Effects of human fibroblasts from myelometaplasic and non-myelometaplasic hematopoietic tissues on CD34+ stem cells

Brouty‐Boyé, Danièle; Briard, Diane; Azzarone, Bruno; Bousse-Kerdilès, M. C. Le; Clay, Denis; Pottin-Clémenceau, Corine; Jasmin, C

doi:10.1002/ijc.1222

Cited by 21 publications

(16 citation statements)

References 19 publications

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“…However, experimental evidence has accumulated demonstrating that fibroblasts do not act as mere supportive cells but are also able to drive differentiation of other neighboring cell types under both physiologic and pathologic conditions (19,20). Especially in the human hemopoietic system (3,21) it has been shown that homogeneous stromal fibroblast populations established in culture from bone marrow were able to directly contribute to the formation of blood cells from all lineages except T/NK lymphocytes, with a majority of granulomonocytes. The results presented in this work clearly show that fibroblasts isolated from human spleen also regulate blood cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…The constitutive expression of IL-15 on the surface of human spleen-derived fibroblasts was quite striking because stromal fibroblasts isolated from other tissue sources did not show such expression unless stimulated by inflammatory cytokines or derived from pathologic lesions (3,26). In contrast, blood-derived cells, including monocytes, monoblastoid cells, and leukemic progenitors, have been reported to constitutively express membrane-associated IL-15 without any IL-15 secretion (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

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Fibroblasts from Human Spleen Regulate NK Cell Differentiation from Blood CD34+ Progenitors Via Cell Surface IL-15

Briard

Brouty‐Boyé

Azzarone

et al. 2002

The Journal of Immunology

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Besides a structural role in tissue architecture, fibroblasts have been shown to regulate the proliferation and differentiation of other neighboring specialized cell types, but differently according to the anatomic site and pathologic status of their tissue of origin. In this study we report a novel regulatory function of human spleen-derived fibroblasts in the development of NK cells from adult resting blood progenitors. When CD34+ cells were cocultured with spleen-derived fibroblasts in monolayers, nonadherent CD56+CD3− NK cells were predominantly produced after 2–3 wk of culture in the absence of exogenous cytokines. Most NK cells expressed class I-recognizing CD94 and NK p46, p44, and p30 receptors as well as perforin and granzyme lytic granules. Moreover, these cells demonstrated spontaneous killing activity. Cell surface immunophenotyping of spleen-derived fibroblasts revealed a low and consistent expression of IL-15, Flt3 ligand, and c-kit ligand. Additionally, low picogram amounts of the three cytokines were produced extracellularly. Neutralizing Abs to IL-15, but not the other two ligands, blocked NK cell development. Additionally, suppressing direct contacts of CD34+ progenitors and fibroblasts by microporous membrane abrogated NK cell production. We conclude that stromal fibroblasts within the human spleen are involved via constitutive cell surface expression of bioactive IL-15 in the development of functional activated NK cells under physiologic conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fibroblasts from Human Spleen Regulate NK Cell Differentiation from Blood CD34+ Progenitors Via Cell Surface IL-15

Briard

Brouty‐Boyé

Azzarone

et al. 2002

The Journal of Immunology

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“…This constitutes a feedback loop that favors the persistence of the inflammatory process in RA. Interestingly, RASFibs share constitutive surface expression of IL-15 with human spleen-derived fibroblasts (19), whereas OASFibs and fibroblasts from other locations do not demonstrate surface IL-15 unless stimulated by inflammatory cytokines (20) or derived from tumor stroma (36). In contrast, fibroblasts from all sources do constitutively express intracellular IL-15 (15).…”

Section: Discussionmentioning

confidence: 99%

IL-15 and the Initiation of Cell Contact-Dependent Synovial Fibroblast-T Lymphocyte Cross-Talk in Rheumatoid Arthritis: Effect of Methotrexate

Miranda-Carús

Balsa

Benito-Miguel

et al. 2004

The Journal of Immunology

119

104

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To characterize the molecules responsible for synovial fibroblast-T lymphocyte (TL) cross-talk in rheumatoid arthritis (RA), synovial fibroblasts from patients with established RA (RASFibs) were cocultured with TLs from peripheral blood of early RA patients (RAPBTL). TLs from peripheral blood of healthy controls and from synovial fluid of RA served as controls. Adhesion molecules and cytokines were determined by flow cytometry, ELISA, and real-time PCR. RAPBTL (n = 20) induced an up-regulation of ICAM-1, intracellular IL-8, IL-6, IL-15, and surface IL-15 in cocultured RASFibs. In turn, RAPBTL showed an up-regulation of TNF-α, IFN-γ, IL-17, CD25, and CD69 expression. Responses seen with TLs from peripheral blood of healthy controls (n = 20) were significantly lower, whereas responses with TLs from synovial fluid of RA (n = 20) were maximal. Blocking Abs to IL-15 and CD54, but not an isotype-control Ab, down-regulated the increased TL cytokine and activation marker expression. Abs to CD69, CD11a, IL-17, TNF-α, and IFN-γ significantly decreased the up-regulation of RASFib cytokine and CD54 expression. Cocultures using 0.4-μm inserts did not result in up-regulation of surface molecules or cytokines. Methotrexate significantly inhibited RASFib/TL cross-talk signals and decreased adhesion of TL to RASFibs. In summary, RASFib production of IL-15 induces the proinflammatory cytokines TNF-α, IFN-γ, and IL-17 in cocultured TLs through a cell contact-dependent mechanism. In turn, these cytokines stimulate the expression of IL-15, IL-8, and IL-6 in RASFibs, thereby creating a feedback loop that favors persistent synovial inflammation. Methotrexate seems to disrupt this loop by decreasing cell adhesion.

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“…This hypothesis is based on the fact that human spleen-derived but not bone marrow-derived myofibroblasts constitutively express a mb-IL-15 (spleen myofibroblast [SMF] membrane-bound [mb]-IL-15) necessary and sufficient to trigger, upon coculture, the differentiation of circulating (but not BM) CD34 ϩ progenitors into functional NK cells. [16][17] The way IL-15 is anchored to the cell membrane seems to have a major effect on its presentation in trans and on its effects on target cells. [4][5][6][7][10][11][18][19] For these reasons, we investigated (1) the mechanism of anchorage of SMFmb-IL-15 at the cell membrane; (2) the type of signal transduction triggered upon contact with normal and leukemic hematopoietic CD34 ϩ cells; and (3) the biologic effects of SMFmb-IL-15 on leukemic cells.…”

Section: Introductionmentioning

confidence: 99%

Membrane-bound and soluble IL-15/IL-15Rα complexes display differential signaling and functions on human hematopoietic progenitors

Giron‐Michel

Giuliani

Fogli

et al. 2005

Blood

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Membrane-bound and soluble interleu-kin-15 (IL-15)/IL-15 receptor (R) complexes trigger differential transcription factor activation and functions on human hematopoietic progenitors. Indeed, human spleen myofibroblasts (SMFs) are characterized by a novel mechanism of IL-15 trans-presentation (SMFmb [mem-brane-bound]-IL-15), based on the association of an endogenous IL-15/IL-15R complex with the IL-15Rc chains. SMFmb-IL-15 (1) induces lineage-specific signaling pathways that differ from those controlled by soluble IL-15 in unprimed and committed normal progenitors ; (2) triggers survival and proliferation of leukemic progenitors expressing low-affinity IL-15R (M07Sb cells); (3) causes only an antiapoptotic effect on leukemic cells expressing high-affinity receptors (TF1 cells). This behavior is likely due to the IL-15R chain present on these cells that interact with the SMFmb-IL-15, inhibiting signal transducer and transcriptional activator 5 (STAT5) activation. On the other hand, the soluble IL-15/ IL-15R complex (hyper IL-15) displays a dominant pattern of action, activating only those cells expressing low-affinity IL-15R (IL-15Rc). Thus, hyper IL-15 induces antiapoptotic effects on M075b cells and the up-regulation of STAT6 activation on adult peripheral blood (PB) pre-natural killer (NK) committed progenitors. The latter effect using 100-fold concentrations of recombinant (r)-IL-15. In conclusion , SMFmb-IL-15 and soluble IL-15R/ IL-15 complexes seem to play a pivotal role in the control of the survival, proliferation and differentiation of both normal and leukemic circulating progenitors, highlighting new functions of IL-15 and of

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Effects of human fibroblasts from myelometaplasic and non-myelometaplasic hematopoietic tissues on CD34+ stem cells

Cited by 21 publications

References 19 publications

Fibroblasts from Human Spleen Regulate NK Cell Differentiation from Blood CD34+ Progenitors Via Cell Surface IL-15

Fibroblasts from Human Spleen Regulate NK Cell Differentiation from Blood CD34+ Progenitors Via Cell Surface IL-15

IL-15 and the Initiation of Cell Contact-Dependent Synovial Fibroblast-T Lymphocyte Cross-Talk in Rheumatoid Arthritis: Effect of Methotrexate

Membrane-bound and soluble IL-15/IL-15Rα complexes display differential signaling and functions on human hematopoietic progenitors

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