scholarly journals Extracellular vesicles shed by follicular lymphoma B cells promote the polarization of bone marrow stromal cell niche

Blood ◽  
2021 ◽  
Author(s):  
Erwan Dumontet ◽  
Celine Pangault ◽  
David Roulois ◽  
Matthis Desoteux ◽  
Simon Léonard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Extracellular Vesicles ◽  
Stromal Cell ◽  
Specific Gene ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

Follicular Lymphoma (FL) originates in the lymph nodes (LN) and infiltrates bone marrow (BM) early in the course of the disease. BM FL B cells are characterized by a lower cytological grade, a decreased proliferation, and a specific phenotypic and subclonal profile. Mesenchymal stromal cells (MSC) obtained from FL BM display a specific gene expression profile (GEP), including enrichment for a lymphoid-stromal cell signature, and an increased capacity to sustain FL B-cell growth. However, the mechanisms triggering the formation of the medullar FL permissive stromal niche have not been yet identified. In the current work, we demonstrated that FL B cells produced extracellular vesicles (EVs) that could be internalized by BM-MSC, making them more efficient to support FL B-cell survival and quiescence. Accordingly, EVs purified from FL BM plasma activated TGF-b dependent and independent pathways in BM-MSC, modified their GEP, triggering an upregulation of factors classically associated with hematopoietic stem cell niche, including CXCL12 or angiopoietin-1. Moreover, we provided the first characterization of BM FL B-cell GEP, allowing the definition of the landscape of molecular interactions they could engage with EV-primed BM-MSC. This work identified FL-derived EVs as putative mediators of BM stroma polarization and supported further investigation of their clinical interest for targeting the crosstalk between BM-MSC and malignant B cells.

scholarly journals Mesenchymal Stromal Cells Orchestrate Follicular Lymphoma Cell Niche Through the CCL2-Dependent Recruitment and Polarization of Monocytes

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1566-1566
Author(s):  
Fabien Guilloton ◽  
Gersende Caron ◽  
Cédric Ménard ◽  
Céline Pangault ◽  
Patricia Amé-Thomas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Cell Growth ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Gene Set Enrichment Analysis ◽  
Cell Niche

Abstract Abstract 1566 Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of solid cancers and hematological malignancies. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and bone marrow (BM). In addition, in vitro functional studies have underlined that mesenchymal cells recruit malignant FL B cells and protect them from spontaneous and drug-induced apoptosis. In particular, we have previously demonstrated that mesenchymal stromal cells (MSC) efficiently support in vitro FL B-cell survival, especially after their engagement towards lymphoid differentiation through treatment with TNF-α and Lymphotoxin-α1β2 (TNF/LT) or after coculture with malignant B cells. However, the mechanisms of this supportive activity remain largely unknown. In this study, we used Affymetrix U133 Plus 2.0 microarrays, to compare the gene expression profile (GEP) of bone marrow-derived MSC (BM-MSC) obtained from 10 FL patients at diagnosis versus 6 age-matched healthy donors (HD). In these conditions, neither the CFU-F concentration in the BM nor the cumulative population doubling of BM-MSC significantly differed between HD and FL patients. Unsupervised analysis was able to perfectly segregate FL-MSC from HD-MSC and we identified, using supervised analyzes, a list of 408 probesets defining FL-MSC signature, including 320 nonredundant genes upregulated in FL-MSC compared to HD-MSC. We then defined the GEP of human lymphoid-like stroma using HD-MSC treated in vitro by TNF/LT and demonstrated, by a Gene Set Enrichment Analysis (GSEA) approach, that the FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 was strongly overexpressed by FL-MSC, was upregulated in HD-MSC by coculture with malignant B cells, and was detected at a higher level in FL BM plasma compared to normal BM plasma (504.4 pg/mL [23.8-4413] versus 33.9 pg/mL [5-126.1]; P <.01). In agreement, FL-MSC triggered a more potent CCL2-dependent monocyte migration than HD-MSC. Moreover, FL-MSC and macrophages cooperated to sustain malignant B-cell growth through both protection from apoptosis and enhancement of cell proliferation. Finally, FL-MSC promoted monocyte differentiation towards a proangiogenic LPS-unresponsive phenotype close to that of tumor-associated macrophages. We unraveled a key role for the Notch pathway in this process and identified an overexpression of JAGGED1 in FL-MSC compared to HD-MSC. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL cell niche. The identification and characterization of this intricate network of cell interactions may provide novel therapeutic targets in this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes

Blood ◽  
2012 ◽  
Vol 119 (11) ◽  
pp. 2556-2567 ◽  
Author(s):  
Fabien Guilloton ◽  
Gersende Caron ◽  
Cédric Ménard ◽  
Céline Pangault ◽  
Patricia Amé-Thomas ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Growth ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Specific Gene ◽  
Wide Range ◽  
Cell Niche

Abstract Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stromal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit monocytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated macrophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease.

scholarly journals TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling

2018 ◽  
Vol 116 (1) ◽  
pp. 211-216 ◽  
Author(s):  
Bochra Zidi ◽  
Christelle Vincent-Fabert ◽  
Laurent Pouyet ◽  
Marion Seillier ◽  
Amelle Vandevelde ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Immune Cell ◽  
B Lymphopoiesis ◽  
Hematopoietic Stem ◽  
Chronic Oxidative Stress ◽  
The Impact ◽  
Deficient Mice

Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.

scholarly journals Closer to Nature: The Role of MSCs in Recreating the Microenvironment of the Hematopoietic Stem Cell Niche in vitro

2022 ◽  
pp. 1-10
Author(s):  
Patrick Wuchter ◽  
Anke Diehlmann ◽  
Harald Klüter
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Model Systems ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

<b><i>Background:</i></b> The stem cell niche in human bone marrow provides scaffolds, cellular frameworks and essential soluble cues to support the stemness of hematopoietic stem and progenitor cells (HSPCs). To decipher this complex structure and the corresponding cellular interactions, a number of in vitro model systems have been developed. The cellular microenvironment is of key importance, and mesenchymal stromal cells (MSCs) represent one of the major cellular determinants of the niche. Regulation of the self-renewal and differentiation of HSPCs requires not only direct cellular contact and adhesion molecules, but also various cytokines and chemokines. The C-X-C chemokine receptor type 4/stromal cell-derived factor 1 axis plays a pivotal role in stem cell mobilization and homing. As we have learned in recent years, to realistically simulate the physiological in vivo situation, advanced model systems should be based on niche cells arranged in a three-dimensional (3D) structure. By providing a dynamic rather than static setup, microbioreactor systems offer a number of advantages. In addition, the role of low oxygen tension in the niche microenvironment and its impact on hematopoietic stem cells need to be taken into account and are discussed in this review. <b><i>Summary:</i></b> This review focuses on the role of MSCs as a part of the bone marrow niche, the interplay between MSCs and HSPCs and the most important regulatory factors that need to be considered when engineering artificial hematopoietic stem cell niche systems. <b><i>Conclusion:</i></b> Advanced 3D model systems using MSCs as niche cells and applying microbioreactor-based technology are capable of simulating the natural properties of the bone marrow niche more closely than ever before.

scholarly journals The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

Blood ◽  
2018 ◽  
Vol 131 (19) ◽  
pp. 2111-2119 ◽  
Author(s):  
Rafael Kramann ◽  
Rebekka K. Schneider
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stromal Cells ◽  
Stem Cell Niche ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Gli Proteins ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Organ Fibrosis

Abstract Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1+ and LepR+ mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1+ MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α (Pdgfrα) signaling in Lepr+ stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1+ cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.

scholarly journals P04.45 Periarteriolar glioblastoma stem cell niches express bone marrow hematopoietic stem cell niche proteins

2018 ◽  
Vol 20 (suppl_3) ◽  
pp. iii289-iii289
Author(s):  
V V V Hira ◽  
J R Wormer ◽  
H Kakar ◽  
B Breznik ◽  
B van der Swaan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Hematopoietic Stem ◽  
Glioblastoma Stem Cell ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Stem Cell Niches

scholarly journals Nidogen-1 Contributes to the Interaction Network Involved in Pro-B Cell Retention in the Peri-sinusoidal Hematopoietic Stem Cell Niche

Cell Reports ◽  
2019 ◽  
Vol 26 (12) ◽  
pp. 3257-3271.e8 ◽  
Author(s):  
Marielle Balzano ◽  
Maria De Grandis ◽  
Thien-Phong Vu Manh ◽  
Lionel Chasson ◽  
Florence Bardin ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Interaction Network ◽  
Cell Retention ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche ◽  
Nidogen 1

scholarly journals Author Correction: Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche

2019 ◽  
Vol 25 (4) ◽  
pp. 701-701 ◽  
Author(s):  
Maria Maryanovich ◽  
Ali H. Zahalka ◽  
Halley Pierce ◽  
Sandra Pinho ◽  
Fumio Nakahara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Niche ◽  
Nerve Degeneration ◽  
Adrenergic Nerve ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

scholarly journals CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells

Blood ◽  
2015 ◽  
Vol 125 (15) ◽  
pp. 2381-2385 ◽  
Author(s):  
Patricia Amé-Thomas ◽  
Sylvia Hoeller ◽  
Catherine Artchounin ◽  
Jan Misiak ◽  
Mounia Sabrina Braza ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Germinal Center ◽  
Helper T Cells ◽  
Follicular Helper T Cells ◽  
Follicular Helper ◽  
Key Points ◽  
Cell Niche

Key Points CD10 identifies a unique subset of fully functional germinal center TFH that are activated and amplified within the FL cell niche. FL CD10pos TFH specifically display an IL-4hiIFN-γlo cytokine profile and encompass the malignant B-cell-supportive TFH subset.

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