Activation of NF-κB driven inflammatory programs in mesenchymal elements attenuates hematopoiesis in low-risk myelodysplastic syndromes

Ping, Zhen; Chen, Si; Hermans, Sjoerd J. F.; Kenswil, Keane Jared Guillaume; Feyen, Jacqueline; Dijk, Claire van; Bindels, Eric; Mylona, Athina; Adisty, Niken; Hoogenboezem, Remco M.; Sanders, Mathijs A.; Cremers, Eline M.P.; Lindenbergh-Kortleve, Dicky J.; Samsom, Janneke N.; Loosdrecht, Arjan A. van de; Raaijmakers, Marc H.G.P.

doi:10.1038/s41375-018-0267-x

Cited by 31 publications

(22 citation statements)

References 14 publications

(23 reference statements)

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“…BM-derived MSCs from MDS patients display an inflammatory signature as well as upregulation of molecules involved in cell adhesion and angiogenic factors ( 57 , 58 ). Activation of the nuclear factor kappa B (NF-κB) transcription factor program was also observed in MSCs of patients with MDS ( 59 ). Of interest, S100A8/A9, secreted in the BM by both MSCs and cells of hematopoietic origin, has been associated with activation of the inflammasome and consequent production of IL-1β and IL-18 by hematopoietic progenitors in MDS ( 56 , 58 ).…”

Section: Inflammation In the Hsc Niche During Malignant Hematopoiesismentioning

confidence: 99%

Regulation of the Bone Marrow Niche by Inflammation

et al. 2020

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Hematopoietic stem cells (HSC) reside in the bone marrow (BM) within a specialized micro-environment, the HSC niche, which comprises several cellular constituents. These include cells of mesenchymal origin, endothelial cells and HSC progeny, such as megakaryocytes and macrophages. The BM niche and its cell populations ensure the functional preservation of HSCs. During infection or systemic inflammation, HSCs adapt to and respond directly to inflammatory stimuli, such as pathogen-derived signals and elicited cytokines, in a process termed emergency myelopoiesis, which includes HSC activation, expansion, and enhanced myeloid differentiation. The cell populations of the niche participate in the regulation of emergency myelopoiesis, in part through secretion of paracrine factors in response to pro-inflammatory stimuli, thereby indirectly affecting HSC function. Here, we review the crosstalk between HSCs and cell populations in the BM niche, specifically focusing on the adaptation of the HSC niche to inflammation and how this inflammatory adaptation may, in turn, regulate emergency myelopoiesis.

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Section: Inflammation In the Hsc Niche During Malignant Hematopoiesismentioning

confidence: 99%

Regulation of the Bone Marrow Niche by Inflammation

et al. 2020

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“…Moreover, inflammasome activation was found to drive MDS demonstrating that cell death mechanisms, specifically pyroptotic cell death, contribute to MDS pathophysiology ( 172 ). Consistent with the complex regulation of hematopoiesis by both intrinsic mechanisms and niche-driven mechanisms, the bone marrow microenvironment plays a central role in the development of MDS ( 173 – 175 ). Monocytes from MDS patients were shown to generate macrophages that exhibit increased TNF production and altered phagocytic capacity ( 176 ), and dysfunctional macrophages are seen early in MDS and may be an initiating event that allows progression of MDS and leukemia.…”

Section: Macrophages In the Pathogenesis Of Bone Marrow Failure Syndrmentioning

confidence: 99%

Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress

2020

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The bone marrow contains distinct cell types that work in coordination to generate blood and immune cells, and it is the primary residence of hematopoietic stem cells (HSCs) and more committed multipotent progenitors (MPPs). Even at homeostasis the bone marrow is a dynamic environment where billions of cells are generated daily to replenish short-lived immune cells and produce the blood factors and cells essential for hemostasis and oxygenation. In response to injury or infection, the marrow rapidly adapts to produce specific cell types that are in high demand revealing key insight to the inflammatory nature of "demand-adapted" hematopoiesis. Here we focus on the role that resident and monocyte-derived macrophages play in driving these hematopoietic programs and how macrophages impact HSCs and downstream MPPs. Macrophages are exquisite sensors of inflammation and possess the capacity to adapt to the environment, both promoting and restraining inflammation. Thus, macrophages hold great potential for manipulating hematopoietic output and as potential therapeutic targets in a variety of disease states where macrophage dysfunction contributes to or is necessary for disease. We highlight essential features of bone marrow macrophages and discuss open questions regarding macrophage function, their role in orchestrating demand-adapted hematopoiesis, and mechanisms whereby they regulate HSC function.

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“…MSCs promote MDS development through the creation of an inflammatory milieu. Hyperactivation of inflammatory pathways in MSCs, including NF-κB, EGF, TGF-β, and TNF-α, inhibits hematopoiesis in low-risk MDSs, accounting for the increased apoptotic rate at this stage of the disease [ 93 , 94 ]. Moreover, an inflamed BM niche may favor the expansion of mutated small clones (e.g., TET2 -mutated ones), such as those accounting for the so-called clonal hematopoiesis of indeterminate potential (CHIP) that would unlikely autonomously evolve to overt myeloid disease [ 95 ].…”

Section: The Role Of Mesenchymal Stem Cells In Myelodysplastic Synmentioning

confidence: 99%

Mesenchymal Stem Cells in Aplastic Anemia and Myelodysplastic Syndromes: The “Seed and Soil” Crosstalk

Fattizzo

Giannotta

Barcellini

2020

IJMS

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There is growing interest in the contribution of the marrow niche to the pathogenesis of bone marrow failure syndromes, i.e., aplastic anemia (AA) and myelodysplastic syndromes (MDSs). In particular, mesenchymal stem cells (MSCs) are multipotent cells that contribute to the organization and function of the hematopoietic niche through their repopulating and supporting abilities, as well as immunomodulatory properties. The latter are of great interest in MDSs and, particularly, AA, where an immune attack against hematopoietic stem cells is the key pathogenic player. We, therefore, conducted Medline research, including all available evidence from the last 10 years concerning the role of MSCs in these two diseases. The data presented show that MSCs display morphologic, functional, and genetic alterations in AA and MDSs and contribute to immune imbalance, ineffective hematopoiesis, and leukemic evolution. Importantly, adoptive MSC infusion from healthy donors can be exploited to heal the “sick” niche, with even better outcomes if cotransplanted with allogeneic hematopoietic stem cells. Finally, future studies on MSCs and the whole microenvironment will further elucidate AA and MDS pathogenesis and possibly improve treatment.

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Activation of NF-κB driven inflammatory programs in mesenchymal elements attenuates hematopoiesis in low-risk myelodysplastic syndromes

Cited by 31 publications

References 14 publications

Regulation of the Bone Marrow Niche by Inflammation

Regulation of the Bone Marrow Niche by Inflammation

Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress

Mesenchymal Stem Cells in Aplastic Anemia and Myelodysplastic Syndromes: The “Seed and Soil” Crosstalk

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