Matrix metalloproteinases in stem cell mobilization

Klein, Gerd; Schmal, Olga; Aicher, Wilhelm K.

doi:10.1016/j.matbio.2015.01.011

Cited by 57 publications

(41 citation statements)

References 76 publications

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“…Proteolytic degradation, in turn, facilitates enhanced movement across the physical barrier of the BM extracellular matrix. [109][110][111] It has been suggested that high levels of thrombin can prime the migration of HSPCs toward a gradient of CXCL12, enabled by upregulation of proteolytic enzymes. 112 Thrombin induced MMP-9 secretion and upregulation of MT1-MMP expression in human cord blood CD34 + cells, leading to enhanced chemoinvasion of HSPCs toward a low CXCL12 gradient.…”

Section: Thrombin/par1 Signaling Regulates Hsc Mobilizationmentioning

confidence: 99%

Regulation of long‐term repopulating hematopoietic stem cells by EPCR/PAR1 signaling

Gur-Cohen

Graf

Esmon

et al. 2016

Annals of the New York Academy of Sciences

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The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adult murine bone marrow (BM) long-term repopulating hematopoietic stem cells (LT-HSCs), endowed with the highest repopulation and self-renewal potential, express endothelial protein C receptor (EPCR), which is used as a marker to isolate them. EPCR/PAR1 signaling in endothelial cells has anticoagulant and anti-inflammatory roles, while thrombin/PAR1 signaling induces coagulation and inflammation. Recent studies define two new PAR1-mediated signaling cascades that regulate EPCR+ LT-HSC BM retention and egress. EPCR/PAR1 signaling facilitates LT-HSC BM repopulation, retention, survival, and chemotherapy resistance by restricting nitric oxide (NO) production, maintaining NOlow LT-HSC BM retention with increased VLA4 expression, affinity, and adhesion. Conversely, acute stress and clinical mobilization upregulate thrombin generation and activate different PAR1 signaling which overcomes BM EPCR+ LT-HSC retention, inducing their recruitment to the bloodstream. Thrombin/PAR1 signaling induces NO generation, TACE-mediated EPCR shedding, and upregulation of CXCR4 and PAR1, leading to CXCL12-mediated stem and progenitor cell mobilization. This review discusses new roles for factors traditionally viewed as coagulation related, which independently act in the BM to regulate PAR1 signaling in bone- and blood-forming progenitor cells, navigating their fate by controlling NO production.

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Section: Thrombin/par1 Signaling Regulates Hsc Mobilizationmentioning

confidence: 99%

Regulation of long‐term repopulating hematopoietic stem cells by EPCR/PAR1 signaling

Gur-Cohen

Graf

Esmon

et al. 2016

Annals of the New York Academy of Sciences

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“…4,5 Several proteases can cleave these interactions, including cell surface enzyme dipeptidyl peptidase IV (CD26); secreted matrix metalloproteases MMP-9 and MMP-13; elastase; and cathepsins G and K. 28,29 This cleavage results in the loss of retention and consequent egress of HSPC. The membrane type-1 MT1-MMP (synonym MMP-14) promotes HSPC motility by degrading pericellular extracellular matrix proteins, vascular cell adhesion molecule-1, SDF-1, and CD44, which triggers the increase of VLA-4 and CXCR4 expression.…”

Section: Introductionmentioning

confidence: 99%

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

Yahata

Ibrahim

Muguruma

et al. 2017

Blood

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Key Points• TGF-b-induced intracellular PAI-1 regulates the balance of HSPCs localization between BM and periphery.• Intracellular PAI-1 inhibits Furin-dependent maturation of MT1-MMP in HSPCs, resulting in the suppression of HSPC motility.Hematopoietic stem and progenitor cells (HSPCs) reside in the supportive stromal niche in bone marrow (BM); when needed, however, they are rapidly mobilized into the circulation, suggesting that HSPCs are intrinsically highly motile but usually stay in the niche. We questioned what determines the motility of HSPCs. Here, we show that transforming growth factor (TGF)-b-induced intracellular plasminogen activator inhibitor (PAI)-1 activation is responsible for keeping HSPCs in the BM niche. We found that the expression of PAI-1, a downstream target of TGF-b signaling, was selectively augmented in niche-residing HSPCs. Functional inhibition of the TGF-b2PAI-1 signal increased MT1-MMP-dependent cellular motility, causing a detachment of HSPCs from the TGF-b-expressing niche cells, such as megakaryocytes. Furthermore, consistently high motility in PAI-1-deficient HSPCs was demonstrated by both a transwell migration assay and reciprocal transplantation experiments, indicating that intracellular, not extracellular, PAI-1 suppresses the motility of HSPCs, thereby causing them to stay in the niche. Mechanistically, intracellular PAI-1 inhibited the proteolytic activity of proprotein convertase Furin, diminishing MT1-MMP activity. This reduced expression of MT1-MMP in turn affected the expression levels of several adhesion/deadhesion molecules for determination of HSPC localization, such as CD44, VLA-4, and CXCR4, which then promoted the retention of HSPCs in the niche. Our findings open up a new field for the study of intracellular proteolysis as a regulatory mechanism of stem cell fate, which has the potential to improve clinical HSPC mobilization and transplantation protocols. (Blood. 2017;130(21):2283-2294

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“…G-CSF stimulates macrophages, osteoblasts, and osteoclasts to upregulate proteases (MMP9, cathepsins, etc.) that subsequently degrade CXCL12 and surface bound VLA-4 and CXCR4 on HSPCs ( 40–45 ). This disrupts the CXCL12-CXCR4 signaling axis and leads to an increase of HSPCs in peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

A Multi-Niche Microvascularized Human Bone-Marrow-on-a-Chip

Ghoshal

Mejías

et al. 2019

Preprint

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21The human bone marrow (hBM) is a complex organ critical for hematopoietic and immune 22 homeostasis, and where many cancers metastasize. Yet, understanding the fundamental biology of 23 the hBM in health and diseases remain difficult due to complexity of studying or manipulating the 24 BM in humans. Accurate in vitro models of the hBM microenvironment are critical to further our 25 understanding of the BM niche and advancing new clinical interventions. Although, in vitro 26 culture models that recapitulate some key components of the BM niche have been reported, there 27 are no examples of a fully human, in vitro, organoid platform that incorporates the various niches 28 of the hBM -specifically the endosteal, central marrow, and perivascular niches -thus limiting 29 their physiological relevance. Here we report an hBM-on-a-chip that incorporates these three 30 niches in a single micro-physiological device. Osteogenic differentiation of hMSCs produced 31 robust mineralization on the PDMS surface ("bone layer") and subsequent seeding of endothelial 32 cells and hMSCs in a hydrogel network ("central marrow") created an interconnected vascular 33 network ("perivascular niche") on top. We show that this multi-niche hBM accurately mimics the 34 ECM composition, allows hematopoietic progenitor cell proliferation and migration, and is 35 affected by radiation. A key finding is that the endosteal niche significantly contributes to hBM 36 physiology. Taken together, this multi-niche micro-physiological system opens up new 37 opportunities in hBM research and therapeutics development, and can be used to better understand 38 hBM physiology, normal and impaired hematopoiesis, and hBM pathologies, including cancer 39 metastasis, multiple myelomas, and BM failures. 40 41 42Hematopoietic stem cells (HSCs) reside and self-renew in the bone marrow (BM) throughout 43 adulthood, where multipotency is maintained and hematopoietic progenitor cells (HPCs) 44 differentiate to maintain hematopoietic homeostasis (1). The microenvironment that maintains 45 HSC potency and regulates differentiation of HPCs, i.e. the HSC niche, is characterized by BM 46 stromal cells, extracellular matrix (ECM), and biochemical and physical signals (2-4). The HSC 47 niche can be disrupted, naturally with age, with radiation or chemotherapies, or by primary and 48 metastatic malignancies in the BM, and also through the mobilization of HSCs for apheresis. 49Novel, human, and potentially patient specific, models of this microenvironment are critical to 50 advancing our understanding of the BM niche, develop new BM directed therapeutics, and 51 evaluate the effects and predict the success (or failure) of clinical interventions (5). 52Our understanding of the location and composition of the BM microenvironment has been 53 changing over the last two decades. Early research had indicated that HSCs resided in a hypoxic, 54 endosteal niche, where potency was maintained (6, 7). However, recent findings have shown that 55 multi-potent HSCs are perivascular and ex...

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Matrix metalloproteinases in stem cell mobilization

Cited by 57 publications

References 76 publications

Regulation of long‐term repopulating hematopoietic stem cells by EPCR/PAR1 signaling

Regulation of long‐term repopulating hematopoietic stem cells by EPCR/PAR1 signaling

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

A Multi-Niche Microvascularized Human Bone-Marrow-on-a-Chip

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