CD8 + T cell metabolism and function are suppressed by long-chain fatty acid uptake from the bone marrow microenvironment in Multiple Myeloma
Bishop GudgeonHannah GilesEmma L. BishopTaylor Fulton-WardCristina Escribano-GonzalezHaydn MunfordAnna James-BottKane FosterFarheen KarimDedunu JayawardanaAnsar MahmoodAdam P. CribbsDaniel A. TennantSupratik BasuGuy PrattSarah Dimeloe
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Abstract Background Multiple Myeloma (MM) is a plasma cell malignancy that develops in the bone marrow. Function of T lymphocytes is impaired in patients with MM and the bone marrow microenvironment is described as hostile for T cell activity. Precise suppressive mechanisms within the bone marrow microenvironment remain poorly defined but will impact efficacy of bispecific T cell engager and chimeric antigen receptor (CAR) T cell therapies. Methods In this study T cell phenotype, function and metabolic activity were analysed within paired bone marrow aspirate and peripheral blood samples from 72 patients across the spectrum of MM, including individuals with premalignant and asymptomatic disease, alongside age-matched controls. This permitted assessment of effects of disease stage and the bone marrow microenvironment. The bone marrow microenvironment was also modelled in vitro using autologous plasma co-culture systems. Results Bone marrow CD8 + T cell function decreased with MM development and was consistently lower within bone marrow samples than matched peripheral blood. These changes were accompanied by decreased mitochondrial mass, which correlated tightly with T cell function. Conversely, long-chain fatty acid uptake and peroxidation was markedly elevated in bone marrow CD8 + T cells. In vitro modelling confirmed uptake of bone marrow lipids suppresses CD8 + T function, which was impaired in autologous bone marrow plasma, but rescued by both lipid removal and inhibition of lipid peroxidation. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8 + T cells in MM, and FATP1 blockade also rescued CD8 + T cell function. Finally, analysis of samples from treated patient cohorts identified CD8 + T cell metabolic dysfunction resolves in treatment-responsive but not relapsed MM patients and is associated with substantial functional restoration. Conclusions CD8 + T cells are functionally impaired within the MM bone marrow microenvironment. This is accompanied by decreased mitochondrial mass but elevated uptake of long-chain fatty acids. Blockade of FATP1 restores CD8 + T cell function in presence of BM lipids and may therefore represent a novel therapeutic target to augment their activity in the bone marrow in MM and improve efficacy of T cell-directed therapies.Objective To study the mechanism of acute leukemic bone marrow stroma in leukemia development.Methods With the method of bone marrow stromal cell culture system or co-culture system of bone marrow stromal cells, investigate the growth properties of leukemic bone marrow stroma, the expression of VCAM-1(vascular cell adhesion molecule-1),Fn(fibronectin) and the content of IL-6(interleukin-6),TNF-α(tumor necrosis factor-alpha) in culture medium.Results The growth of acute leukemic bone marrow stromal cells was delayed. The time of sticking to wall, the time of microplexus formation, the time of colony formation, the time of confluence formation, were all significantly delayed (P0.05). The number of CFU-F and the content of VCAM-1 in stromal cells was respectively significantly decreased with that of controls(P0.05),in addition, the content of Fn in stromal cells from acute leukemia was identical with that of controls(P0.05),whereas, the content of IL-6 and TNF-α in the culture medium from acute leukemic bone marrow stromal cells was significantly increased compared with that of controls.Conclusion There were many abnormalities in hematopoietic inductive microenvironment(HIM)of acute leukemia.
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Objective To reveal the abnormity of bone marrow microenvironment of psoriasis patients by comparing the level of TNF-α、LIF and HGF secreted by bone marrow stromal cells in patients and control.Methods Separate bone marrow mononuclear cells of patients and control by density gradient centrifugating.Bone marrow stromal cells were cultured with the method of adherent.When the cells were cultured for three passages and 72h,bone marrow stromal cells and supernatant liquid were collected.The phenotypes of cells were identified by flow cytometry and the level of TNF-α,LIF and HGF were detected by ELISA kits.Results The purity of bone marrow stromal cells was over 90%.The level of TNF-α,LIF and HGF in patients was significantly lower than that in control(P0.05).Conclusions Some of the cytokines which secreted by psoriatic bone marrow stromal cells are abnormal.This shows that psoriatic bone marrow microenvironment may be abnormal.
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Bone marrow is the point of origin of several cell types, including stromal cells. Adherent bone marrow stromal cells can differentiate into chondrocytes, adipocytes and osteoblasts. Several substances which modulate the dynamics and differentiation of bone marrow stromal cells have been identified. Recently it has been discovered that those bone marrow cells which are non-adherent in tissue culture for 3 days have osteogenic potential comparable to that of whole bone marrow cells. In the future, implantation of non-adherent bone marrow stromal cells may be of use as an aid in bone fracture healing, similar to whole marrow or adherent stromal cell grafting at present.
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Objective To search a kind of ideal seeded cell of bone tissue engineering. Methods Bone marrow tissue was fetched from rabbit,got bone marrow stromal cells by the method of density centrifuge,observed the conformation,growing feature and osteogeneric capability of the cells during culture in vitro by light microscope,transmission electron microscope and measure of osteogeneric capability. Results Most of the cultivated bone marrow stromal cells were triangle-like or shuttle-like cells. They growed and breeded rapidly,and had osteogeneric capability. They were easy to differentiate to osteoblasts. Conclusion The cultivated bone marrow stromal cells are matured ones,and could become the more ideal seeded cells for bone tissue engineering.
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Objective To investigate the role of bone marrow-derived stromal cells in hematopoietic reconstitution in vivo.Methods Stromal cells isolated from Balb/c mice were incubated in medium with bFGF.Cultured stromal cells plus whole BMCs were injected in vein into Balb/c mice irradiated lethally.Mortality rate and leukocyte were counted.Results More mice transplanted with BMCs plus stromal cells survived than those with BMCs only and hematopoietic recovery with BMCs plus stromal cells was rapid.MSCs can be transplantated i.v.without any toxicity.Conclusion Bone marrow-derived stromal cells can enhance hematopoitic reconstitution and can be transplanted in security.
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Objective To investigate the effects of combined radiation burn injury on bone marrow stromal cells in mice. Methods Mice were treated with 6.0 GY ray radiation and 15% (TBSA) Ⅲ° burn. The culture of CFU GM and bone marrow stromal adherent cells were performed. Cell cycle, DNA content and the expression of adhesion molecules were detected by flow cytometry. Results ①The adherent capacity of bone marrow stromal cells and the numbers of CFU F after combined radiation burn injury were significant decreased. ②Three days later, cultured stromal adherent cell inhibited the growth of CFU GM, but when the agar layer existed that inhibition were weaken or disappear. ③The cell proportion of G 0 and G 1 was decreased, and the proportion of S and G 2+M was increased after combined injury. ④The DNA content in the bone marrow stromal cells was significantly lower in the combined injury group after 3 days. ⑤The expression of cell adhesion molecules including vascular cell adhesion molecule 1 (VCAM 1), fibronection (Fn), laminin (Ln), and collagen type Ⅳ (Col Ⅳ) on bone marrow stromal cell were decreased in combined radiation burn injury. Conclusions The damage of bone marrow stromal cells in bone marrow hematopoietic inductive microenvironment might be one of the most important factors in hematopoietic disorder in combined radiation burn injury.
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Objective To investigate the change of Notch expression in murine bone marrow stromal cell after exposure to γ-rays in vitro. Methods Cultured murine bone marrow stromal cells irradiated with 8.0 Gy ~ 60 Co γ-rays were used in this study. The Notch_1, Jegged_1, Hes_1 genes expressions were analyzed by RT-PCR at 2 h, 4 h, 8 h, and 12 h after the irradiation. Results There were no expression of Notch_1, Jegged_1, and Hes_1 genes in normal murine bone marrow stromal cells at mRNA level, while Notch_1, Jegged_1, and Hes_1 genes were expressed at 2 h after the irradiation, and reached a peak at 4 h, then returned back to the normal level at 8-12 h. The differences between the exposed group and the control group were statistically significant (P0.001). Conclusions Notch signaling pathway was activated in cultured murine bone marrow stromal cellls after exposure to γ-rays, it is suggested that Notch signaling pathway is involved in the radiation damage to murine bone marrow stromal cells.;
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Objective To introductorily investigate the expression of SCL gene in leukemic and normal human bone marrow stromal cells.Methods Selectively augment the quantity of bone marrow stromal cells by long-term hematopoietic cells culture in vitro.The collected stromal cells were further detected the expression of SCL gene by RT-PCR-ELISA assay.Results The expression of SCL gene could be identified in the bone marrow stromal cells from most cases with CML,AML or CLL,and SCL gene could be detected in stromal cells from a part of normal individuals.Conclusions SCL may be involved in the regulation of hematopoiesis in leukemic and normal bone stromal cells.
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AIM: To investigate the effect of cytomegalovirus (CMV) on the expression of ICAM-1 and VCAM-1 in bone marrow stromal cells and on the adhesion of bone marrow stromal cells to hematopoietic cells. METHODS: Flow cytometry was used to detect the expression of adhesion molecules ICAM-1 and VCAM-1 in bone marrow stromal cells, MTT method was used to perform the adhesion assay of bone marrow stromal cells to normal hematopoietic cells. RESULTS: Bone marrow stromal cells could be infected by the CMV used in this experiment; CMV below the dose of 100TCID 50 could not destroy bone marrow stromal cells apparently; The expression of ICAM-1 increased at the early stage(18 h) of CMV infection, the expression of ICAM-1 decreased at the late stage (120 h) of CMV infection. Inactived CMV could also increase the expression of ICAM-1 as alive CMV; The adhesion rate of bone marrow stromal cells to hematopoietic cells increased at the early stage of CMV infection. CMV had no significant effects on the expression of VCAM-1 in bone marrow stromal cells. CONCLUSION: The adhesion capacity of bone marrow stromal cells to hematopoietic cells increased at the early stage of CMV infection, while the adhesion capacity of bone marrow stromal cells to hematopoietic cells decreased at the late stage of CMV infection.
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To reveal the abnormity of bone marrow microenvironment of patients with psoriasis by comparing the level of IL-1α,IL-1β and IL-11 secreted by bone marrow stromal cells of patients and control individuals,separate bone marrow mononuclear cells of patients and controls were isolated by density gradient centrifugation.and the bone marrow stromal cells were cultivated by the adherence method.When the cells were cultured for 3 passages and another 72 hours,bone marrow stromal cells and the supernatant liquid were collected.the phenotypes of cells were identified by flow cytometry and the level of IL-1α,IL-1β and IL-11 were assayed by ELISA kits.The results showed that the purity of bone marrow stromal cells was over 90%,and the level of IL-1α and IL-1β secreted by bone marrow stromal cells of patients was lower than that of control(P0.05).However,the level of IL-11 showed no significant difference between these two groups(P0.05).It is concluded that abnormality exists in the secretion of IL-α and IL-β by bone marrow stromal cells in patients with psorriasis,indicating an abnormal bone marrow microenviorment in this kind of patients.
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