Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades

Adamiak, Mateusz; Abdelbaset‐Ismail, Ahmed; Suszyńska, Malwina; Abdel‐Latif, Ahmed; Ratajczak, Janina; Ratajczak, Mariusz Z.

doi:10.1038/leu.2016.278

Cited by 38 publications

(113 citation statements)

References 16 publications

(28 reference statements)

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“…During mobilization, HSPCs are released from their bone marrow (BM) niches and migrate across the BM–PB endothelial barrier in BM sinusoids. This process is regulated by several redundant mechanisms, but, as we have proposed, activation of the complement cascade (ComC) through the mannan-binding lectin (MBL)-dependent pathway has a crucial role [ 8 , 9 ]. Here we suggest the novel view that mobilization is due to the release from cells of extracellular nucleotides (EXNs), mainly ATP, that activate the ComC and purinergic signaling receptors in the BM microenvironment [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…Here we suggest the novel view that mobilization is due to the release from cells of extracellular nucleotides (EXNs), mainly ATP, that activate the ComC and purinergic signaling receptors in the BM microenvironment [ 1 ]. As ATP is an important danger-associated molecular pattern (DAMP) molecule recognized by MBL, it provides an important link between purinergic signaling and ComC activation as a trigger of “sterile inflammation” in the BM microenvironment [ 8 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…We recently became interested in the role of ATP in the mobilization of HSPCs. Our interest was prompted by discovery of the role of ATP as a DAMP molecule in activation of mannan-binding lectin (MBL) pathway activation of the ComC but also as a major mediator of purinergic signaling within the BM microenvironment [ 1 , 8 , 9 ]. We demonstrate for first time that purinergic signaling involving ATP and its metabolite adenosine have an important role in the egress of HSPCs from BM niches into PB.…”

Section: Introductionmentioning

confidence: 99%

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Novel evidence that extracellular nucleotides and purinergic signaling induce innate immunity-mediated mobilization of hematopoietic stem/progenitor cells

et al. 2018

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Pharmacological mobilization of hematopoietic stem progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) is a result of mobilizing agent-induced “sterile inflammation” in the BM microenvironment due to complement cascade (ComC) activation. Here we provide evidence that ATP, as an extracellular nucleotide secreted in a pannexin-1-dependent manner from BM cells, triggers activation of the ComC and initiates the mobilization process. This process is augmented in a P2X7 receptor-dependent manner, and P2X7-KO mice are poor mobilizers. Furthermore, after its release into the extracellular space, ATP is processed by ectonucleotidases: CD39 converts ATP to AMP, and CD73 converts AMP to adenosine. We observed that CD73-deficient mice mobilize more HSPCs than do wild-type mice due to a decrease in adenosine concentration in the extracellular space, indicating a negative role for adenosine in the mobilization process. This finding has been confirmed by injecting mice with adenosine along with pro-mobilizing agents. In sum, we demonstrate for the first time that purinergic signaling involving ATP and its metabolite adenosine regulate the mobilization of HSPCs. Although ATP triggers and promotes this process, adenosine has an inhibitory effect. Thus, administration of ATP together with G-CSF or AMD3100 or inhibition of CD73 by small molecule antagonists may provide the basis for more efficient mobilization strategies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel evidence that extracellular nucleotides and purinergic signaling induce innate immunity-mediated mobilization of hematopoietic stem/progenitor cells

et al. 2018

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“…We have recently proposed that eATP-induced mobilization of HSPCs couples Nlrp3 inflammasome purinergic signaling with activation of the complement cascade (ComC) and release of ComC cleavage fragments, including C3-and C5-derived C3a and C5a anaphylatoxins, respectively [23,44,65,66]. The Nlrp3 inflammasome is then activated in a positive feedback manner by C3a and C5a anaphylatoxins, which maintains a sterile inflammation state in the BM microenvironment.…”

Section: The Role Of the Nlrp3 Inflammasome In Stem Cell Mobilizationmentioning

confidence: 99%

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

et al. 2020

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Recent investigations indicate that hematopoiesis is coregulated by innate immunity signals and by pathways characteristic of the activation of innate immunity cells that also operate in normal hematopoietic stem progenitor cells (HSPCs). This should not be surprising because of the common developmental origin of these cells from a hemato/lymphopoietic stem cell. An important integrating factor is the Nlrp3 inflammasome, which has emerged as a major sensor of changes in body microenvironments, cell activation, and cell metabolic activity. It is currently the best-studied member of the inflammasome family expressed in hematopoietic and lymphopoietic cells, including also HSPCs. It is proposed as playing a role in (i) the development and expansion of HSPCs, (ii) their release from bone marrow (BM) into peripheral blood (PB) in stress situations and during pharmacological mobilization, (iii) their homing to BM after transplantation, and (iv) their aging and the regulation of hematopoietic cell metabolism. The Nlrp3 inflammasome is also involved in certain hematological pathologies, including (i) myelodysplastic syndrome, (ii) myeloproliferative neoplasms, (iii) leukemia, and (iv) graft-versus-host disease (GvHD) after transplantation. The aim of this review is to shed more light on this intriguing intracellular protein complex that has become a "rising star" in studies focused on both normal steady-state and pathological hematopoiesis.

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“…Furthermore, complement affects the patient's response to chemotherapy and contributes to mobilization of hematopoietic cells from the bone marrow to the peripheral blood. The latter (involving mannose-binding lectin, MBL) is of particular importance in patients treated with hematopoietic stem cell transplantation (HSCT) (25). Regarding possible direct involvement of ficolins in anticancer immunity, ficolin-2 was found to suppress EMT and metastasis of hepatocellular carcinoma (26).…”

Section: Introductionmentioning

confidence: 99%

Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations

et al. 2020

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A prospective study of 312 patients [194 with multiple myeloma (MM) and 118 with lymphomas (LYMPH)] receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) was conducted. Ficolins are innate immune defense factors, able to distinguish between "self" "abnormal self," and "non-self" and contribute to the elimination of the last two by direct opsonization and/or initiation of complement activation via the lectin pathway. Concentrations of ficolin-1, ficolin-2, and ficolin-3 in serially taken serum samples were determined as were the polymorphisms of the corresponding (FCN1, FCN2, and FCN3) genes. Serum samples were collected before conditioning chemotherapy, before HSCT, and once weekly post-HSCT (four to five samples in total); some patients were also sampled at 1 and/or 3 months posttransplantation. The control group (C) consisted of 267 healthy unrelated individuals. Median ficolin-1 and ficolin-2 (but not ficolin-3) levels in MM patients' sera taken before chemotherapy were lower (and correspondingly frequencies of the lowest concentrations were higher) compared with controls. That appeared to be associated with the malignant disease itself rather than with post-HSCT complications (febrile neutropenia, infections accompanied, or not with bacteremia). Higher frequencies of the FCN1 genotype G/A-C/C-G/G (corresponding to polymorphisms at positions −542, −144, and +6658, respectively) and FCN2 gene heterozygosity for the −857 C>A polymorphism were found among patients diagnosed with MM compared with the C group. Furthermore, Ś wierzko et al. Ficolins in Hematological CancersFCN2 G/G homozygosity (−557 A>G) was found more frequently and heterozygosity G/T at +6424 less frequently among LYMPH patients than among the healthy subjects. Heterozygosity for +1637delC mutation of the FCN3 gene was more common among patients diagnosed with lymphomas who experienced hospital infections. Although no evidence for an association of low ficolin-1 or ficolin-2 with infections during neutropenia following chemotherapy before HSCT was found, we observed a possible protective effect of ficolins during follow-up.

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Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades

Abstract: Novel evidence that the mannan-binding lectin (MBL) pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades

Cited by 38 publications

References 16 publications

Novel evidence that extracellular nucleotides and purinergic signaling induce innate immunity-mediated mobilization of hematopoietic stem/progenitor cells

Novel evidence that extracellular nucleotides and purinergic signaling induce innate immunity-mediated mobilization of hematopoietic stem/progenitor cells

The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis

Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations

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