TGF-β–induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche

Yahata, Takashi; Ibrahim, Abd Aziz; Muguruma, Yukari; Eren, Mesut; Shaffer, Alexander; Watanabe, Nobuo; Kaneko, Satoko; Nakabayashi, Tetsuo; Dan, Takashi; Hirayama, Noriaki; Vaughan, Douglas E.; Miyata, Toshio; Ando, Kiyoshi

doi:10.1182/blood-2017-02-767384

Cited by 38 publications

(37 citation statements)

References 59 publications

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“…Recently, we showed that TGF-β signaling regulates the motility of HSPCs in the niche through selective upregulation of iPAI-1 expression in HSPCs 17,20 . Therefore, we hypothesized that the TGF-β−iPAI-1 axis is similarly operational in CML-LSCs.…”

Section: Tgf-β-ipai-1 Axis Is Activated In Cml-lscsmentioning

confidence: 99%

“…Like their normal hematopoietic counterparts, CML-LSCs are presumed to reside in specific niches in the BM microenvironment, which likely to contribute to relapse after chemotherapy [14][15][16] . Recently, we have uncovered a pathway by which TGF-β signaling regulates HSPC retention in the niche 17 . TGF-β induces the expression of plasminogen activator inhibitor-1 (PAI-1), a major physiologic serine protease 4 inhibitor (SERPIN) of the fibrinolytic system.…”

Section: Introductionmentioning

confidence: 99%

“…TGF-β induces the expression of plasminogen activator inhibitor-1 (PAI-1), a major physiologic serine protease 4 inhibitor (SERPIN) of the fibrinolytic system. In HSPCs, PAI-1, known conventionally as an extracellular fibrinolysis-related serpin, functions intracellularly (hereinafter referred to as iPAI-1) and inhibits the proteolytic activity of proprotein convertase, furin, which consequently diminishes membrane type-1 metalloprotease (MT1-MMP) activity 17 . MT1-MMP promotes HSPC motility by breaking down pericellular matrix proteins and adhesion molecules necessary for anchoring HSPCs to the niche 18,19 .…”

Section: Introductionmentioning

confidence: 99%

“…Genetic or pharmacological inhibition of TGF-β-iPAI-1 signaling increases MT1-MMP-dependent cellular motility, causing a detachment of HSPCs from the niche, making them receptive to extraneous stimuli 17,20 . In line with our report, a number of studies have demonstrated that both TGF-β and PAI-1 play important roles in numerous physiological and pathological conditions, including wound healing, obesity, cardiovascular disease and cancer [21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

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Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells

Yahata¹,

Ibrahim²,

Hirano³

et al. 2020

haematol

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Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells. Word counts: The submission includes 3,997 words in the main text; 192 words in the abstract; 6 figures; 2 supplemental figures; 1 supplemental table; 1 supplemental method; 50 references. 2 AbstractTherapeutic strategies that target leukemic stem cells (LSCs) provide potential advantages in the treatment of chronic myeloid leukemia (CML). Here, we show that selective blockade of plasminogen activator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSCs to tyrosine kinase inhibitor (TKI), which facilitates the eradication of CML-LSCs and leads to sustained remission of the disease. We demonstrated for the first time that TGF-β−PAI-1 axis was selectively augmented in CML-LSCs in the bone marrow (BM), whereby protecting CML-LSCs from TKI treatment. Furthermore, the combined administration of TKI plus a PAI-1 inhibitor, in a mouse model of CML, significantly enhanced the eradication of CML cells in the BM and prolonged the survival of CML mice. The combined therapy of imatinib and a PAI-1 inhibitor prevented the recurrence of CML-like disease in serially transplanted recipients, indicating the elimination of CML-LSCs. Interestingly, PAI-1 inhibitor treatment augmented membrane-type matrix metalloprotease-1 (MT1-MMP)-dependent motility of CML-LSCs, and the anti-CML effect of PAI-1 inhibitor was extinguished by the neutralizing antibody for MT1-MMP, underlining the mechanistic importance of MT1-MMP. Our findings provide evidence of, and a rationale for, a novel therapeutic tactic, based on the blockade of PAI-1 activity, for CML patients.

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Section: Tgf-β-ipai-1 Axis Is Activated In Cml-lscsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells

Yahata¹,

Ibrahim²,

Hirano³

et al. 2020

haematol

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“…Moreover, $20% of BM LT-HSCs that are physically connected to megakaryocytes are quiescent, as assessed by their cell cycle status (G0) and intracellular ROS concentration [8,45] (Figure 2C). TGFb from megakaryocytes promotes HSPC retention in the niche, at least partly by repressing expression of MMP14, which is downstream of Smad3 and PAI-1 in the TGFbR signaling pathway; and, inhibition of TGFb signaling with the small-molecule inhibitor LY364947 activates MMP14 and the subsequent disruption of adhesion molecules can promote LT-HSC mobility [46]. Megakaryocytes express TIMPs as well as MMP2 and MMP9, which could provide a means of local TGFb regulation, and HSPCs express MMP2, 9, and 14.…”

Section: Tgfbmentioning

confidence: 99%

Metalloproteases: On the Watch in the Hematopoietic Niche

Saw

Weiss

Khokha

et al. 2019

Trends in Immunology

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Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble factors in the niche respond to stress and enable progenitor activity. Metalloproteases (MMPs, ADAMs, ADAMTSs) and their inhibitors (TIMPs) control certain physical and biochemical features of the niche by altering protease-dependent bioavailability of local niche factors (e.g., CXCL12, SCF, TGFb, VEGF), matrix turnover, and cellular interactions. With over 40 examples of diverse metalloprotease substrates known to trigger fate-changing decisions, the spatially confined activity of this multi-member protease family is ideally positioned to constitute a higher order control over hematopoiesis. Comprehension of regulated proteolysis in the bone marrow may fuel innovative strategies to harness HSC fate and function. Metalloproteases Can Orchestrate Physical and Biochemical Cues for Mammalian HematopoiesisHSCs are the only cells able to reconstitute all blood cell lineages. HSCs reside in a niche that provides instructions for self-renewal or the signals to develop into specific progenitors. The niche serves as a physical address (perivascular bone marrow for most adult HSC) and comprises various entities, including support cells (macrophages, megakaryocytes, osteoblasts, endothelial, perivascular, and specialized reticular cells), the extracellular matrix (ECM; comprising structural collagens, fibronectin, and laminin), local growth factors and cytokines, shear forces of circulation, oxygen tension, and sympathetic innervation [1-3]. These features create a discrete environment for the quiescence and maintenance of the HSC pool or proliferation and differentiation into progenitors, which give rise to all effector blood cells during homeostasis and following stress (e.g., pregnancy, anemia, infection, and irradiation). In both mice and humans, the initial location of hematopoietic cells is the early embryonic yolk sac and aorta-gonad-mesonephros; they subsequently reside in the embryonic liver before taking up residence in the bone marrow (BM) [4]. The spleen and liver provide additional poststress sites of hematopoiesis for mobilized HSCs in the adult. Most HSCs are perivascular in the BM, with other cellular players providing support through cell-cell contact or delivery of soluble factors (detailed elsewhere) [1,2].Along with structural and physical properties of the ECM shaping the niche, the ECM is a growth factor-rich scaffold that mediates many of the extracellular interactions. Multiple aspects of the niche entities are subject to regulation by metalloproteases and their natural inhibitors. Metalloproteases are the largest of the five groups of proteases in the human genome (Box 1), where metzincins have a zinc at the active site and include enzymes such as matrix metalloproteases (MMPs), a disintegrin and metalloproteases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs); these are inhibited by tissue inhibitors of metalloproteases (TIM...

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Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations

Zhang,

Tian,

Majumdar

et al. 2024

Comprehensive Physiology

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Bone marrow adipose tissue (BMAT) is a metabolically and clinically relevant fat depot that exists within bone. Two subtypes of BMAT, regulated and constitutive, reside in hematopoietic‐rich red marrow and fatty yellow marrow, respectively, and exhibit distinct characteristics compared to peripheral fat such as white and brown adipose tissues. Bone marrow adipocytes (BMAds) are evolutionally preserved in most vertebrates, start development after birth and expand throughout life, and originate from unique progenitor populations that control bone formation and hematopoiesis. Mature BMAds also interact closely with other cellular components of the bone marrow niche, serving as a nearby energy reservoir to support the skeletal system, a signaling hub that contributes to both local and systemic homeostasis, and a final fuel reserve for survival during starvation. Though BMAT and bone are often inversely correlated, more BMAT does not always mean less bone, and the prevention of BMAT expansion as a strategy to prevent bone loss remains questionable. BMAT adipogenesis and lipid metabolism are regulated by the nervous systems and a variety of circulating hormones. This contributes to the plasticity of BMAT, including BMAT expansion in common physiological or pathological conditions, and BMAT catabolism under certain extreme circumstances, which are often associated with malnutrition and/or systemic inflammation. Altogether, this article provides a comprehensive overview of the local and systemic functions of BMAT and discusses the regulation and plasticity of this unique adipose tissue depot in health and disease. © 2024 American Physiological Society. Compr Physiol 14:5521‐5579, 2024.

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TGF-β–induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche

Cited by 38 publications

References 59 publications

Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells

Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells

Metalloproteases: On the Watch in the Hematopoietic Niche

Function and Regulation of Bone Marrow Adipose Tissue in Health and Disease: State of the Field and Clinical Considerations

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