committed progenitors. In the present study, we examined the regulation of c-kit mRNA and cell-surface expression by TGF-beta. Among the murine hematopoietic progenitor cells tested, the myeloid cell line FDC-P1 and the mast-cell line MC-6, as well as progenitor-enriched bone marrow cells, constitutively expressed functional cell-surface c-kit. Treatment of these progenitor cell lines and primary progenitor cells with TGF-beta resulted in downregulation of cell-surface c-kit expression. This effect was not a secondary event of cell-cycle status. TGF-beta inhibition was dose- and time-dependent, with 50% inhibition seen between 0.3 to 3 ng/mL TGF-beta and maximal inhibition at 30 ng/mL. Using the FDC-P1 cell line, we observed that the inhibition of cell-surface c-kit expression by TGF-beta is preceded by a marked reduction in c-kit mRNA levels starting 2 hours after TGF-beta treatment, and reaches a maximum by 6 hours. The inhibition in steady-state c-kit mRNA levels is explained, in part, by a decrease in the half-life of c-kit transcripts (2 to 4 hours for control cells v 0.5 to 1.5 hours for TGF-beta-treated cells). These findings suggest that TGF-beta regulates the responsiveness of murine hematopoietic progenitors to SLF through a decrease in c-kit message stability leading to decreased cell-surface expression.
Topics: Animals; Cell Cycle; Cell Line; Female; Gene Expression Regulation; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; RNA, Messenger; Receptor Protein-Tyrosine Kinases; Receptors, Colony-Stimulating Factor; Stem Cell Factor; Transforming Growth Factor beta
PubMed: 7514900
DOI: No ID Found