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Itoh, K., J. Friel, N. Kluge, T. Kina, A. Kondo-Takaori, S. Kawamata, T. Uchiyama i W. Ostertag. "A novel hematopoietic multilineage clone, Myl-D-7, is stromal cell- dependent and supported by an alternative mechanism(s) independent of stem cell factor/c-kit interaction". Blood 87, nr 8 (15.04.1996): 3218–28. http://dx.doi.org/10.1182/blood.v87.8.3218.bloodjournal8783218.
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A strictly stroma-dependent hematopoietic clone, Myl-D-7, with lympho- myeloid potential has been isolated. A subset of cells expresses myeloid-macrophage (Mac-1 and Gr-1), erythroid (TER119), and lymphoid (Thy-1 and B220) lineage markers. Spontaneous differentiation to the myeloid-macrophage, erythroid, or lymphoid pathway can be seen by morphologic criteria, detection of beta major globin synthesis, or expression of the early lymphoid specific transcription factor, Ikaros. By sorting lineage marker (Mac-1, Gr-1, B220, and TER119)-negative (LIN- ) cells, we showed that the LIN- population actively self-renews on top of MS-5 stromal cells, and differentiates to LIN+ cells. Removal of stroma induces apoptosis and none of the growth factors tested can prevent apoptosis. Granulocyte-macrophage colony-stimulating factor accelerates the differentiation towards the myeloid-macrophage lineage. Using this clone, we show that (1) contact with stroma induces expression of bcl-2, (2) stromal cells derived from SI/SI homozygous fetuses can support long-term growth, and (3) conditioned media of specific stromal cells contains an activity that supports proliferation and self-renewal of the clone. Myl-D-7 can thus be used as an indicator cell for unknown factors that may provide stromal cell support.
2
Kierney, PC, i K. Dorshkind. "B lymphocyte precursors and myeloid progenitors survive in diffusion chamber cultures but B cell differentiation requires close association with stromal cells". Blood 70, nr 5 (1.11.1987): 1418–24. http://dx.doi.org/10.1182/blood.v70.5.1418.1418.
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Abstract The aim of this study was to investigate the relative contribution of direct contact with stromal cells v stromal cell-derived soluble mediators to the differentiation of B lymphocytes and cells from other hematopoietic lineages. This was investigated by making a comparison between hemopoietic cells grown in direct contact with stroma to those in diffusion chambers (DCs) placed over purified populations of stroma. The source of stromal cells was adherent layers from myeloid or lymphoid long-term bone marrow cultures that had been treated with mycophenolic acid, an antibiotic that depletes hemopoietic cells from the cultures but retains a functional stroma. The cells seeded into the chambers were fresh marrow cells that had been passed through two consecutive nylon wool columns to deplete cell populations capable of forming an adherent cell layer in vitro. DCs were placed in wells in which the adherent stroma, growing under myeloid or lymphoid conditions, was present. The results indicate that progenitors of granulocytes and macrophages survived and differentiated in DCs under myeloid culture conditions, as the number of cells and absolute number of CFU-GM increased over that present in the reseed population. These levels, however, were markedly less than in parallel cultures in which the cells were seeded directly onto stroma. Hematopoiesis in DCs placed over hemopoietically active stroma was not optimal, suggesting that factors were used by those hemopoietic cells closest to the stroma. A B lymphocyte precursor survived in DCs under myeloid but not lymphoid conditions, and its differentiation into B lymphocytes was dependent on close association with stromal cells; B lymphopoiesis initiated when cells from DCs grown under myeloid conditions were harvested from the chambers and seeded directly onto stroma initiated and maintained under lymphoid bone marrow culture conditions. B lymphopoiesis did not initiate if the DC from the myeloid conditions was left intact and placed directly over a lymphoid stromal cell layer in lymphoid conditions.
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Kierney, PC, i K. Dorshkind. "B lymphocyte precursors and myeloid progenitors survive in diffusion chamber cultures but B cell differentiation requires close association with stromal cells". Blood 70, nr 5 (1.11.1987): 1418–24. http://dx.doi.org/10.1182/blood.v70.5.1418.bloodjournal7051418.
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The aim of this study was to investigate the relative contribution of direct contact with stromal cells v stromal cell-derived soluble mediators to the differentiation of B lymphocytes and cells from other hematopoietic lineages. This was investigated by making a comparison between hemopoietic cells grown in direct contact with stroma to those in diffusion chambers (DCs) placed over purified populations of stroma. The source of stromal cells was adherent layers from myeloid or lymphoid long-term bone marrow cultures that had been treated with mycophenolic acid, an antibiotic that depletes hemopoietic cells from the cultures but retains a functional stroma. The cells seeded into the chambers were fresh marrow cells that had been passed through two consecutive nylon wool columns to deplete cell populations capable of forming an adherent cell layer in vitro. DCs were placed in wells in which the adherent stroma, growing under myeloid or lymphoid conditions, was present. The results indicate that progenitors of granulocytes and macrophages survived and differentiated in DCs under myeloid culture conditions, as the number of cells and absolute number of CFU-GM increased over that present in the reseed population. These levels, however, were markedly less than in parallel cultures in which the cells were seeded directly onto stroma. Hematopoiesis in DCs placed over hemopoietically active stroma was not optimal, suggesting that factors were used by those hemopoietic cells closest to the stroma. A B lymphocyte precursor survived in DCs under myeloid but not lymphoid conditions, and its differentiation into B lymphocytes was dependent on close association with stromal cells; B lymphopoiesis initiated when cells from DCs grown under myeloid conditions were harvested from the chambers and seeded directly onto stroma initiated and maintained under lymphoid bone marrow culture conditions. B lymphopoiesis did not initiate if the DC from the myeloid conditions was left intact and placed directly over a lymphoid stromal cell layer in lymphoid conditions.
4
Dorshkind, K., L. Green, A. Godwin i WH Fletcher. "Connexin-43-type gap junctions mediate communication between bone marrow stromal cells". Blood 82, nr 1 (1.07.1993): 38–45. http://dx.doi.org/10.1182/blood.v82.1.38.bloodjournal82138.
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Several morphologic studies have suggested that gap junctions exist between bone marrow stromal cells. This possibility was examined by analysis of stromal cells present in the adherent layer of primary long- term lymphoid bone marrow cultures and in additional studies using a stromal cell line. Results showing that the fluorescent dye lucifer yellow, when microinjected into a single stromal cell, transferred between most other contacting stroma and that stromal cells were electronically coupled provided support that cell-cell communication occurs between these microenvironmental elements. Additional studies showed that transcripts for connexin (Cx) 43, but not for Cx26 or Cx32, were present in a stromal cell line. To examine the potential for regulated cell-cell communication between the stroma, cells were treated with interleukin-1 (IL-1), a cytokine known to affect stromal cell function, and the effects on dye transfer were examined. IL-1 treatment resulted in a reversible decrease in the ability of dye to transfer between stromal cells in contact. Taken together, these studies show that gap junctions exist between stromal cells and that their permeability can be regulated. However, gap junction-mediated cell-cell communication could not be shown between the stroma and developing lymphoid cells.
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Qotrunnada, Alvionika Nadyah, Tecky Indriana, Jane Kosasih, Meiske Margaretha i Mei Syafriadi. "Role of cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression in the pathogenesis of Warthin’s tumor growth". Dental Journal (Majalah Kedokteran Gigi) 55, nr 4 (12.10.2022): 194–99. http://dx.doi.org/10.20473/j.djmkg.v55.i4.p194-199.
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Background: One of the benign salivary gland tumors is Warthin’s tumor, which is a benign tumor consisting of a papillary cystic structure covered by a double epithelial layer cells and lymphoid stroma with germinal center. Several cases have reported the Warthin’s tumor transformation into a malignant tumor such as lymphoma that develops from their stromal. Expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) as part of the immune checkpoint when highly expressed leads to a more rapid development or progression of tumors. Purpose: To analyze CTLA-4 expression in Warthin’s tumors associated with the pathogenesis of its growth through an escape mechanism from immune checkpoints and analyze based on CTLA expression whether this marker has the potential to be used as immunotherapy by administering anti CTLA-4. Methods: The tissue sections slides of Warthin’s tumor (n=8) were stained with Hematoxylin Eosin and immunostained with Recombinant Anti-CTLA4 antibody [CAL49] (ab237712). The slide with positive CTLA-4 is shown as staining on the cell membrane and/or cytoplasm. Observations were carried out using Optilab. The result is presented as figures. Results: Tumor cells expressed of CTLA-4 show in cytoplasm and/or cell membranes of the epithelial and stromal components of Warthin’s lymphoid. CTLA-4 is expressed lymphoid stroma, which is associated with inhibition of T cell activity against tumor cells, while the exact mechanism of CTLA-4 expression in epithelial components is not known but is thought to induce tumorigenesis and inhibit apoptosis. Conclusion: CTLA-4 is expressed in epithelial and stromal cells of Warthin’s tumor and this expression indicates that Warthin’s tumor cell growth is through the escape mechanism of the CTLA-4 check point immune. Further research is necessary to investigate whether CTLA-4 expression in lymphoid stroma has relate to their transformation toward a malignant tumor of lymphoma.
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Tang, J., B. L. Nuccie, I. Ritterman, J. L. Liesveld, C. N. Abboud i D. H. Ryan. "TGF-beta down-regulates stromal IL-7 secretion and inhibits proliferation of human B cell precursors." Journal of Immunology 159, nr 1 (1.07.1997): 117–25. http://dx.doi.org/10.4049/jimmunol.159.1.117.
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Abstract Development of lymphoid progenitors in vivo requires interaction with a bone marrow stromal microenvironment containing multiple cytokines involved in the development of nonlymphoid hemopoietic lineages. We tested the effect of one such cytokine, TGF-beta, on the proliferation of early human clonogenic lymphoid progenitors using a stroma-dependent in vitro culture system. TGF-beta caused a dose-dependent inhibition of lymphoid progenitor colonies that was reversible at low TGF-beta doses by addition of exogenous IL-7 to the cultures. IL-7 was unable to reverse the inhibitory effect of higher TGF-beta concentrations or inhibition caused by IL-1alpha, IL-4, or TNF-alpha. Stromal IL-7 mRNA expression and protein secretion were markedly down-regulated by TGF-beta, suggesting that inhibition of stromal IL-7 secretion partially accounts for the inhibitory effect of TGF-beta on lymphopoiesis in this culture system. It is likely that higher TGF-beta concentrations do not inhibit lymphopoiesis by down-regulating IL-7 receptor expression, since this cytokine did not reduce IL-7R alpha or gamma c mRNA levels in normal B cell precursors. Since direct stromal contact is required for in vitro lymphopoiesis, the potential regulation of the IL-7 pathway by cell adhesion was examined. Adhesion of human B cell precursors to stroma did not alter stromal IL-7 expression or expression of IL-7R alpha or gamma c-chains by B cell precursors. These results indicate that TGF-beta is a significant negative regulator of stroma-dependent proliferation of early human lymphoid progenitors and acts in part by down-regulating stromal IL-7 secretion.
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Baptista, Antonio P., i Michael Y. Gerner. "Lymphoid stromal cells proGrem dendritic cell homeostasis". Nature Immunology 22, nr 5 (26.04.2021): 541–43. http://dx.doi.org/10.1038/s41590-021-00924-2.
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Jankovic-Velickovic, Ljubinka, Irena Dimov, Dragan Petrovic, Slavica Stojnev, Stefan Dacic, Stefan Velickovic i Vladisav Stefanovic. "Stromal reaction and prognosis in acinic cell carcinoma of the salivary gland". Vojnosanitetski pregled 70, nr 12 (2013): 1155–58. http://dx.doi.org/10.2298/vsp1312155j.
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Introduction. Primary acinic cell carcinoma (ACC) is an uncommon malignant neoplasm of the salivary gland (SG), which usually presents as slow growing tumor. Case report. We reported a 69-year-old woman with tumor in the right parotid gland with a 5-year progress. Biopsy sections revealed a hybrid form of ACC with a low- and high-grade component and prominent lymphoid tissue in tumor stroma. Immunohistochemistry was performed to define the molecular profile of this unusual ACC, with special interest for stromal influence on to the proliferative activity of ACC with dedifferentiation. We detected that the level and the type of stromal lymphoid reaction (particularly CD8+/CD4+ ratio) had a significant influence on to Ki-67 index in the high-grade component of ACC, as well as the involvement of the CXCR4 signaling axis in the stromal reaction influence. Conclusion. We suggest that tumor stroma may be a source of potential new tumor biomarkers which can determine the aggressivity of this tumor.
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Brightman, B. K., K. G. Chandy, R. H. Spencer i H. Fan. "A T lymphoid cell line responds to a thymic stromal cell line by expression of Thy-1 and CD4." Journal of Immunology 143, nr 9 (1.11.1989): 2775–82. http://dx.doi.org/10.4049/jimmunol.143.9.2775.
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Abstract We have cloned both T lymphoid and stromal lines from a single murine thymic tumor that was induced by a retrovirus carrying the v-myc oncogene (M-MuLV(myc]. The T lymphoid line, L4, was cloned by growth in agar. L4 cells were initially negative for Thy-1.2 and CD4 (although they contained rearranged TCR-beta genes), and they remained so if passaged in medium alone. However, cocultivation of these Thy-1.2- CD4- cells with the cloned stromal cell line, St3, resulted in sequential expression of Thy-1.2 and CD4 in subpopulations of cells. Thy-1.2+ CD4- and Thy-1.2+ CD4+ L4 subclones were obtained from the cocultures by subsequent cloning in agar. Derivation of these subclones from the starting Thy-1.2- CD4- clone was verified by Southern blot analyses specific for TCR-beta gene rearrangements and for M-MuLV(myc) proviral integration sites. Continuous cocultivation of Thy-1.2+ CD4+ L4 subclones with the St3 stromal cells was necessary for maintenance of CD4 on the cell surface. Furthermore, CD4 expression which was lost when CD4+ L4 cells were removed from the stroma could be reinduced if they were again cultured on St3 stroma. These cells may provide a model system for studying thymocyte-stromal cell interactions in induction and maintenance of expression of Thy-1 and CD4 molecules.
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Guilloton, Fabien, Gersende Caron, Cédric Ménard, Céline Pangault, Patricia Amé-Thomas, Joëlle Dulong, John De Vos i in. "Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes". Blood 119, nr 11 (15.03.2012): 2556–67. http://dx.doi.org/10.1182/blood-2011-08-370908.
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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.
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Miyake, K., C. B. Underhill, J. Lesley i P. W. Kincade. "Hyaluronate can function as a cell adhesion molecule and CD44 participates in hyaluronate recognition." Journal of Experimental Medicine 172, nr 1 (1.07.1990): 69–75. http://dx.doi.org/10.1084/jem.172.1.69.
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A cell adhesion model was previously used to select a series of monoclonal antibodies (mAbs), which were subsequently found to recognize CD44/Pgp-1. Interest in these reagents increased with the finding that they totally inhibited production of lymphoid or myeloid cells in long-term bone marrow cultures. Further investigation has now revealed that hyaluronate is a potential ligand for CD44 and that hyaluronate recognition accounts for the adhesion between B lineage hybridoma and stromal cells. The hybridoma cells adhered to hyaluronate-coated plastic wells as well as to monolayers of stromal cells. The adhesion in both cases was inhibited by treatment with hyaluronidases, and did not require divalent cations. Addition of exogenous hyaluronate also diminished binding of lymphoid cells to stromal cells. One of several mAbs to Pgp-1/CD44 was particularly effective at blocking these interactions. Since hyaluronate and Pgp-1/CD44 were present on both cell types, experiments were done to determine the cellular location of interacting molecules required for the adhesion process. Treatment of lymphoid cells with an anti-Pgp-1/CD44 antibody was more inhibitory than antibody treatment of the stromal cells. Conversely, hyaluronidase treatment of stromal cells reduced subsequent binding more than treatment of the lymphoid cells. Adhesive interactions that involve hyaluronate and CD44 could contribute to a number of cell recognition processes, including ones required for normal lympho-hemopoiesis.
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Pandey, Shubham, Frédéric Mourcin, Tony Marchand, Saba Nayar, Marion Guirriec, Céline Pangault, Céline Monvoisin i in. "IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma". Blood 129, nr 18 (4.05.2017): 2507–18. http://dx.doi.org/10.1182/blood-2016-08-737239.
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Key Points FL-infiltrating stromal cells overexpress CXCL12, which triggers FL B-cell migration, adhesion, and activation. Polarization into CXCL12hi stroma involves IL-4+ TFH cells, unlike malignant B cells, revealing an indirect protumoral activity of FL-TFH cells.
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Buettner, Manuela, Reinhard Pabst i Ulrike Bode. "Stromal cell heterogeneity in lymphoid organs". Trends in Immunology 31, nr 2 (luty 2010): 80–86. http://dx.doi.org/10.1016/j.it.2009.11.003.
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Park, Gyeongsin, Byunghoo Song, Yuji Lee, Ahwon Lee, Yang-Guk Chung, Chang Suk Kang i Il-Hoan Oh. "Stromal Interaction of Lymphoma Cells Regulates Survival and Chemoresistance". Blood 118, nr 21 (18.11.2011): 5195. http://dx.doi.org/10.1182/blood.v118.21.5195.5195.
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Abstract Abstract 5195 High-grade lymphomas are aggressive but largely curable, whereas low-grade lymphomas are indolent, but frequently recur to be incurable, paradoxically. Mesenchymal stromal cells (MSCs) have been known to participate for reconstituting microenvironment. Studies show that signalings between normal lymphoid cells and stromal cells were frequently altered in high grade lymphomas, but relatively conserved in low grade lymphomas. However, which cell and mechanism is responsible for lymphoma recurrence remains unclear. Here we hypothesized that the interaction with stroma may play a role for lymphoma cell growth and survival. For this, we investigated the effect of MSCs on lymphoma cell growth and chemo-resistance by using a coculture system with MSCs (derived from tonsil), as a stromal microenvironment for lymphoma cells. First, coculture of lymphoma cell line (Pfeiffer) and primary lymphoma cells with/without MSCs for 3 days showed that the MSC-cocultured cells grew more rapidly (1.4 times and 1.8 times for Pfeiffer and primary cells, respectively) than MSC-free lymphoma cells. To further investigate the underlying mechanism of promoting growth, lymphoma cells were cocultured with MSCs in the presence or absence of transwell filter. At day 4, the proliferation of lymphoma cells in the absence of transwell was 3.5 times higher than in the presence of transwell. Interestingly, the lymphoma cells cocultured with MSCs showed increased expression of CXCR4 compared with lymphoma cells cultured alone. When the cyto-protective effect of MSCs was examined by doxorubicin treatment (1ug/ml) in the presence or absence of MSCs, 91% of MSC-cocultured cells survived, whereas only 28% of stroma-free cultured cells survived. These results demonstrate that the direct contact interaction with stroma might be important for lymphoma cell growth and survival. In conclusion, our data suggest that the interaction with stromal microenvironment is an important factor for survival of lymphoma cells which cells might be responsible for chemoresistance, and raise the possibility that the stromal interaction could be a potential target for lymphoma treatment. Disclosures: No relevant conflicts of interest to declare. This research was supported by a grant (10172KFDA993) from Korea Food & Drug Administration in 2011. Disclosures: No relevant conflicts of interest to declare.
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Salles, G., CY Chen, EL Reinherz i MA Shipp. "CD10/NEP is expressed on Thy-1low B220+ murine B-cell progenitors and functions to regulate stromal cell-dependent lymphopoiesis". Blood 80, nr 8 (15.10.1992): 2021–29. http://dx.doi.org/10.1182/blood.v80.8.2021.2021.
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Abstract To further characterize the function of the common acute lymphoblastic leukemia antigen (CALLA; CD10, neutral endopeptidase 24.11, NEP) in early lymphoid development, we have identified murine lymphoid progenitors expressing CD10/NEP and analyzed the effects of inhibiting the enzyme in in vitro assays of murine lymphoid differentiation. CD10/NEP transcripts and enzymatic activity were primarily restricted to the subpopulation of murine lymphoid progenitors, termed pro-B cells, which were isolated from bone marrow (BM) and modified Whitlock- Witte cultures and defined by coexpression of B220 and low levels of Thy-1. CD10/NEP transcripts and cell surface enzymatic activity were also detected in BM stromal cells known to support the development of B- lymphoid progenitors. In contrast, Abelson and H-ras transformed pre-B- cell lines were CD10/NEP- as were Thy-1-B220+ pre-B cells from BM and modified Whitlock-Witte cultures and Thy-1lowLin- (B220-Mac-1-GR-1-Ly- 2/3-) uncommitted hematopoietic progenitors from BM. The expression of CD10/NEP on murine pro-B cells and BM stromal cells suggests a role for the enzyme in early B-cell ontogeny. In modified Whitlock-Witte cultures in which Thy-1lowLin- progenitors plated on BM stromal cells differentiate into Thy-1lowB220+ pro-B and Thy-1-B220+ pre-B cells, the addition of specific CD10/NEP inhibitors increased the number of lymphoid colonies at days 5 through 7 by 34% (P < .001). The results suggest that CD10/NEP participates in the regulation of the earliest stages of stromal cell-dependent B lymphopoiesis.
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Salles, G., CY Chen, EL Reinherz i MA Shipp. "CD10/NEP is expressed on Thy-1low B220+ murine B-cell progenitors and functions to regulate stromal cell-dependent lymphopoiesis". Blood 80, nr 8 (15.10.1992): 2021–29. http://dx.doi.org/10.1182/blood.v80.8.2021.bloodjournal8082021.
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To further characterize the function of the common acute lymphoblastic leukemia antigen (CALLA; CD10, neutral endopeptidase 24.11, NEP) in early lymphoid development, we have identified murine lymphoid progenitors expressing CD10/NEP and analyzed the effects of inhibiting the enzyme in in vitro assays of murine lymphoid differentiation. CD10/NEP transcripts and enzymatic activity were primarily restricted to the subpopulation of murine lymphoid progenitors, termed pro-B cells, which were isolated from bone marrow (BM) and modified Whitlock- Witte cultures and defined by coexpression of B220 and low levels of Thy-1. CD10/NEP transcripts and cell surface enzymatic activity were also detected in BM stromal cells known to support the development of B- lymphoid progenitors. In contrast, Abelson and H-ras transformed pre-B- cell lines were CD10/NEP- as were Thy-1-B220+ pre-B cells from BM and modified Whitlock-Witte cultures and Thy-1lowLin- (B220-Mac-1-GR-1-Ly- 2/3-) uncommitted hematopoietic progenitors from BM. The expression of CD10/NEP on murine pro-B cells and BM stromal cells suggests a role for the enzyme in early B-cell ontogeny. In modified Whitlock-Witte cultures in which Thy-1lowLin- progenitors plated on BM stromal cells differentiate into Thy-1lowB220+ pro-B and Thy-1-B220+ pre-B cells, the addition of specific CD10/NEP inhibitors increased the number of lymphoid colonies at days 5 through 7 by 34% (P < .001). The results suggest that CD10/NEP participates in the regulation of the earliest stages of stromal cell-dependent B lymphopoiesis.
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Minami, Hirohito, Kohshi Ohishi, Masahiro Masuya i Naoyuki Katayama. "LFA-1-Mediated Adhesion to ICAM-2 Is Critical for Stromal Cell-Dependent Early T-Lymphoid Differentiation from Human Hematopoietic Precursors". Blood 126, nr 23 (3.12.2015): 2397. http://dx.doi.org/10.1182/blood.v126.23.2397.2397.
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Abstract The regulatory mechanism of human early T-lymphoid differentiation remains less defined. We previously reported that human telomerized bone marrow stromal cells support the generation of CD7+ CD56- early T- as well as CD10+ CD19+ early B-lymphoid precursors from human hematopoietic precursors. Here we examined whether and how early T lymphopoiesis is regulated by interaction with stromal cells. Low or no levels of LFA-1 were expressed on CD34+ CD38- CD45RA- immature hematopoietic precursors. However, high levels of LFA-1 were detected on CD34+ CD38- CD45RA+ CD10+ CD7+/- CD19- immature lymphoid precursors, while those of LFA-1 were diminished on CD34+ CD38+ CD45RA+ CD10+ CD19+ more mature pro B cells. On the other hand, ICAM-1 and ICAM-2 were expressed in a portion of the telomerized stromal cells. ICAM-3 was not detected. Various levels of ICAM-1, ICAM-2, or ICAM-3 were also expressed on hematopoietic and lymphoid precursors. To examine the role of LFA-1-mediated adhesion to stromal cells or adjacent hematopoietic precccursors in early lymphoid differentiation, we examined the effect of anti-LFA-1 blocking antibody (Ab) on the differentiation of CD34+ CD45RA- CD7- CD10- CD38lo/- hematopoietic precursors in the cultures on stromal cells or with conditioned medium (CM) obtained from cultures of stromal cells. In the cultures on stromal cells, anti-LFA-1 Ab strongly inhibited the generation of CD7+ CD10- CD45RA+ and CD7- CD10+ CD45RA+ lymphoid precursors from hematopoietic precursors after 21 days of culture. Significant number of CD14+ monocytic cells was generated with or without anti-LFA-1 Ab. In the cultures with CM, anti-LFA-1 Ab showed marginable effect on lymphoid differentiation. To elucidate the effect of anti-LFA-1 Ab on more mature lymphoid precursors, CD7+ CD10- CD45RA+ or CD7- CD10+ CD45RA+ cells were isolated after culture of hematopoietic cells for 14 days and cultured on stromal cells in the presence or absence of anti-LFA-1 Ab. Anti-LFA-1 Ab remarkably inhibited the generation of CD7+ and CD10+ CD19+ lymphoid cells from the CD7+ CD10- CD45RA+ early T-lymphoid precursors. Notably, few or no CD45RA+ CD14- lymphoid cells were detected. Anti-LFA-1 Ab did not affect B-lineage differentiation from CD10+ CD19- CD45RA+ early B-lymphoid precursors to CD10+ CD19+ CD45RA+ proB cells. We next examined which ICAM ligand is responsible for the observed effects by anti-LFA-1 Ab. Anti-ICAM-2 Ab inhibited the generation of CD7+ CD45RA+ and CD10+ CD45RA+ lymphoid precursors from CD34+ CD45RA- CD7- CD10- CD38lo/- hematopoietic precursors on stromal cells, as observed with anti-LFA-1 Ab. No effect was observed with anti-ICAM-1 Ab. Anti-ICAM-2 Ab further suppressed the generation of CD7+ and CD10+ lymphoid cells from the cultured CD7+ CD10- CD45RA+ early T-lymphoid precursors, but did not depress B-lymphoid differentiation from the cultured CD7- CD10+ CD45RA+ early B-lymphoid precursors. Taken together, these data indicate that LFA-1-mediated adhesion to ICAM-2 is essential for stromal cell-dependent early lymphoid differentiation of hematopoietic and CD7+ early T-lymphoid precursors. Disclosures No relevant conflicts of interest to declare.
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Randle-Barrett, Elise S., i Richard L. Boyd. "Thymic Microenvironment and Lymphoid Responses to Sublethal Irradiation". Developmental Immunology 4, nr 2 (1995): 101–16. http://dx.doi.org/10.1155/1995/14923.
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Sublethal irradiation of the murine thymus has been a useful tool for depleting the thymus of dividing immature thymocyte subsets, to sequence thymocyte differentiation events occurring from radiation-resistant precursors. This massive reduction in thymocytes also represents a model in which the bidirectional interplay between the thymic stromal cells and lymphocytes can be investigated. The purpose of this study was thus twofold: to precisely map the initiation of thymopoiesis as a prelude to assessing the effects of injected mAb to novel thymic antigens; and to use a panel of mAbs to determine the alterations in the thymic stroma during the T-cell depletion and reconstitution phases. The striking finding from this study was that following T-cell depletion, there was a marked upregulation of specific stromal antigens, which retracted with the reappearance of T cells. Thus, following sublethal irradiation, there are modifications in the thymic microenvironment that may be necessary to support renewed thymopoiesis and the complete restoration of the thymus involved the synchronous development of both the stromal and lymphocytic components.
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Moreau, I., V. Duvert, J. Banchereau i S. Saeland. "Culture of human fetal B-cell precursors on bone marrow stroma maintains highly proliferative CD20dim cells". Blood 81, nr 5 (1.03.1993): 1170–78. http://dx.doi.org/10.1182/blood.v81.5.1170.1170.
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Abstract Growth of human B-cell precursors (BCP) was achieved by plating fetal CD10+ surface-mu (s mu)- cells in liquid medium onto bone marrow- derived fibroblastic stromal cell layers deprived of hematopoietic cells. Proliferation of the fetal BCP was strongly potentiated by the addition of interleukin-7 (IL-7) to the cultures. Cultures included both a stroma-adherent and -nonadherent fraction of lymphoid cells, allowing us to expand the number of input BCP to 13-fold. In the presence of exogenous IL-7, proliferation was dose-dependent relative to the number of stromal cells, demonstrating that soluble IL-7 does not act alone to promote optimal growth. We further showed that the lymphoid cells recovered remain CD10+ sIg- BCP and that most cells expressed the maturation-associated CD20 antigen when IL-7 was added to the cultures. Whereas both freshly isolated CD20- and CD20bright BCP proliferated in the presence of stroma, we observed that high- proliferative capacity CD20dim cells were maintained in the cultures. Finally, CD20dim sorted cells were shown to subsequently acquire high levels of CD20 expression in culture, thus demonstrating a partial maturation sequence. The present culture system thus represents a useful model for studying the regulatory signals in early human B lymphopoiesis.
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Moreau, I., V. Duvert, J. Banchereau i S. Saeland. "Culture of human fetal B-cell precursors on bone marrow stroma maintains highly proliferative CD20dim cells". Blood 81, nr 5 (1.03.1993): 1170–78. http://dx.doi.org/10.1182/blood.v81.5.1170.bloodjournal8151170.
Pełny tekst źródłaStreszczenie:
Growth of human B-cell precursors (BCP) was achieved by plating fetal CD10+ surface-mu (s mu)- cells in liquid medium onto bone marrow- derived fibroblastic stromal cell layers deprived of hematopoietic cells. Proliferation of the fetal BCP was strongly potentiated by the addition of interleukin-7 (IL-7) to the cultures. Cultures included both a stroma-adherent and -nonadherent fraction of lymphoid cells, allowing us to expand the number of input BCP to 13-fold. In the presence of exogenous IL-7, proliferation was dose-dependent relative to the number of stromal cells, demonstrating that soluble IL-7 does not act alone to promote optimal growth. We further showed that the lymphoid cells recovered remain CD10+ sIg- BCP and that most cells expressed the maturation-associated CD20 antigen when IL-7 was added to the cultures. Whereas both freshly isolated CD20- and CD20bright BCP proliferated in the presence of stroma, we observed that high- proliferative capacity CD20dim cells were maintained in the cultures. Finally, CD20dim sorted cells were shown to subsequently acquire high levels of CD20 expression in culture, thus demonstrating a partial maturation sequence. The present culture system thus represents a useful model for studying the regulatory signals in early human B lymphopoiesis.
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Peschel, C., I. Green i W. E. Paul. "Preferential proliferation of immature B lineage cells in long-term stromal cell-dependent cultures with IL-4." Journal of Immunology 142, nr 5 (1.03.1989): 1558–68. http://dx.doi.org/10.4049/jimmunol.142.5.1558.
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Abstract IL-4 influences the cellular composition of stromal cell dependent long term cultures. In bone marrow-derived long term lymphoid cultures initiated in presence of IL-4, the majority of cells exhibited a more immature phenotype than is usually seen in lymphoid cells grown in Whitlock-Witte type cultures. This immature cell population, lacking the B220 Ag, was purified by cell sorting. When transferred to mixed stromal layers used in conventional lymphoid long term cultures, these cells differentiated into B lineage cells that could be identified by expression of the B220 Ag and surface IgM. Abelson murine leukemia virus-transformed cell lines resulting from this immature cell population express a DJH rearrangement and contained RNA that hybridized with a VJ558 probe, suggesting transcription of germ-line V genes. A culture modification allowed selective proliferation of a non-transformed cell population with characteristics of very immature B lineage cells. The proliferation of these cells was supported by a homogeneous stromal cell line that was propagated with horse serum in presence of IL-4. The lymphoid cells proliferating under those culture conditions expressed the Ag detected by the BP-1 and 6C3 mAb and were Fc gamma RII and Ia-positive. However, more mature B cell markers were lacking. DNA analysis of these cell lines revealed JH rearrangement without evidence for deletion of any member of the DSP-2 family. These cell lines retained their immature phenotype after transfer to mixed stromal layers of Whitlock-Witte type. The mechanisms providing these unique culture conditions initiated by IL-4 in bone marrow stromal cells are discussed.
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Pinner, Sophie, i Shannon Turley. "Podoplanin-rich stromal networks induce dendritic cell motility via activation of CLEC-2 (102.21)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 102.21. http://dx.doi.org/10.4049/jimmunol.186.supp.102.21.
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Abstract Cell motility is crucial for leukocytes to traffic between tissues and to interact with one another and their microenvironment. Stromal cells provide 3-dimensional scaffolds and molecular cues that coordinate leukocyte migration and compartmentalization within secondary lymphoid organs. Dendritic cells (DCs) are antigen presenting cells whose migration via stromal networks is critical for the induction of both immunogenic and tolerogenic T cell responses. DCs migrate in an amoeboid, integrin-independent manner, utilizing the chemokine receptor CCR7 to navigate their way to lymph nodes (LNs). However the molecules utilised by DCs and other leukocytes to interact with stroma are still largely unknown. Here we describe a novel motility mechanism driven by the glycoprotein podoplanin (gp38) that induces motility of DCs that express the C-type lectin-like receptor 2 (CLEC-2, CLEC-1b). Podoplanin-mediated activation of CLEC-2 promotes dynamic, actin-rich protrusions, and migration along stroma. The podoplanin-CLEC-2 interaction endows DCs with the capacity to crawl along stromal cell scaffolds of secondary lymphoid organs and to find and properly activate T cells. Our results illuminate a novel mechanism of leukocyte migration pertaining to multiple steps in the adaptive immune response which we propose functions in concert with chemokine gradients to ensure efficient, directional leukocyte trafficking.
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Waller, EK, OW Kamel, ML Cleary, AS Majumdar, MR Schick, M. Lieberman i IL Weissman. "Growth of primary T-cell non-Hodgkin's lymphomata in SCID-hu mice: requirement for a human lymphoid microenvironment". Blood 78, nr 10 (15.11.1991): 2650–65. http://dx.doi.org/10.1182/blood.v78.10.2650.2650.
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Abstract We reasoned that the SCID-hu mouse could provide an appropriate lymphoid or stromal microenvironment to support the growth of primary human lymphoma. Heterotransplantation of nine cases of primary T-cell non-Hodgkin's lymphoma (NHL) into untreated SCID mice and SCID mice reconstituted with human fetal thymus, spleen, and liver (SCID-hu) resulted in the development of lymphoid tumors in five (56%) cases. Two clonal T-cell NHL grew after a mean of 90 days after injection of primary lymphoma cell suspensions into the thymus xenografts in SCID-hu mice and failed to grow in a variety of sites in SCID mice, except for small tumors that developed after a long (157-day) latency period after intracranial injection of tumor cell suspensions into weanling SCID mice. Successful serial transplantation of NHL in SCID and SCID-hu mice required the presence of a human lymphoid or tumor microenvironment, and was enhanced by pretreating the SCID mice with 175 rad radiation and antiasialo antisera. Analysis of the primary and transplanted T- cell tumors showed identical patterns of T-cell surface markers by flow cytometry and immunophenotyping of fixed tissue sections, and, in one case, reactivity with a specific monoclonal antibody to V beta 5.1. Genotyping of the transplanted tumors showed T-cell receptor gene rearrangements identical to those present in the primary tumors. In one case, the presence of Epstein-Barr virus-positive B cells in association with the primary tumor resulted in the growth of a lymphoblastoid B-cell neoplasm in addition to the malignant T-cell lymphoma after transplantation of tumor fragments to SCID mice. The data support the hypothesis that a human lymphoid microenvironment enhances the growth of T-cell NHL in SCID mice. The SCID-hu thymus graft provides an apparently unique microenvironment that supports the growth of primary T-cell NHL, and can be used to study the interaction between lymphoma cells, nontransformed lymphoid cells, and the surrounding stromal microenvironment in vivo.
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Waller, EK, OW Kamel, ML Cleary, AS Majumdar, MR Schick, M. Lieberman i IL Weissman. "Growth of primary T-cell non-Hodgkin's lymphomata in SCID-hu mice: requirement for a human lymphoid microenvironment". Blood 78, nr 10 (15.11.1991): 2650–65. http://dx.doi.org/10.1182/blood.v78.10.2650.bloodjournal78102650.
Pełny tekst źródłaStreszczenie:
We reasoned that the SCID-hu mouse could provide an appropriate lymphoid or stromal microenvironment to support the growth of primary human lymphoma. Heterotransplantation of nine cases of primary T-cell non-Hodgkin's lymphoma (NHL) into untreated SCID mice and SCID mice reconstituted with human fetal thymus, spleen, and liver (SCID-hu) resulted in the development of lymphoid tumors in five (56%) cases. Two clonal T-cell NHL grew after a mean of 90 days after injection of primary lymphoma cell suspensions into the thymus xenografts in SCID-hu mice and failed to grow in a variety of sites in SCID mice, except for small tumors that developed after a long (157-day) latency period after intracranial injection of tumor cell suspensions into weanling SCID mice. Successful serial transplantation of NHL in SCID and SCID-hu mice required the presence of a human lymphoid or tumor microenvironment, and was enhanced by pretreating the SCID mice with 175 rad radiation and antiasialo antisera. Analysis of the primary and transplanted T- cell tumors showed identical patterns of T-cell surface markers by flow cytometry and immunophenotyping of fixed tissue sections, and, in one case, reactivity with a specific monoclonal antibody to V beta 5.1. Genotyping of the transplanted tumors showed T-cell receptor gene rearrangements identical to those present in the primary tumors. In one case, the presence of Epstein-Barr virus-positive B cells in association with the primary tumor resulted in the growth of a lymphoblastoid B-cell neoplasm in addition to the malignant T-cell lymphoma after transplantation of tumor fragments to SCID mice. The data support the hypothesis that a human lymphoid microenvironment enhances the growth of T-cell NHL in SCID mice. The SCID-hu thymus graft provides an apparently unique microenvironment that supports the growth of primary T-cell NHL, and can be used to study the interaction between lymphoma cells, nontransformed lymphoid cells, and the surrounding stromal microenvironment in vivo.
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Jacobsen, K., K. Miyake, P. W. Kincade i D. G. Osmond. "Highly restricted expression of a stromal cell determinant in mouse bone marrow in vivo." Journal of Experimental Medicine 176, nr 4 (1.10.1992): 927–35. http://dx.doi.org/10.1084/jem.176.4.927.
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B lymphocyte precursor cells in mouse bone marrow develop in close association with stromal cells which provide essential growth signals. To identify molecules that may normally play a role in this interaction we have examined the in vivo binding of a new monoclonal antibody (mAb) (KMI6) that recognizes a determinant on a bone marrow stromal cell line (BMS2) in vitro. Flow cytometric and radioautographic evaluations revealed that the antigen recognized by KMI6 is represented on the surface of an extremely small number of cells in bone marrow cell suspensions from adult mice. An apparent molecular mass of 110 kD was obtained by surface labeling of a stromal cell clone and immunoprecipitation. Purified mAb KMI6 labeled with 125I was then given intravenously to young C3H/HeJ mice. Unbound mAb was washed out by cardiac perfusion and femoral bone marrow was examined by light and electron microscope radioautography. KMI6 labeling was heavy on the plasma membrane of many stromal cells, especially those located towards the outer subosteal region. The KMI6-labeled stromal cells were usually associated with cells of lymphoid morphology which they often completely surrounded. The labeling was restricted to areas of stromal cell plasma membranes in contact with lymphoid cells. The lymphoid cells themselves, as well as macrophages and other hemopoietic cells, failed to bind mAb KMI6 significantly. Stromal cells in bone marrow depleted of hemopoietic cells by gamma-irradiation (9,5 Gy) bound mAb KMI6 at reduced intensity. The results demonstrate that the KMI6 determinant, a 110-kD protein, is expressed on bone marrow stromal cells in vivo. Its restriction to areas of interaction with lymphoid cells suggests a role in forming microenvironmental niches of B lymphopoiesis. The surface membrane of individual stromal cells may thus be functionally polarized towards interacting B cell precursors and other hemopoietic cells.
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Umiel, T., CW Rettenmier, S. Siegel, S. Ota, H. Shimada, TW Tran i PK Pattengale. "Establishment and characterization of a human mixed-lineage, T- lymphoid/myeloid cell line (USP-91)". Blood 82, nr 6 (15.09.1993): 1829–37. http://dx.doi.org/10.1182/blood.v82.6.1829.1829.
Pełny tekst źródłaStreszczenie:
Abstract We report the establishment of a novel cell line from a pediatric patient with recurrent non-Hodgkin's lymphoma. This cell line, termed USP-91, showed both T-lymphoid cell as well as myeloid (ie, nonlymphoid) cell characteristics using a comprehensive multiparameter approach. The initial growth of this cell line was dependent on the presence of the murine stromal cell line, 14F1.1. Subsequently, a phenotypically stable, stroma-independent cell line was established. Although the recurrent biopsy material and the derivative cell line, USP-91, were clonally-derived from T-lineage lymphoid cells, as evidenced by the same rearrangement of the T-cell receptor-beta locus, USP-91 coexpressed both the T-cell antigens CD7, CD3, and CD4, and the myeloid antigens CD13, CD33, CD11b, and CD34. The myeloid features of USP-91 were most consistent with monocytic differentiation as these cells expressed alpha-napthol acetate esterase, lysozyme, alpha-1- antitrypsin, alpha-1-antichymotrypsin, as well as the cell surface receptor for macrophage colony-stimulating factor. In addition, incubation in the presence of phorbol esters induced USP-91 to exhibit morphologic and functional properties of mature mononuclear phagocytes. The expression of this bilineage phenotype suggests that USP-91 represents the malignant transformation of a progenitor cell capable of either myelomonocytic or T-lymphoid differentiation.
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Umiel, T., CW Rettenmier, S. Siegel, S. Ota, H. Shimada, TW Tran i PK Pattengale. "Establishment and characterization of a human mixed-lineage, T- lymphoid/myeloid cell line (USP-91)". Blood 82, nr 6 (15.09.1993): 1829–37. http://dx.doi.org/10.1182/blood.v82.6.1829.bloodjournal8261829.
Pełny tekst źródłaStreszczenie:
We report the establishment of a novel cell line from a pediatric patient with recurrent non-Hodgkin's lymphoma. This cell line, termed USP-91, showed both T-lymphoid cell as well as myeloid (ie, nonlymphoid) cell characteristics using a comprehensive multiparameter approach. The initial growth of this cell line was dependent on the presence of the murine stromal cell line, 14F1.1. Subsequently, a phenotypically stable, stroma-independent cell line was established. Although the recurrent biopsy material and the derivative cell line, USP-91, were clonally-derived from T-lineage lymphoid cells, as evidenced by the same rearrangement of the T-cell receptor-beta locus, USP-91 coexpressed both the T-cell antigens CD7, CD3, and CD4, and the myeloid antigens CD13, CD33, CD11b, and CD34. The myeloid features of USP-91 were most consistent with monocytic differentiation as these cells expressed alpha-napthol acetate esterase, lysozyme, alpha-1- antitrypsin, alpha-1-antichymotrypsin, as well as the cell surface receptor for macrophage colony-stimulating factor. In addition, incubation in the presence of phorbol esters induced USP-91 to exhibit morphologic and functional properties of mature mononuclear phagocytes. The expression of this bilineage phenotype suggests that USP-91 represents the malignant transformation of a progenitor cell capable of either myelomonocytic or T-lymphoid differentiation.
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Guilloton, Fabien, Gersende Caron, Cédric Ménard, Céline Pangault, Patricia Amé-Thomas, Joelle Dulong, John De Vos i in. "Mesenchymal Stromal Cells Orchestrate Follicular Lymphoma Cell Niche Through the CCL2-Dependent Recruitment and Polarization of Monocytes". Blood 118, nr 21 (18.11.2011): 1566. http://dx.doi.org/10.1182/blood.v118.21.1566.1566.
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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.
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Minami, Hirohito, Kohshi Ohishi, Yoshiki Nakamori, Masahiro Masuya i Naoyuki Katayama. "Direct Contact with Stromal Cells in Association with SDF-1 Is Important for B-Lineage Differentiation Toward CD19+ ProB Cells from Human Hematopoietic Precursors, but Dispensable for Generation of CD7+CD45RA+ Multipotent Lymphoid Precursors". Blood 124, nr 21 (6.12.2014): 5138. http://dx.doi.org/10.1182/blood.v124.21.5138.5138.
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Abstract The regulatory mechanism of human early B- and T- lymphoid differentiation has not been well studied. Coculture on telomerized human bone marrow stromal cells supported the generation of CD7+CD45RA+ multipotent precursors with differentiation potential for T-, B-, NK-lineage, and monocytic cells, CD10+CD19-CD45RA+ B-biased precursors, and CD10+CD19+CD45RA+ proB cells from human CD34+lin- hematopoietic progenitors. CD7+CD45RA+ and CD10+CD19- lymphoid precursors can be developed from hematopoietic progenitors by soluble factors produced from stromal cells, but the generation of CD19+ proB cells was reduced. Replating analysis showed that direct contact with stromal cells promoted B-lineage differentiation toward CD19+ proB cells from CD34+lin- cell-derived CD7+CD45RA+ and CD10+CD19- lymphoid precursors. SDF-1 is shown to be critical for B-lineage differentiation from studies of mice. SDF-1 was produced from the human telomerized stromal cells. Inhibition of binding to SDF-1 with neutralizing antibody against CXCR4 suppressed B-lineage differentiation to CD19+ proB cells from hematopoietic precursors, while the generation of CD7+CD45RA+ cells was not significantly affected. By replating analysis, anti-CXCR4 Ab inhibited the differentiation to CD19+ proB cells from CD7+CD45RA+ and CD10+CD19- lymphoid precursors on stromal cells. These data indicate that direct contact with stromal cells in association with SDF-1 produced from stromal cells is important for B-lineage differentiation toward CD19+ proB cells from CD7+CD45RA+ and CD10+CD19- lymphoid precursors but dispensable for differentiation toward CD7+CD45RA+ multipotent lymphoid precursors. Disclosures No relevant conflicts of interest to declare.
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Clark, R. A., R. Alon i T. A. Springer. "CD44 and hyaluronan-dependent rolling interactions of lymphocytes on tonsillar stroma." Journal of Cell Biology 134, nr 4 (15.08.1996): 1075–87. http://dx.doi.org/10.1083/jcb.134.4.1075.
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Little is known about how lymphocytes migrate within secondary lymphoid organs. Stromal cells and their associated reticular fibers form a network of fibers that radiate from high endothelial venules to all areas of the lymph node and may provide a scaffold for lymphocyte migration. We studied interactions of lymphocytes with cultured human tonsillar stromal cells and their extracellular matrix using shear stress to distinguish transient interactions from firm adhesion. Tonsillar lymphocytes and SKW3 T lymphoma cells tethered and rolled on monolayers of cultured tonsillar stromal cells and their matrix. A significant proportion of these rolling interactions were independent of divalent cations and were mediated by CD44 binding to hyaluronan, as shown by inhibition with mAb to CD44, soluble hyaluronan, as hyaluronidase treatment of the substrate, and O-glycoprotease treatment of the rolling cells. O-glycoprotease treatment of the substrate also blocked binding completely to stromal matrix and partially to stromal monolayers. SKW3 cells tethered and rolled on plastic-immobilized hyaluronan, confirming the specificity of this interaction. By contrast, monolayers of resting or stimulated human umbilical vein endothelial cells failed to support CD44- and hyaluronan-dependent rolling. SKW3 cells added under flow conditions to frozen sections of human tonsil bound and rolled along reticular fibers in the presence of EDTA. Rolling was blocked by either CD44 mAb or hyaluronan. We propose that lymphocytes migrating through secondary lymphoid organs may use CD44 to bind to hyaluronan immobilized on stromal cells and reticular fibers.
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Dumontet, Erwan, Céline Pangault, David Roulois, Matthis Desoteux, Simon Léonard, Tony Marchand, Maelle Latour i in. "Extracellular vesicles shed by follicular lymphoma B cells promote polarization of the bone marrow stromal cell niche". Blood 138, nr 1 (24.02.2021): 57–70. http://dx.doi.org/10.1182/blood.2020008791.
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Abstract Follicular lymphoma (FL) originates in the lymph nodes (LNs) and infiltrates bone marrow (BM) early in the course of the disease. BM FL B cells are characterized by a lower cytological grade, decreased proliferation, and a specific phenotypic and subclonal profile. Mesenchymal stromal cells (MSCs) 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 identified. In the current work, we demonstrate that FL B cells produce extracellular vesicles (EVs) that can be internalized by BM-MSCs, making them more efficient to support FL B-cell survival and quiescence. Accordingly, EVs purified from FL BM plasma activate transforming growth factor β–dependent and independent pathways in BM-MSCs and modify their GEP, triggering an upregulation of factors classically associated with hematopoietic stem cell niche, including CXCL12 and angiopoietin-1. Moreover, we provide 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-MSCs. This work identifies FL-derived EVs as putative mediators of BM stroma polarization and supports further investigation of their clinical interest for targeting the crosstalk between BM-MSCs and malignant B cells.
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Miller, Jeffrey S., Valarie McCullar i Catherine M. Verfaillie. "Ex Vivo Culture of CD34+/Lin−/DR− Cells in Stroma-Derived Soluble Factors, Interleukin-3, and Macrophage Inflammatory Protein-1α Maintains Not Only Myeloid But Also Lymphoid Progenitors in a Novel Switch Culture Assay". Blood 91, nr 12 (15.06.1998): 4516–22. http://dx.doi.org/10.1182/blood.v91.12.4516.
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Abstract We have demonstrated that long-term culture initiating cells (LTC-IC) are maintained in a stroma noncontact (SNC) culture where progenitors are separated from stroma by a microporous membrane and LTC-IC can proliferate if the culture is supplemented with interleukin-3 (IL-3) and macrophage inflammatory protein-1α (MIP-1α). We hypothesize that the same conditions, which result in LTC-IC proliferation, may also maintain lymphoid progenitors. Natural killer (NK) cells are of lymphoid lineage and a stromal-based culture can induce CD34+/Lin−/DR−cells to differentiate along the NK cell lineage. We developed a three-step switch culture assay that was required to demonstrate the persistence of NK progenitors in CD34+/Lin−/DR− cells assayed in SNC cultures supplemented with IL-3 and MIP-1α. When CD34+/Lin−/DR− progeny from the SNC culture were plated sequentially into “NK cell progenitor switch” conditions (contact with stromal ligands, hydrocortisone-containing long-term culture medium, IL-2, IL-7, and stem cell factor [SCF]) followed by “NK cell differentiation” conditions (contact with stromal ligands, human serum, no hydrocortisone, and IL-2), significant numbers of CD56+/CD3− NK resulted, which exhibited cytotoxic activity against K562 targets. All steps are required because a switch from SNC cultures with IL-3 and MIP-1α directly to “NK cell differentiation” conditions failed to yield NK cells suggesting that critical step(s) in lymphoid commitment were missing. Additional experiments showed that CD34+/CD33− cells present after SNC cultures with IL-3 and MIP-1α, which contained up to 30% LTC-IC, are capable of NK outgrowth using the three-step switch culture. Limiting dilution analysis from these experiments showed a cloning frequency within the cultured CD34+/CD33− population similar to fresh sorted CD34+/Lin−/DR− cells. However, after addition of FLT-3 ligand, the frequency of primitive progenitors able to develop along the NK lineage increased 10-fold. In conclusion, culture of primitive adult marrow progenitors ex vivo in stroma-derived soluble factors, MIP-1α, and IL-3 maintains both very primitive myeloid (LTC-IC) and lymphoid (NK) progenitors and suggests that these conditions may support expansion of human hematopoietic stem cells. Addition of FLT-3 ligand to IL-2, IL-7 SCF, and stromal factors are important in early stages of NK development.
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Miller, Jeffrey S., Valarie McCullar i Catherine M. Verfaillie. "Ex Vivo Culture of CD34+/Lin−/DR− Cells in Stroma-Derived Soluble Factors, Interleukin-3, and Macrophage Inflammatory Protein-1α Maintains Not Only Myeloid But Also Lymphoid Progenitors in a Novel Switch Culture Assay". Blood 91, nr 12 (15.06.1998): 4516–22. http://dx.doi.org/10.1182/blood.v91.12.4516.412k05_4516_4522.
Pełny tekst źródłaStreszczenie:
We have demonstrated that long-term culture initiating cells (LTC-IC) are maintained in a stroma noncontact (SNC) culture where progenitors are separated from stroma by a microporous membrane and LTC-IC can proliferate if the culture is supplemented with interleukin-3 (IL-3) and macrophage inflammatory protein-1α (MIP-1α). We hypothesize that the same conditions, which result in LTC-IC proliferation, may also maintain lymphoid progenitors. Natural killer (NK) cells are of lymphoid lineage and a stromal-based culture can induce CD34+/Lin−/DR−cells to differentiate along the NK cell lineage. We developed a three-step switch culture assay that was required to demonstrate the persistence of NK progenitors in CD34+/Lin−/DR− cells assayed in SNC cultures supplemented with IL-3 and MIP-1α. When CD34+/Lin−/DR− progeny from the SNC culture were plated sequentially into “NK cell progenitor switch” conditions (contact with stromal ligands, hydrocortisone-containing long-term culture medium, IL-2, IL-7, and stem cell factor [SCF]) followed by “NK cell differentiation” conditions (contact with stromal ligands, human serum, no hydrocortisone, and IL-2), significant numbers of CD56+/CD3− NK resulted, which exhibited cytotoxic activity against K562 targets. All steps are required because a switch from SNC cultures with IL-3 and MIP-1α directly to “NK cell differentiation” conditions failed to yield NK cells suggesting that critical step(s) in lymphoid commitment were missing. Additional experiments showed that CD34+/CD33− cells present after SNC cultures with IL-3 and MIP-1α, which contained up to 30% LTC-IC, are capable of NK outgrowth using the three-step switch culture. Limiting dilution analysis from these experiments showed a cloning frequency within the cultured CD34+/CD33− population similar to fresh sorted CD34+/Lin−/DR− cells. However, after addition of FLT-3 ligand, the frequency of primitive progenitors able to develop along the NK lineage increased 10-fold. In conclusion, culture of primitive adult marrow progenitors ex vivo in stroma-derived soluble factors, MIP-1α, and IL-3 maintains both very primitive myeloid (LTC-IC) and lymphoid (NK) progenitors and suggests that these conditions may support expansion of human hematopoietic stem cells. Addition of FLT-3 ligand to IL-2, IL-7 SCF, and stromal factors are important in early stages of NK development.
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Bilwani, Fareena, i Katherine Knight. "Adipocytes inhibit B lymphopoiesis at the common lymphoid progenitor (CLP) to pre-proB cell stage (111.30)". Journal of Immunology 188, nr 1_Supplement (1.05.2012): 111.30. http://dx.doi.org/10.4049/jimmunol.188.supp.111.30.
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Abstract Like in humans, B lymphopoiesis declines in rabbits with age, and we previously showed that adult rabbit BM stroma is unable to support generation of proB cells. We investigated changes in BM stroma of adult rabbits and found an increase in adipocytes similar to that in aged humans. We also found that both rabbit and human adipocytes secrete a soluble factor(s) that inhibits B lymphopoiesis. We investigated the stage at which the inhibitory molecule blocks B lymphopoiesis by co-culturing cord blood-derived human HSC and OP9 stromal cells with rabbit adipocyte-conditioned media (CM) and found that the inhibitory factor does not impair the generation of CLP but inhibits generation of pre-proB cells. We tested if the inhibitory molecule acts via stromal cells by treating OP9 stromal cells with adipocyte CM and then co-culturing them with rabbit BM mononuclear cells (MNC). The capacity of pre-treated OP9 stromal cells to support B lymphopoiesis was unchanged. In contrast, treatment of BM MNC of adult rabbit with the adipocyte CM and subsequent co-culture with OP9 stromal cells without adipocyte CM, showed that pre-treated cells were unable to differentiate into proB cells. We conclude that the adipocyte-derived soluble factor acts on early lymphoid precursors to inhibit B lymphopoiesis from the CLP to pre-proB cell stage. Such inhibition likely contributes to the decline of B lymphopoiesis in aged rabbits and humans and can be exploited to enhance immunity in elderly.
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Hao, Qian-Lin, Elzbieta M. Smogorzewska, Lora W. Barsky i Gay M. Crooks. "In Vitro Identification of Single CD34+CD38− Cells With Both Lymphoid and Myeloid Potential". Blood 91, nr 11 (1.06.1998): 4145–51. http://dx.doi.org/10.1182/blood.v91.11.4145.
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Abstract Human hematopoietic stem cells are pluripotent, ie, capable of producing both lymphoid and myeloid progeny, and are therefore used for transplantation and gene therapy. An in vitro culture system was developed to study the multi-lineage developmental potential of a candidate human hematopoietic stem cell population, CD34+CD38− cells. CD34+CD38− cells cocultivated on the murine stromal line S17 generated predominantly CD19+ B-cell progenitors. Transfer of cells from S17 stroma to myeloid-specific conditions (“switch culture”) showed that a fraction of the immunophenotypically uncommitted CD19− cells generated on S17 stroma had myeloid potential (defined by expression of CD33 and generation of colony-forming unit-cells). Using the switch culture system, single CD34+CD38− cells were assessed for their lymphoid and myeloid potential. Nineteen of 50 (38%) clones generated from single CD34+CD38− cells possessed both B-lymphoid and myeloid potential. 94.7% of the CD34+CD38− cells with lympho-myeloid potential were late-proliferating (clonal appearance after 30 days), demonstrating that pluripotentiality is detected significantly more often in quiescent progenitors than in cytokine-responsive cells (P = .00002). The S17/switch culture system permits the in vitro assessment of the pluripotentiality of single human hematopoietic cells.
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Hao, Qian-Lin, Elzbieta M. Smogorzewska, Lora W. Barsky i Gay M. Crooks. "In Vitro Identification of Single CD34+CD38− Cells With Both Lymphoid and Myeloid Potential". Blood 91, nr 11 (1.06.1998): 4145–51. http://dx.doi.org/10.1182/blood.v91.11.4145.411a10_4145_4151.
Pełny tekst źródłaStreszczenie:
Human hematopoietic stem cells are pluripotent, ie, capable of producing both lymphoid and myeloid progeny, and are therefore used for transplantation and gene therapy. An in vitro culture system was developed to study the multi-lineage developmental potential of a candidate human hematopoietic stem cell population, CD34+CD38− cells. CD34+CD38− cells cocultivated on the murine stromal line S17 generated predominantly CD19+ B-cell progenitors. Transfer of cells from S17 stroma to myeloid-specific conditions (“switch culture”) showed that a fraction of the immunophenotypically uncommitted CD19− cells generated on S17 stroma had myeloid potential (defined by expression of CD33 and generation of colony-forming unit-cells). Using the switch culture system, single CD34+CD38− cells were assessed for their lymphoid and myeloid potential. Nineteen of 50 (38%) clones generated from single CD34+CD38− cells possessed both B-lymphoid and myeloid potential. 94.7% of the CD34+CD38− cells with lympho-myeloid potential were late-proliferating (clonal appearance after 30 days), demonstrating that pluripotentiality is detected significantly more often in quiescent progenitors than in cytokine-responsive cells (P = .00002). The S17/switch culture system permits the in vitro assessment of the pluripotentiality of single human hematopoietic cells.
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Johnson, A., i K. Dorshkind. "Stromal cells in myeloid and lymphoid long-term bone marrow cultures can support multiple hemopoietic lineages and modulate their production of hemopoietic growth factors". Blood 68, nr 6 (1.12.1986): 1348–54. http://dx.doi.org/10.1182/blood.v68.6.1348.1348.
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Abstract Hemopoiesis in long-term bone marrow cultures (LTBMC) is dependent on adherent stromal cells that form an in vitro hemopoietic microenvironment. Myeloid bone marrow cultures (MBMC) are optimal for myelopoiesis, while lymphoid bone marrow cultures (LBMC) only support B lymphopoiesis. The experiments reported here have made a comparative analysis of the two cultures to determine whether the stromal cells that establish in vitro are restricted to the support of myelopoiesis or lymphopoiesis, respectively, and to examine how the different culture conditions affect stromal cell physiology. In order to facilitate this analysis, purified populations of MBMC and LBMC stroma were prepared by treating the LTBMC with the antibiotic mycophenolic acid; this results in the elimination of hemopoietic cells while retaining purified populations of functional stroma. Stromal cell cultures prepared and maintained under MBMC conditions secreted myeloid growth factors that stimulated the growth of granulocyte-macrophage colonies, while no such activity was detected from purified LBMC stromal cultures. However, this was not due to the inability of LBMC stroma to mediate this function. Transfer of LBMC stromal cultures to MBMC conditions resulted in an induction of myeloid growth factor secretion. When seeded under these conditions with stromal cell- depleted populations of hemopoietic cells, obtained by passing marrow through nylon wool columns, the LBMC stromal cells could support long- term myelopoiesis. Conversely, transfer of MBMC stroma to LBMC conditions resulted in a cessation of myeloid growth factor secretion; on seeding these cultures with nylon wool-passed marrow, B lymphopoiesis, but not myelopoiesis, initiated. These findings indicate that the stroma in the different LTBMC are not restricted in their hemopoietic support capacity but are sensitive to culture conditions in a manner that may affect the type of microenvironment formed.
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Johnson, A., i K. Dorshkind. "Stromal cells in myeloid and lymphoid long-term bone marrow cultures can support multiple hemopoietic lineages and modulate their production of hemopoietic growth factors". Blood 68, nr 6 (1.12.1986): 1348–54. http://dx.doi.org/10.1182/blood.v68.6.1348.bloodjournal6861348.
Pełny tekst źródłaStreszczenie:
Hemopoiesis in long-term bone marrow cultures (LTBMC) is dependent on adherent stromal cells that form an in vitro hemopoietic microenvironment. Myeloid bone marrow cultures (MBMC) are optimal for myelopoiesis, while lymphoid bone marrow cultures (LBMC) only support B lymphopoiesis. The experiments reported here have made a comparative analysis of the two cultures to determine whether the stromal cells that establish in vitro are restricted to the support of myelopoiesis or lymphopoiesis, respectively, and to examine how the different culture conditions affect stromal cell physiology. In order to facilitate this analysis, purified populations of MBMC and LBMC stroma were prepared by treating the LTBMC with the antibiotic mycophenolic acid; this results in the elimination of hemopoietic cells while retaining purified populations of functional stroma. Stromal cell cultures prepared and maintained under MBMC conditions secreted myeloid growth factors that stimulated the growth of granulocyte-macrophage colonies, while no such activity was detected from purified LBMC stromal cultures. However, this was not due to the inability of LBMC stroma to mediate this function. Transfer of LBMC stromal cultures to MBMC conditions resulted in an induction of myeloid growth factor secretion. When seeded under these conditions with stromal cell- depleted populations of hemopoietic cells, obtained by passing marrow through nylon wool columns, the LBMC stromal cells could support long- term myelopoiesis. Conversely, transfer of MBMC stroma to LBMC conditions resulted in a cessation of myeloid growth factor secretion; on seeding these cultures with nylon wool-passed marrow, B lymphopoiesis, but not myelopoiesis, initiated. These findings indicate that the stroma in the different LTBMC are not restricted in their hemopoietic support capacity but are sensitive to culture conditions in a manner that may affect the type of microenvironment formed.
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Cooper, Christopher L., Richard R. Hardy, Michael Reth i Stephen Desiderio. "Non–cell-autonomous hedgehog signaling promotes murine B lymphopoiesis from hematopoietic progenitors". Blood 119, nr 23 (7.06.2012): 5438–48. http://dx.doi.org/10.1182/blood-2011-12-397976.
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Abstract The role of hedgehog (Hh) signaling in B lymphopoiesis has remained unclear. We observed that the proliferation of pro-B cells in stromal cocultures was impaired by interruption of Hh signaling, prompting us to investigate whether the target of Hh antagonism was intrinsic or extrinsic to the B-lymphoid compartment. In the present study, using conditional deletion of the pathway activator gene Smo, we found that cell-autonomous Hh signaling is dispensable for B-cell development, B-lymphoid repopulation of the BM, and humoral immune function. In contrast, depletion of the Smo protein from stromal cells was associated with impaired generation of B-lymphoid cells from hematopoietic stem progenitor cells, whereas reciprocal removal of Smo from these cells had no effect on the production of B-cell progenitors. Depletion of Smo from stromal cells was associated with coordinate down-regulation of genes for which expression is associated with osteoblastoid identity and B-lymphopoietic activity. The results of the present study suggest that activity of the Hh pathway within stromal cells promotes B lymphopoiesis in a non–cell-autonomous fashion.
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Maillard, Ivan. "From Graft-Versus-Host Disease to Lymphoma Pathogenesis: Emerging Roles for Stromal Notch Ligands in Hematology". Blood 134, Supplement_1 (13.11.2019): SCI—47—SCI—47. http://dx.doi.org/10.1182/blood-2019-121067.
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Notch signaling is a highly conserved signaling pathway with multiple functions in health and disease. Notch ligands of the Delta-like and Jagged families interact with Notch1-4 on adjacent cells to trigger proteolytic activation of the Notch receptors, followed by context-dependent transcriptional activation of Notch target genes. In the hematopoietic system, Notch was first identified for its oncogenic role in T cell acute lymphoblastic leukemia (T-ALL). More recently, Notch has been recognized as a recurrent oncogenic pathway in multiple B cell lymphoproliferative disorders, including CLL/SLL, mantle cell lymphoma and marginal zone lymphoma. In parallel, essential functions of Notch signaling have been identified in early T cell development and B cell homeostasis, as well as in regulating T and B cell immune responses in secondary lymphoid organs. We have discovered a conserved pathogenic function of Notch signaling in the control of graft-versus-host disease (GVHD), both in mouse and non-human primate models of hematopoietic cell transplantation. Within days after allogeneic hematopoietic cell transplantation, donor-derived T cells interact with Delta-like Notch ligands expressed by specialized subsets of non-hematopoietic fibroblastic stromal cells in spleen and lymph nodes. In turn, Notch signaling programs alloreactive T cells to become pathogenic effector cells that mediate long-term damage in GVHD target tissues, while suppressing the expansion of regulatory T cells. Emerging evidence suggests the existence of an active crosstalk between T cells, B cells and well-defined specialized immunological stromal niches expressing Notch ligands in secondary lymphoid organs, both in GVHD and in other types of immune responses. Moreover, many B cell lymphomas demonstrate oncogenic Notch activation as a result of gain-of-function mutations that increase the persistence of intracellular Notch after proteolytic cleavage, thus requiring the presence of Notch ligands in the microenvironment to trigger oncogenic Notch signals. New evidence suggests that key Notch ligands in human lymphomas are present in the lymph node microenvironment, and that oncogenic Notch activation can happen even in the absence of mutations in a substantial fraction of lymphoma patients, including the majority of patients with CLL/SLL. In these cases, lymphoma cells appear to interact with microenvironmental Notch ligands in secondary lymphoid organs through unmutated Notch receptors, borrowing from the playbook of normal lymphocytes. Furthermore, the expression of Notch ligands by defined subsets of fibroblastic stromal cells illustrates a new paradigm through which microenvironmental signals can profoundly influence the differentiation and function of adjacent lymphoid cells. We speculate that better understanding the regulation of Notch signaling and fibroblastic stromal cells in secondary lymphoid organs will provide valuable new information with translational potential both in immunobiology and in malignant hematology. Disclosures Maillard: Genentech: Consultancy; Regeneron: Consultancy.
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Genovese, Luca, i Andrea Brendolan. "Lymphoid Tissue Mesenchymal Stromal Cells in Development and Tissue Remodeling". Stem Cells International 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/8419104.
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Secondary lymphoid organs (SLOs) are sites that facilitate cell-cell interactions required for generating adaptive immune responses. Nonhematopoietic mesenchymal stromal cells have been shown to play a critical role in SLO function, organization, and tissue homeostasis. The stromal microenvironment undergoes profound remodeling to support immune responses. However, chronic inflammatory conditions can promote uncontrolled stromal cell activation and aberrant tissue remodeling including fibrosis, thus leading to tissue damage. Despite recent advancements, the origin and role of mesenchymal stromal cells involved in SLO development and remodeling remain unclear.
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Terra, Rafik, Isabelle Louis, Richard Le Blanc, Sophie Ouellet, Juan Carlos Zúñiga-Pflücker i Claude Perreault. "T-cell generation by lymph node resident progenitor cells". Blood 106, nr 1 (1.07.2005): 193–200. http://dx.doi.org/10.1182/blood-2004-12-4886.
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In the thymus, 2 types of Lin–Sca-1+ (lineage-negative stem cell antigen-1–positive) progenitors can generate T-lineage cells: c-Kithi interleukin-7 receptor α–negative (c-KithiIL-7Rα–) and c-KitloIL-7Rα+. While c-KithiIL-7Rα– progenitors are absent, c-KitloIL-7Rα+ progenitors are abundant in the lymph nodes (LNs). c-KitloIL-7Rα+ progenitors undergo abortive T-cell commitment in the LNs and become arrested in the G1 phase of the cell cycle because they fail both to up-regulate c-myb, c-myc, and cyclin D2 and to repress junB, p16INK4a, and p21Cip1/WAF. As a result, development of LN c-KitloIL-7Rα+ progenitors is blocked at an intermediate CD44+CD25lo development stage in vivo, and LN-derived progenitors fail to generate mature T cells when cultured with OP9-DL1 stromal cells. LN stroma can provide key signals for T-cell development including IL-7, Kit ligand, and Delta-like–1 but lacks Wnt4 and Wnt7b transcripts. LN c-KitloIL-7Rα+ progenitors are able to generate mature T cells when cultured with stromal cells producing wingless-related MMTV integration site 4 (Wnt4) or upon in vivo exposure to oncostatin M whose signaling pathway intersects with Wnt. Thus, supplying Wnt signals to c-KitloIL-7Rα+ progenitors may be sufficient to transform the LN into a primary T-lymphoid organ. These data provide unique insights into the essence of a primary T-lymphoid organ and into how a cryptic extrathymic T-cell development pathway can be amplified.
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Watanabe, Takeshi, Yuka Kobayashi i Hiroshi Kawamoto. "Formation of human lymphoid organoids and their immunological function". Journal of Immunology 204, nr 1_Supplement (1.05.2020): 145.49. http://dx.doi.org/10.4049/jimmunol.204.supp.145.49.
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Abstract We previously reported that the artificially synthesized and immunologically active lymphoid tissues (aLTs) could be stably constructed in mice by implantation of lymphoid stromal cell-embedded biocompatible scaffold (collagen sponge) as well as by applying the chemokine/lymphokine-trapped gel-embedded scaffold. The aLTs possessed the structures and functions resemble to the secondary/tertiary lymphoid organ. The antigen-specific immune response was effectively induced in the aLTs. In the present study, we have aimed to generate the aLTs composed of human lymphoid cells and human stromal cells expressing LTbR, VCAM-1, ICAM-1 and several lymphoid chemokines. The spheroids were formed as the scaffolds from the stromal cells. Then, the stromal cell spheroids were transplanted into renal subcapsular space of the immunodeficient mice together with human PBMCs absorbed in the collagen sponges. After 3 weeks, the secondary lymph node-like three-dimensional organoids (LTOs) containing clusters of the human T and B cells and the scattered human DC cells were stably formed. Next, the human LTOs were constructed by using the PBMCs prepared from healthy donors who had received once the vaccination of varicella zoster virus (VZV). The immunodeficient mice carrying human LTOs were immunized with inactivated VZV. The GC-like B cell proliferation and the production of the anti-VZV specific antibody as well as human IFNg was remarkedly induced in the LTOs. These data indicate that the immunologically functional human LTOs could be generated by applying human PBMCs with the appropriate human lymphoid stromal cells. Currently, induction of immune responses against various protein antigens as well as human cancers is under investigation.
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Murakami, Takaya, Xin Chen, Koji Hase, Ayako Sakamoto, Chie Nishigaki i Hiroshi Ohno. "Splenic CD19−CD35+B220+ cells function as an inducer of follicular dendritic cell network formation". Blood 110, nr 4 (15.08.2007): 1215–24. http://dx.doi.org/10.1182/blood-2007-01-068387.
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Abstract Follicular dendritic cells (FDCs) form a reticular FDC network in the lymphoid follicle that is essential for the retention and presentation of native antigens in the form of antigen-antibody immune complexes (ICs) to B cells during secondary immune response. Although the presence of migrating precursors of FDCs has been hypothesized, their entity has not been elucidated. Here we report the identification of murine splenic CD19−CD11c−CD35+B220+ cells as an inducer of FDC network formation. We demonstrated that CD19−CD11c−CD35+B220+ cells, together with stromal cells, had the remarkable ability to form lymphoid-follicle–like structures that contained B220+FDC-M1+ reticular cells originally derived from CD19−CD11c−CD35+B220+ cells in the CD35+ reticulum. Our results indicate that CD19−CD11c−CD35+B220+ cells function as an inducer of FDC network formation and that the interaction between CD19−CD11c−CD35+B220+ cells and stromal cells is required to initiate lymphoid follicle formation.
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Rehm, Armin, Angela Mensen, Kristina Schradi, Kerstin Gerlach, Stefanie Wittstock, Susann Winter, Gilbert Büchner, Bernd Dörken, Martin Lipp i Uta E. Höpken. "Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs". Blood 118, nr 4 (28.07.2011): 1020–33. http://dx.doi.org/10.1182/blood-2010-11-321265.
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Abstract Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Eμ-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Eμ-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T-cell zone led to a significant survival advantage compared with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38+ fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell–presented lymphotoxin, which acted on lymphotoxin-β–receptor-bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-α deletion and using a lymphotoxin-β receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy.
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Fleige, Henrike, Sarina Ravens, Georgios Leandros Moschovakis, Jasmin Bölter, Stefanie Willenzon, Gerd Sutter, Susanne Häussler, Ulrich Kalinke, Immo Prinz i Reinhold Förster. "IL-17–induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs". Journal of Experimental Medicine 211, nr 4 (24.03.2014): 643–51. http://dx.doi.org/10.1084/jem.20131737.
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Ectopic lymphoid tissue, such as bronchus-associated lymphoid tissue (BALT) in the lung, develops spontaneously at sites of chronic inflammation or during infection. The molecular mechanisms underlying the neogenesis of such tertiary lymphoid tissue are still poorly understood. We show that the type of inflammation-inducing pathogen determines which key factors are required for the formation and maturation of BALT. Thus, a single intranasal administration of the poxvirus modified vaccinia virus Ankara (MVA) is sufficient to induce highly organized BALT with densely packed B cell follicles containing a network of CXCL13-expressing follicular DCs (FDCs), as well as CXCL12-producing follicular stromal cells. In contrast, mice treated with P. aeruginosa (P.a.) develop BALT but B cell follicles lack FDCs while still harboring CXCL12-positive follicular stromal cells. Furthermore, in IL-17–deficient mice, P.a.-induced BALT largely lacks B cells as well as CXCL12-expressing stromal cells, and only loose infiltrates of T cells are present. We show that Toll-like receptor pathways are required for BALT induction by P.a., but not MVA, and provide evidence that IL-17 drives the differentiation of lung stroma toward podoplanin-positive CXCL12-expressing cells that allow follicle formation even in the absence of FDCs. Taken together, our results identify distinct pathogen-dependent induction and maturation pathways for BALT formation.
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Fritz, Jörg H., i Jennifer L. Gommerman. "Cytokine/Stromal Cell Networks and Lymphoid Tissue Environments". Journal of Interferon & Cytokine Research 31, nr 3 (marzec 2011): 277–89. http://dx.doi.org/10.1089/jir.2010.0121.
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Kaisho, T., T. Nagasawa, T. Kishimoto i H. Kikutani. "A stromal cell-specific monoclonal antibody augments the stromal cell-dependent B lymphopoiesis." Journal of Immunology 148, nr 4 (15.02.1992): 989–95. http://dx.doi.org/10.4049/jimmunol.148.4.989.
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Abstract We produced the mAb R25 against the stromal cell line ST2, which could support B lymphopoiesis in vitro. R25 enhanced the ability of ST2 to support B lymphopoiesis and precipitated molecules of 110 and 120 kDa (p110/120) from ST2 cell lysates. p110/120 were also expressed on other stromal and fibroblast cell lines but not on freshly isolated bone marrow hematopoietic cells, spleen cells, and lymphoid cell lines. However, R25 had no or weak effect on the stromal cell-dependent myelopoiesis. Even under conditions in which bone marrow cells were separated from stromal cells with a membrane filter, R25 could augment the stromal cell-dependent B lymphopoiesis. However, R25 did not induce the increase of IL-7 mRNA of ST2 cells. Taken together, these findings suggest that the stromal cell surface molecules p110/120 are involved in the stromal cell-dependent B lymphopoiesis and that certain soluble factors distinct from IL-7 may contribute to the p110/120-mediated B cell generation.
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Gimble, J. M., M. A. Dorheim, K. Youkhana, J. Hudson, M. Nead, M. Gilly, W. J. Wood, G. G. Hermanson, M. Kuehl i R. Wall. "Alternatively spliced pp52 mRNA in nonlymphoid stromal cells." Journal of Immunology 150, nr 1 (1.01.1993): 115–21. http://dx.doi.org/10.4049/jimmunol.150.1.115.
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Abstract The 52-kDa phosphoprotein, also reported as lymphocyte-specific gene 1 and WP34, is transcribed as a 1.6-kb mRNA in B lymphocytes, B cell lines, and untransformed T cells. This gene encodes a cytoplasmic and plasma membrane-associated protein that is phosphorylated at a casein kinase II site and reportedly binds calcium. Based on these properties, it has been hypothesized that lymphoid form of the 52-kDa phosphoprotein protein may play a role in lymphocyte signal transduction. We show that alternatively spliced mRNA are expressed from this gene in nonlymphoid cell lines (myocytes, stromal cells, fibroblasts). These cell lines do not express the 1.6-kb lymphoid cell-specific transcript. Instead, mRNA of 2.0 and 2.8 kb are detected in varying abundance. A full-length 2.0-kb cDNA has been cloned and sequenced from the BMS2 stromal cell line by conventional screening and polymerase chain reaction-based methods. This cDNA clone, designated S37, has a single open reading frame encoding a 328 amino acid peptide. The nucleotide sequence of the S37 stromal cell cDNA is identical to that of the lymphocyte derived pp52 cDNA from the 3' poly(A) tail to the codon encoding the amino acid at residue 24. This region of the S37 cDNA clone encodes a protein that is identical to that encoded by the lymphoid pp52 cDNA and includes a casein kinase II phosphorylation site. However, the two clones differ in their 5' nucleotide sequence and their NH3 terminal amino acid sequence. This organization is consistent with alternative exon utilization. These results suggest that tissue-specific control mechanisms are used to generate different forms of lymphoid form of the 52-kDa phosphoprotein mRNA in lymphoid cells versus mesoderm-derived, nonlymphoid cell lineages.
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Jarvis, Lisa J., Jean E. Maguire i Tucker W. LeBien. "Contact Between Human Bone Marrow Stromal Cells and B Lymphocytes Enhances Very Late Antigen-4/Vascular Cell Adhesion Molecule-1–Independent Tyrosine Phosphorylation of Focal Adhesion Kinase, Paxillin, and ERK2 in Stromal Cells". Blood 90, nr 4 (15.08.1997): 1626–35. http://dx.doi.org/10.1182/blood.v90.4.1626.
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Abstract Contact with bone marrow stromal cells is crucial for the normal growth and development of B-cell precursors. We have previously shown that human bone marrow stromal cell tyrosine kinase activity can be activated by direct contact with B-lymphoid cells (J Immunol 155:2359, 1995). In the present study, we show that increased tyrosine phosphorylation of focal adhesion kinase, paxillin, and extracellular-related kinase 2 (or p42 MAP kinase) accounted for the major changes occurring in stromal cell tyrosine phosphorylation after 5 to 10 minutes of contact with the RAMOS B-lymphoma cell line. Although adhesion of B-cell precursors to stromal cells is primarily mediated by very late antigen-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1), VLA-4–deficient and adhesion-deficient RAMOS cells were equally capable of stimulating stromal cell tyrosine phosphorylation. Similar changes in the tyrosine phosphorylation pattern of stromal cells were induced by contact with normal human B-cell precursors and several other B-lineage cell lines. After 5 to 30 minutes of contact with stromal cells, no change in protein tyrosine phosphorylation was detected in RAMOS or normal human B-cell precursors removed from stromal cells. Pretreatment of stromal cells with cytochalasin D abrogated contact-mediated enhancement of stromal cell tyrosine phosphorylation, suggesting that an intact cytoskeleton was essential. These results suggest that B-cell contact activates stromal cell signaling cascades that regulate cytoskeletal organization and transcription, independent of the interaction mediated by VLA-4 and VCAM-1.