Pro-inflammatory cytokines: Emerging players regulating HSC function in normal and diseased hematopoiesis

Mirantes, Cristina; Passegué, Emmanuelle; Pietras, Eric M.

doi:10.1016/j.yexcr.2014.08.017

Cited by 186 publications

(165 citation statements)

References 54 publications

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“…We observed increased secretion of proinflammatory cytokines such as IL-6, IFN␥, TNF␣, and IL-1␤, which have been shown to drive HSPC myeloid differentiation fate (Fig. 4E) (19,21), consistent with transcriptional analyses.…”

Section: Msc Evs Lead To Nf-b Induction and Cytokinesupporting

confidence: 85%

Mesenchymal Stromal Cell-derived Extracellular Vesicles Promote Myeloid-biased Multipotent Hematopoietic Progenitor Expansion via Toll-Like Receptor Engagement

Goloviznina

Verghese

Yoon

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerMesenchymal stromal cells (MSCs) present in the bone marrow microenvironment secrete cytokines and angiogenic factors that support the maintenance and regenerative expansion of hematopoietic stem and progenitor cells (HSPCs). Here, we tested the hypothesis that extracellular vesicles (EVs) released by MSCs contribute to the paracrine crosstalk that shapes hematopoietic function. We systematically characterized EV release by murine stromal cells and demonstrate that MSC-derived EVs prompt a loss of HSPC quiescence with concomitant expansion of murine myeloid progenitors. Our studies reveal that HSPC expansion by MSC EVs is mediated via the MyD88 adapter protein and is partially blocked by treatment with a TLR4 inhibitor. Imaging of fluorescence protein-tagged MSC EVs corroborated their cellular co-localization with TLR4 and endosomal Rab5 compartments in HSPCs. The dissection of downstream responses to TLR4 activation reveals that the mechanism by which MSC EVs impact HSPCs involves canonical NF-B signaling and downstream activation of Hif-1␣ and CCL2 target genes. Our aggregate data identify a previously unknown role for MSC-derived EVs in the regulation of hematopoiesis through innate immune mechanisms and illustrate the expansive cell-cell crosstalk in the bone marrow microenvironment.A small population of long-lived quiescent HSPCs 3 residing in the bone marrow sustains lifelong hematopoietic function and provides regenerative capacity through cycles of self-renewal and differentiation (1). Cell fate commitment yields a cascade of successively more restricted progenitor populations that give rise to circulating blood and mature immune cells (2). HSPC activation relies on cell-autonomous programs as well as extrinsic cues from the surrounding bone marrow microenvironment where mesenchymal stromal cells, osteoprogenitors, and endothelial cells act through the paracrine action of secreted cytokines and angiogenic factors (3-6).Recent studies indicate that HSPC self-renewal and emergence from quiescence are also regulated by type I and II interferons as well as Toll-like receptors (TLRs), signals associated with innate immunity (7-10), and known to contribute to regenerative HSPC responses (11)(12)(13)(14)(15). TLR signaling involves a number of transmembrane receptors and several critical adaptor molecules (16). Among them, the myeloid differentiation factor (MyD88) occupies a central role in transducing both surface and endosomal signals for most TLRs. Evidence supports TLR activation in the HSPC response to diverse stimuli, including radiation, bleeding, and infection (reviewed in Ref. 12). More recent reports, however, indicate that these mechanisms are also relevant for "tonic" homeostatic function and as well as developmental emergence of HSPCs (15,17,18). Indeed, many cytokines central to the inflammatory response are also critical to HSPC maintenance and differentiation (19 -21).Extracellular vesicles (EVs) are constitutively released from cells and are powerful paracrine regulator...

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Section: Msc Evs Lead To Nf-b Induction and Cytokinesupporting

confidence: 85%

Mesenchymal Stromal Cell-derived Extracellular Vesicles Promote Myeloid-biased Multipotent Hematopoietic Progenitor Expansion via Toll-Like Receptor Engagement

Goloviznina

Verghese

Yoon

et al. 2016

Journal of Biological Chemistry

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“…[48][49][50][51][52] The elevated IL-6, TGF-b, and TNF-a signaling pathways in the Sipa1 2/2 stromal cells may contribute to myeloproliferation possibly via altering HSC lineage fate decision in the Sipa1 2/2 mice, as previously suggested. 50,53 THPO-MPL signaling is critical for maintaining HSCs in adult BM 54 and is involved in the pathogenesis of MPN. 55,56 The upregulation of Thpo in the Sipa1 2/2 BM stromal cells may be associated with the enhanced granulopoiesis and the overproduction of MEPs and MK hyperplasia in the aged Sipa1 2/2 mice under steady state and after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

et al. 2018

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Key Points• Sipa1 loss leads to BM niche alterations prior to the initiation of MPN.• Sipa1-deficient BM niche induces lethal MPN from normal hematopoietic cells.Mutations of signal-induced proliferation-associated gene 1 (SIPA1), a RAP1 GTPaseactivating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear.We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the

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“…http://dx.doi.org/10.1101/289553 doi: bioRxiv preprint first posted online Mar. 27, 2018; paracrine signaling from proximal MSCs mediate HSC activation and quiescence through production of factors such as CXCL12 [32], IL-6 [33,34], and TPO [35] that regulate HSC activity via diffusive signaling and direct cell-cell contact [6,28,31,[36][37][38][39]. While co-cultures of HSCs and MSCs within a hydrogel matrix offer the opportunity to identify heterotypic cultures that support HSC quiescence or self-renewal, such studies are significantly complicated by the dynamic reciprocity between inhabiting cells and the surrounding matrix.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stromal cell remodeling of a gelatin hydrogel microenvironment defines an artificial hematopoietic stem cell niche

Gilchrist

Lee

et al. 2018

Preprint

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We identify a combination of an initially low-diffusivity (autocrine dominated) hydrogel and a 1:1 HSCP:MSC seeding ratio as conducive to enhanced HSC population maintenance. Further, gene expression and serial mechanical testing data suggests that MSC-mediated matrix remodeling is significant for the long-term HSC culture, reducing HSC autocrine feedback and potentially enhancing MSC-mediated paracrine signaling over 7-day culture in vitro. This work demonstrates the design of an HSC culture system that couples initial hydrogel properties, MSC co-culture, and concepts of dynamic reciprocity mediated by MSC remodeling to achieve enhanced HSC maintenance.

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Pro-inflammatory cytokines: Emerging players regulating HSC function in normal and diseased hematopoiesis

Cited by 186 publications

References 54 publications

Mesenchymal Stromal Cell-derived Extracellular Vesicles Promote Myeloid-biased Multipotent Hematopoietic Progenitor Expansion via Toll-Like Receptor Engagement

Mesenchymal Stromal Cell-derived Extracellular Vesicles Promote Myeloid-biased Multipotent Hematopoietic Progenitor Expansion via Toll-Like Receptor Engagement

Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

Mesenchymal stromal cell remodeling of a gelatin hydrogel microenvironment defines an artificial hematopoietic stem cell niche

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