Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Sakamaki, Sumio; Hirayama, Yasuo; Matsunaga, Takuya; Kuroda, Hiroyuki; Kusakabe, Toshiro; Akiyama, Takehide; Konuma, Yuichi; Sasaki, Katsunori; Tsuji, Naoki; Okamoto, Takahiro; Kobune, Masayoshi; Kogawa, Katsuhisa; Kato, Junji; Takimoto, Rishu; Koyama, Ryota; Niitsu, Yoshiro

doi:10.1182/blood.v94.6.1961

Cited by 71 publications

(43 citation statements)

References 38 publications

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“…Large Mk colonies arise from more primitive Mk progenitors. These results are in agreement with previously published data showing that TPO-mediated TGF-b activity is focused on mid CFU-Mk (Sakamaki et al, 1999).…”

Section: Patients D +7 D +14supporting

confidence: 94%

Carboxy‐terminal fragment of osteogenic growth peptide in vitro increases bone marrow cell density in idiopathic myelofibrosis

et al. 2003

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Summary. Idiopathic myelofibrosis (IMF) is a clonal stem cell disorder characterized by reactive fibrosis of bone marrow sustained by a complex cytokine network. At present, no efficacious therapy for this disease exists. Synthetic carboxy‐terminal pentapeptide of osteogenic growth factor (sOGP10‐14) can increase bone marrow cellularity and the number of haematopoietic colonies; this study evaluated the activity of sOGP10‐14 in IMF. Fragments of bone marrow biopsies from patients affected by IMF were cultured with or without the addition of sOGP10‐14. Cellular density was evaluated by image analysis, and transforming growth factor‐β1 (TGF‐β1) concentration was immunologically assayed in the supernatant of cultured bone marrow biopsies. The proliferation rate of the megakaryoblastic M07‐e cell line, cultured in the presence of either granulocyte–macrophage colony stimulating factor or thrombopoietin (TPO), and with or without sOGP10‐14, was evaluated. Megakaryocyte colony forming unit (CFU‐Mk) assay was performed on bone marrow samples of IMF patients with or without sOGP10‐14. After 14 d, bone marrow cellularity was significantly increased in samples cultured with the pentapeptide. Moreover, sOGP10‐14 induced a significant increase of TGF‐β in culture supernatants. TPO‐primed proliferation of M07‐e was reduced by sOGP10‐14, and the pentapeptide significantly reduced CFU‐Mk on IMF bone‐marrow‐derived cells. sOGP10‐14 increased ex vivo bone marrow cellularity in IMF. This action could be related to the megakaryocyte inhibition induced by the interference of this pentapeptide with growth factor activities. These findings suggest that a deficiency of osteoblast‐related factors may play a role in bone marrow failure in IMF.

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Section: Patients D +7 D +14supporting

confidence: 94%

Carboxy‐terminal fragment of osteogenic growth peptide in vitro increases bone marrow cell density in idiopathic myelofibrosis

et al. 2003

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“…60 45,64 These mediators control HSC proliferation, as noted above, and also constrain MK maturation. [64][65][66][67] PF4 and TGF-could potentially affect other immune cells through their receptors CXCR3B and TGF-R. 68,69 For example, PF4 and TGF-are potent neutrophil activators and promote neutrophil survival and migration, suggesting that MKs could modulate neutrophils before they are released into blood. [70][71][72][73][74][75] TGFis required for Th17 and inducible Treg differentiation.…”

Section: Megakaryocyte Immunoreceptors and Effector Moleculesmentioning

confidence: 99%

Megakaryocytes as immune cells

Cunin

Nigrović

2019

Journal of Leukocyte Biology

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Platelets play well‐recognized roles in inflammation, but their cell of origin—the megakaryocyte—is not typically considered an immune lineage. Megakaryocytes are large polyploid cells most commonly identified in bone marrow. Egress via sinusoids enables migration to the pulmonary capillary bed, where elaboration of platelets can continue. Beyond receptors involved in hemostasis and thrombosis, megakaryocytes express receptors that confer immune sensing capacity, including TLRs and Fc‐γ receptors. They control the proliferation of hematopoietic cells, facilitate neutrophil egress from marrow, possess the capacity to cross‐present antigen, and can promote systemic inflammation through microparticles rich in IL‐1. Megakaryocytes internalize other hematopoietic lineages, especially neutrophils, in an intriguing cell‐in‐cell interaction termed emperipolesis. Together, these observations implicate megakaryocytes as direct participants in inflammation and immunity.

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“…The concentrations of active TGF-␤ in bone marrow and peripheral blood were measured using the ELISA kit QuantikineTM (R&D Systems, Minneapolis, MN) [5]. Before the assay was run, 1 ml of bone marrow samples was diluted with normal saline (3-fold) containing 100 units/ml of heparin.…”

Section: Assay For Tgf-␤mentioning

confidence: 99%

“…However, its causative mechanism has not been clarified. We have recently reported that thrombopoietin (TPO) from bone marrow (BM) stromal cells plays an essential role in megakaryopoiesis under various pathophysiological conditions [4] and have furthermore identified transforming growth factor (TGF)-␤ as a strong suppressor of megakaryopoiesis [5]. Taking these facts into account, we focused on the effects of TPO and TGF-␤ in patients with cGVHD.…”

Section: Introductionmentioning

confidence: 99%

Thrombopoietin concentrations in peripheral blood correlated with platelet numbers in two patients with thrombocytopenia by chronic graft‐versus‐host disease

Hirayama¹,

Sakamaki²,

Tsuji³

et al. 2003

American J Hematol

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Thrombocytopenia is well known to be one of the clinical manifestations of chronic graft-versus-host disease (cGVHD). However, there exist cases in which the cause of thrombocytopenia has been unexplained. Recently, thrombopoietin (TPO) from bone marrow (BM) stromal cells and transforming growth factor (TGF)-␤ from platelets and megakaryocytes have been identified as strong positive and negative regulators of megakaryopoiesis in vivo. We hypothesized that the decreased TPO production from BM could be one of the causes of thrombocytopenia in the patients with cGVHD. In the present study, therefore, TPO and TGF-␤ concentrations in peripheral blood (PB) and BM were measured serially in two patients with acute leukemia who had received fully matched stem cell transplantation from relatives and subsequently developed extensive cGVHD with thrombocytopenia. The results showed that platelet numbers correlated well with the TPO concentrations, which were consistently higher in BM than in PB. The difference in TPO concentrations between BM and PB was decreased when the platelet levels were low, indicating that the amount of TPO production from BM decreased throughout the duration of thrombocytopenia. TGF-␤ concentrations were normal during all periods in which measurements were carried out. Thus, our results suggest that one mechanism of thrombocytopenia in patients with cGVHD is low TPO production by BM cells. Am. J. Hematol. 73:285-289, 2003.

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Transforming Growth Factor-β1 (TGF-β1) Induces Thrombopoietin From Bone Marrow Stromal Cells, Which Stimulates the Expression of TGF-β Receptor on Megakaryocytes and, in Turn, Renders Them Susceptible to Suppression by TGF-β Itself With High Specificity

Cited by 71 publications

References 38 publications

Carboxy‐terminal fragment of osteogenic growth peptide in vitro increases bone marrow cell density in idiopathic myelofibrosis

Carboxy‐terminal fragment of osteogenic growth peptide in vitro increases bone marrow cell density in idiopathic myelofibrosis

Megakaryocytes as immune cells

Thrombopoietin concentrations in peripheral blood correlated with platelet numbers in two patients with thrombocytopenia by chronic graft‐versus‐host disease

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