Production of granulocyte colony‐stimulating factor and granulocyte/macrophage‐colony‐stimulating factor after interleukin‐1 stimulation of marrow stromal cell cultures from normal or aplastic anemia donors

Migliaccio, Anna Rita; Migliaccio, Giovanni; Adamson, John W.; Torok‐Storb, Beverly

doi:10.1002/jcp.1041520125

Cited by 14 publications

(3 citation statements)

References 40 publications

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“…Assays for inhibiting activities were negative, suggesting that the lack of CFU-GM growth was due to the absence of colony-stimulating activities. By using a sensitive nuclease protection assay we could demonstrate that AD169-infected stromal cells lack G-CSF transcripts but have unaltered levels of GM-CSF, a result in keeping with the bioassay results and the data of Migliaccio et al, which showed that CFU-GM-stimulating activity is accounted for by G-CSF whereas the burst-promoting activity is attributable to GM-CSF (29).…”

Section: Discussionsupporting

confidence: 87%

Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells.

Simmons

Kaushansky

Torok‐Storb

1990

Proc. Natl. Acad. Sci. U.S.A.

175

108

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Infection with cytomegalovirus (CMV) continues to be one of the most common complications following allogeneic bone marrow transplantation. To study the role of CMV in the suppression of hemopoiesis that frequently accompanies infection, we investigated the effect ofCMV on the growth ofisolated committed myeloid progenitors and on hemopoiesis in long-term bone marrow cultures. Laboratory strain AD169 had no effect on the growth and development of progenitor cells. In contrast, 40% of clinical isolates of CMV inhibited colony formation by up to 100%. In long-term bone marrow cultures all CMV isolates resulted in myelosuppression, which in the majority of cases was associated with the infection of stromal elements. Analysis of RNA from stromal cells infected with AD169 and one clinical isolate demonstrated a specific deficiency of granulocyte colony-stimulating factor transcripts. For a small proportion of the clinical isolates tested in long-term bone mlarrow cultures, suppression of hemopoiesis was correlated Okh infection of developing granulocytes. These studies suggest that CMV can impair hemopoiesis either through infection of stromal cells and consequent perturbation of growth factor production or by direct infection of myeloid cells.Human cytomegalovirus (CMV), a member of the herpesvirus family, infects the majority ofthe population by adulthood (1). The consequences of CMV infection ranges from subclinical asymptomatic illness to a rapidly progressive disseminated disease in immunocompromised individuals. In patients undergoing bone marrow transplants, CMV can be associated with delayed platelet engraftment (2), phenotypically abnormal peripheral blood leukocytes (3), and graft failure (4).Several mechanisms acting alone or in combination could mediate the myelosuppression associated with CMV. Hemopoietic progenitor cells or accessory cells such as monocytes and T lymphocytes, hypothesized to provide growth factors, may be targets for infection (5-8). Alternatively, since the maintenance of primitive hemopoietic progenitor cells is crucially dependent on their interactions with stromal cells of the marrow microenvironment (9), the perturbation of stromal cell function by CMV could also result in myelosuppression.We studied the myelosuppressive effects of CMV in vitro using a laboratory-adapted strain and low-passage clinical isolates to infect human long-term bone marrow cultures (LTBMC) (Table 1). AD169 and 12 of 19 clinical isolates had no effect on the growth of colonies nor was viral IEA detected in cytospin preparations. However, 8 clinical isolates inhibited growth of CFU-GM, BFU-E, and CFU-Mix colonies, ranging from 17% to 100% of growth obtained in mock-infected control cultures.Addition of CMV to LTBMCs: Effects on Hemopoiesis. CMV has been demonstrated to infect and replicate in bone marrow-derived stromal cells of simian and human origin (21,22). To investigate whether infection with CMV impaired the ability of marrow stromal cells to maintain hemopoietic development, LTBMCs establi...

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Section: Discussionsupporting

confidence: 87%

Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells.

Simmons

Kaushansky

Torok‐Storb

1990

Proc. Natl. Acad. Sci. U.S.A.

175

108

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“…The formation of an adherent stromal layer was reduced in the majority of aplastic samples compared to controls, which all grew to 75-100% confluence. Growth impairment ranged from massive (<5-10% of normal; patients 1-6) to moderate (25-502 of normal; patients [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Stroma confluence was comparable to normal in only one-third of AA marrows (patients 2 1-30).…”

Section: Growth Of Bone Marrow Stroma and Fibroblast Culturesmentioning

confidence: 99%

“…Several investigators have used this culture system to evaluate the func-tion of stromal cells in AA in terms of growth and hematopoietic activity. Results have shown abnormalities in function and morphology of cells in AA cultures, but the incidence of stromal defects varied widely between individual studies (8)(9)(10)(11)(12)(13)(14)(15). The role of stroma-derived growth factors in the etiology and clinical manifestation of AA remains therefore poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Stem‐cell factor in aplastic anemia: in vitro expression in bone marrow stroma and fibroblast cultures

Krieger

Nissen

Wodnar-Filipowicz

1995

European J of Haematology

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In vitro expression of stem‐cell factor (SCF) by bone marrow (BM) cells of 30 patients with aplastic anemia (AA) has been analyzed at the mRNA and protein levels. While no deficiencies were found in SCF mRNA expression, low levels of soluble SCF protein were measured in poorly growing AA stroma cultures. The SCF protein concentration in the supernatant and the confluence of AA stroma growth were found to correlate (R = 0.70). Defective proliferation was observed in the majority (20/30) of AA stroma cultures and was paralleled by poor growth of homogeneous cultures of fibroblasts from the same marrow sample. AA stroma growth was enhanced by addition of exogenous SCF in combination with interleukin‐11 (IL‐11), leukemia inhibitory factor (LIF), and basic fibroblast growth factor (bFGF). Our results demonstrate that deficient growth of stroma cells results in decreased production of SCF. Therefore, SCF and other stroma‐derived cytokines may be of therapeutic value in AA patients with documented defects within the BM microenvironment.

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Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: Effects of dexamethasone and IL-1α

1996

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We previously reported the purification, culture-expansion, and osteogenic differentiation potential of mesenchymal progenitor cells (MPCs) derived from human bone marrow. As a first step to establishing the phenotypic characteristics of MPCs, we reported on the identification of unique cell surface proteins which were detected with monoclonal antibodies. In this study, the phenotypic characterization of human marrow-derived MPCs is further established through the identification of a cytokine expression profile under standardized growth medium conditions and in the presence of regulators of the osteogenic and stromal cell lineages, dexamethasone and interleukin-1 alpha (IL-1 alpha), respectively. Constitutively expressed cytokines in this growth phase include G-CSF, SCF, LIF, M-CSF, IL-6, and IL-11, while GM-CSF, IL-3, TGF-beta 2 and OSM were not detected in the growth medium. Exposure of cells in growth medium to dexamethasone resulted in a decrease in the expression of LIF, IL-6, and IL-11. These cytokines have been reported to exert influence on the differentiation of cells derived from the bone marrow stroma through target cell receptors that utilize gp130-associated signal transduction pathways. Dexamethasone had no effect on the other cytokines expressed under growth medium conditions and was not observed to increase the expression of any of the cytokines measured in this study. In contrast, IL-1 alpha increased the expression of G-CSF, M-CSF, LIF, IL-6 and IL-11 and induced the expression of GM-CSF. IL-1 alpha had no effect on SCF expression and was not observed to decrease the production of any of the cytokines assayed. These data indicate that MPCs exhibit a distinct cytokine expression profile. We interpret this cytokine profile to suggest that MPCs serve specific supportive functions in the microenvironment of bone marrow. MPCs provide inductive and regulatory information which are consistent with the ability to support hematopoiesis, and also supply autocrine, paracrine, and juxtacrine factors that influence the cells of the marrow microenvironment itself. In addition, the cytokine profiles expressed by MPCs, in response to dexamethasone and IL-1 alpha, identify specific cytokines whose levels of expression change as MPCs differentiate or modulate their phenotype during osteogenic or stromagenic lineage entrance/progression.

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Production of granulocyte colony‐stimulating factor and granulocyte/macrophage‐colony‐stimulating factor after interleukin‐1 stimulation of marrow stromal cell cultures from normal or aplastic anemia donors

Cited by 14 publications

References 40 publications

Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells.

Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells.

Stem‐cell factor in aplastic anemia: in vitro expression in bone marrow stroma and fibroblast cultures

Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: Effects of dexamethasone and IL-1α

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