Induction of IL-6 production by bone marrow stromal cells on the adhesion of IL-6-dependent hematopoietic cells

Ogasawara, Hiroyuki; Tsuji, Takashi; Hirano, Daisuke; Aoki, Yoshiko; Nakamura, Motonao; Kodama, Hisashi

doi:10.1002/(sici)1097-4652(199610)169:1<209::aid-jcp21>3.0.co;2-6

Cited by 20 publications

(11 citation statements)

References 41 publications

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“…14,15 IL-6 is produced by MSCs 11 and by other BM stromal cells 16,26,27 ; through cytokine production, stromal cells may thus stimulate hematopoiesis in LTBMCs. Stromal formation in LTBMCs is IL-6 concentration-dependent 15 ; reduced stromal growth was observed in cultures established in horse serum with low IL-6 concentrations (170 mU/mL, equivalent to approximately 15 pg/mL), but IL-6 addition (10 U/mL) did not improve the morphology of these cultures.…”

Section: Discussionmentioning

confidence: 99%

“…24,25 IL-6 is produced by MSCs as well as by other BM stromal cells. 26,27 MSCs do not express the IL-6 receptor and do not respond to IL-6 11 ; however, the IL-6-rich For personal use only. on May 9, 2018. by guest www.bloodjournal.org From environment in BM stroma can induce osteoblastic differentiation of marrow-derived mesenchymal progenitors in the presence of glucocorticoids and Taking into consideration the role of IL-6 in hematopoietic progenitor and MSC regulation, we analyzed whether the hematopoietic deficiency observed in IL-6 Ϫ/Ϫ mice can be attributed to a defect in the hematopoietic supportive activity of IL-6 Ϫ/Ϫ BM stromal cells, and the extent to which development and maintenance of the MSC compartment is affected by the absence of IL-6.…”

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confidence: 99%

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Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support

Rodrı́guez

Bernad

Aracil

2004

Blood

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Interleukin-6 (IL-6) is a critical factor in the regulation of stromal function and hematopoiesis. In vivo bromodeoxyuridine incorporation analysis indicates that the percentage of Lin ؊ Sca-1 ؉ hematopoietic progenitors undergoing DNA synthesis is diminished in IL-6-deficient (IL-6 ؊/؊ ) bone marrow (BM) compared with wild-type BM. Reduced proliferation of IL-6 ؊/؊ BM progenitors is also observed in IL-6 ؊/؊ long-term BM cultures, which show defective hematopoietic support as measured by production of total cells, granulocyte macrophage-colony-forming units (CFU-GMs), and erythroid burstforming units (BFU-Es). Seeding experiments of wild-type and IL-6 ؊/؊ BM cells on irradiated wild-type or IL-6-deficient stroma indicate that the hematopoietic defect can be attributed to the stromal and not to the hematopoietic component. In IL-6 ؊/؊ BM, stromal mesenchymal precursors, fibroblast CFUs (CFU-Fs), and stroma-initiating cells (SICs) are reduced to almost 50% of the wild-type BM value. Moreover, IL-6 ؊/؊ stromata show increased CD34 and CD49e expression and reduced expression of the membrane antigens vascular cell adhesion molecule-1 (VCAM-1), Sca-1, CD49f, and Thy1. These data strongly suggest that IL-6 is an in vivo growth factor for mesenchymal precursors, which are in part implicated in the reduced longevity of the long-term repopulating stem cell compartment of IL-6 ؊/؊ mice. IntroductionInterleukin-6 (IL-6) is a multifunctional cytokine with a major role in inflammatory responses and is the primary inducer of acutephase proteins. 1 IL-6 also regulates the proliferation and differentiation of hematopoietic cells from several lineages at different maturation stages. 1 In synergy with IL-3, IL-6 stimulates proliferation of granulocyte-macrophage, megakaryocyte, and erythroid progenitors. [2][3][4][5] This cooperation has also been shown in several in vivo model systems designed to evaluate the effect of IL-6 on the stem cell compartment. 3,4,6 The specific contribution of IL-6 to homeostasis in the lymphohematopoietic system has been evaluated in the IL-6 Ϫ/Ϫ mouse model, which showed a clear reduction in the number of the earliest clonogenic precursors and in the function of long-term repopulating stem cells (LTRSCs). 7 IL-6 Ϫ/Ϫ mice show a decrease in absolute numbers of spleen colonyforming units (CFU-Ss) at day 12 and of pre-CFU-S hematopoietic progenitors, as well as a deficit in the LTRSC compartment. 7 In addition to the effects in early hematopoiesis, IL-6 Ϫ/Ϫ mice show defects in T-and B-cell function 8 and in acute-phase responses. 9 These results strongly suggest an important in vivo role for IL-6 in the survival and self-renewal of hematopoietic stem cells (HSCs) and early progenitors.IL-6 is produced by a variety of cells including T and B cells, macrophages, fibroblasts, bone marrow stromal cells, and mesenchymal cells. [10][11][12] The adherent stromal cell layer in long-term bone marrow cultures (LTBMCs) is necessary for balanced proliferation and differentiation of hematopoietic progenitors. 13 ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support

Rodrı́guez

Bernad

Aracil

2004

Blood

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“…Noticeable positive blotting was observed for the genes of IL‐6 and IL‐8. IL‐6 is reported to show an extremely high level of expression in the bone marrow stroma compared with other cytokines and to play an important role in maintaining MSC in the undifferentiated state, in addition to its other diverse biological functions . IL‐8 is a potent chemokine known to recruit inflammatory cells and endothelial cells .…”

Section: Discussionmentioning

confidence: 99%

Bone‐healing capacity of conditioned medium derived from three‐dimensionally cultivated human mesenchymal stem cells and electrical stimulation on collagen sponge

Hwang

Cho

Lee

et al. 2017

J Biomedical Materials Res

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Continuing from our previous study, we hypothesized that combining electrical stimulation (ES) and three-dimensional (3D) culture would be a useful strategy to obtain more bioactive factors in conditioned medium (CM) derived from human mesenchymal stem cells (hMSC). Our aim in this study was to investigate the bone-healing capacity of CM derived from hMSC after 4 days of culture on a collagen sponge-exposed (CM-ES) or unexposed (CM-control; CM-CON) to ES in comparison with that of hMSC implantation. A cytokine assay of both CMs revealed the presence of cytokines, growth factors, and trophic factors. In vitro evaluation of both CMs showed increased cell growth and alkaline phosphatase activity of the hMSC, with little difference between CMs. We investigated the bone-healing effect using two bone disease models: bone defect and inflammatory bone loss. The calvaria defect was implanted with whole CM or 3D-precultured hMSC unexposed to ES. Microcomputed tomography analysis after 4 weeks indicated a twofold greater bone volume in the CM-CON and CM-ES groups than in the hMSC and vehicle groups, though we found no difference between the CM groups. However, CM-ES enhanced the bone healing of interleukin-1-induced bone loss to a level comparable with hMSC, whereas CM-CON did not. These results show that 3D-cultured CM had a greater or similar capacity for bone healing as treatment using hMSC transplantation, and CM-ES was especially effective against inflammatory bone loss. Thus, 3D-cultured CM with or without ES presents an encouraging alternative to MSC-based bone healing. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 311-320, 2018.

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“…However, the tumor cells still failed to engraft and grow in the bone marrow and spleen and to circulate in the blood stream of these Tg-SCID mice. To improve these models by overcoming this problem, one approach may be the introduction of other hematopoietic growth factors belonging to the receptor tyrosine kinase groups or the gp130 groups, adhesion molecules, or extracellular matrixes to provide a more appropriate microenvironment for hematopoietic cells [22,23,24,25,26,27] in the hGM-CSF and hIL-3 Tg-SCID by mating with other Tg mice. The development of Tg-NOD/SCID may be another approach [6,28], because NOD-SCID mice have a superior capacity to support normal and leukemic human transplants due to their multiple defects in immunological function when compared with SCID mice of other strain backgrounds [29,30,31].…”

Section: Discussionmentioning

confidence: 99%

Human acute myeloblastic leukemia-ascites model using the human GM-CSF- and IL-3-releasing transgenic SCID mice

Fukuchi¹,

Miyakawa

Kizaki

et al. 1999

Annals of Hematology

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To generate an appropriate model for human acute myeloblastic leukemia (AML), we have successfully established a human hematopoietic growth factor-dependent AML cell line (TF-1 and UT-7/GM)-ascites model using human granulocyte-macrophage colony-stimulating factor (hGM-CSF)- and human interleukin 3 (hIL-3)-releasing transgenic (Tg)-SCID mice. When 1 x 10(7) cells of TF-1, a human erythroleukemia cell line, were transplanted into the peritoneum of irradiated Tg-SCID mice (TF-1 ip/Tg-SCID mice), TF-1 cells grew in both the single cell suspension form (asTF-1) and solid form in ascites and invaded various tissues: lungs, liver, pancreas, and genitals, 3-6 weeks following transplantation. Subsequently, 0.5-1 x 10(7) cells of UT-7/GM, a subline of the UT-7 human megakaryoblastic leukemia cell line, grown in the back of hGM-CSF Tg-SCID mice after subcutaneous inoculation, were transplanted into the peritoneum of other irradiated hGM-CSF Tg-SCID mice. After 4 weeks, UT-7/GM cells (asUT-7/GM) also grew in the same manner as TF-1 cells in hGM-CSF Tg-SCID mice. Analysis of the cells from the peritoneum and tissues by PCR amplifying ALU and human GM-CSF receptor beta sequences and by immunohistochemical staining using anti-human CD45 revealed that they possessed the original characteristics of the parental cells. To confirm the usefulness of this human AML-ascites model, experimental treatment of AML cells grown in these mice was carried out with a differentiation inducer, delta-aminolevulinic acid (deltaALA), which induces hemoglobin synthesis for TF-1 in vitro and is thus regarded as an anti-leukemia drug candidate. Unexpectedly, growth promotion of TF-1 cells was observed in the treated TF-1 ip/hIL-3 Tg-SCID mice without differentiation to erythroid cells after treatment with delta-ALA (5 mM) for 7 days. These results indicate that Tg-SCID mice can support the growth of human hematopoietic growth factor-dependent AML cell lines which are usually rejected by SCID mice, without modification of the parental cell characteristics. In addition, this Tg-SCID leukemia-ascites model may become a useful preclinical tool for estimation of drug efficacy in vivo, since the drug candidate which was promising in vitro did not act in the same manner in vivo.

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Induction of IL-6 production by bone marrow stromal cells on the adhesion of IL-6-dependent hematopoietic cells

Cited by 20 publications

References 41 publications

Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support

Interleukin-6 deficiency affects bone marrow stromal precursors, resulting in defective hematopoietic support

Bone‐healing capacity of conditioned medium derived from three‐dimensionally cultivated human mesenchymal stem cells and electrical stimulation on collagen sponge

Human acute myeloblastic leukemia-ascites model using the human GM-CSF- and IL-3-releasing transgenic SCID mice

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