scholarly journals Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

2020 ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Age Related ◽  
Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

scholarly journals Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Age Related ◽  
Myeloid Progenitors

AbstractMyeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

scholarly journals Human myeloid-derived suppressor cells derived from the bone marrow maintain their functional ability with aging but have a reduced frequency of induction

2020 ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Myeloid Derived Suppressor Cells ◽  
Age Related ◽  
Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

scholarly journals Human Myeloid-derived Suppressor Cells Derived From the Bone Marrow Are Decreased With Age but Maintain Their Functional Ability

2020 ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Myeloid Derived Suppressor Cells ◽  
Age Related ◽  
Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known toinhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses onthe role of age-related processes in myelopoiesis.

scholarly journals MicroRNA 21 (miR-21) and miR-181b Couple with NFI-A To Generate Myeloid-Derived Suppressor Cells and Promote Immunosuppression in Late Sepsis

2014 ◽  
Vol 82 (9) ◽  
pp. 3816-3825 ◽  
Author(s):  
Clara McClure ◽  
Laura Brudecki ◽  
Donald A. Ferguson ◽  
Zhi Q. Yao ◽  
Jonathan P. Moorman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cecal Ligation ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Repertoire ◽  
Myeloid Progenitors

ABSTRACTThe sepsis initial hyperinflammatory reaction, if not treated early, shifts to a protracted state of immunosuppression that alters both innate and adaptive immunity and is associated with elevated mortality. Myeloid-derived suppressor cells (MDSCs) are myeloid progenitors and precursors that fail to differentiate into mature innate-immunity cells and are known for their potent immunosuppressive activities. We previously reported that murine MDSCs expand dramatically in the bone marrow during late sepsis, induced by cecal ligation and puncture, and demonstrated that they contribute to late-sepsis immunosuppression. However, the molecular mechanism responsible for generating these immature Gr1+CD11b+myeloid cells during sepsis remains unknown. We show here that sepsis generates a microRNA (miRNA) signature that expands MDSCs. We found that miRNA 21 (miR-21) and miR-181b expression is upregulated in early sepsis and sustained in late sepsis. Importantly, we found that simultaneousin vivoblockade of both miRNAs via antagomiR (a chemically modified miRNA inhibitor) injection after sepsis initiation decreased the bone marrow Gr1+CD11b+myeloid progenitors, improved bacterial clearance, and reduced late-sepsis mortality by 74%. Gr1+CD11b+cells isolated from mice injected with antagomiRs were able to differentiateex vivointo macrophages and dendritic cells and produced smaller amounts of the immunosuppressive interleukin 10 (IL-10) and transforming growth factor β (TGF-β) after stimulation with bacterial lipopolysaccharide, suggesting that immature myeloid cells regained their maturation potential and have lost their immunosuppressive activity. In addition, we found that the protein level of transcription factor NFI-A, which plays a role in myeloid cell differentiation, was increased during sepsis and that antagomiR injection reduced its expression. Moreover, knockdown of NFI-A in the Gr1+CD11b+cells isolated from late-septic mice increased their maturation potential and reduced their production of the immunosuppressive mediators, similar to antagomiR injection. These data support the hypothesis that sepsis reprograms myeloid cells and thus alters the innate immunity cell repertoire to promote immunosuppression, and they demonstrate that this process can be reversed by targeting miR-21 and miR-181b to improve late-sepsis survival.

scholarly journals Age-related Changes in Bone Marrow Mesenchymal Stromal Cells

2017 ◽  
Vol 26 (9) ◽  
pp. 1520-1529 ◽  
Author(s):  
Payal Ganguly ◽  
Jehan J. El-Jawhari ◽  
Peter V. Giannoudis ◽  
Agata N. Burska ◽  
Frederique Ponchel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Current Knowledge ◽  
The Elderly ◽  
Cellular Level ◽  
Age Related ◽  
Population Doublings

Aging at the cellular level is a complex process resulting from accumulation of various damages leading to functional impairment and a reduced quality of life at the level of the organism. With a rise in the elderly population, the worldwide incidence of osteoporosis (OP) and osteoarthritis (OA) has increased in the past few decades. A decline in the number and “fitness” of mesenchymal stromal cells (MSCs) in the bone marrow (BM) niche has been suggested as one of the factors contributing to bone abnormalities in OP and OA. It is well recognized that MSCs in vitro acquire culture-induced aging features such as gradual telomere shortening, increased numbers of senescent cells, and reduced resistance to oxidative stress as a result of serial population doublings. In contrast, there is only limited evidence that human BM-MSCs “age” similarly in vivo. This review compares the various aspects of in vitro and in vivo MSC aging and suggests how our current knowledge on rejuvenating cultured MSCs could be applied to develop future strategies to target altered bone formation processes in OP and OA.

In Vitro, In Silico and Ex Vivo Studies of Dihydroartemisinin Derivatives as Antitubercular Agents

2019 ◽  
Vol 19 (8) ◽  
pp. 633-644 ◽  
Author(s):  
Komal Kalani ◽  
Sarfaraz Alam ◽  
Vinita Chaturvedi ◽  
Shyam Singh ◽  
Feroz Khan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
In Silico ◽  
Ex Vivo ◽  
Virulent Strain ◽  
Infection Model ◽  
Mouse Bone Marrow ◽  
Significant Activity ◽  
Macrophage Infection ◽  
In Silico Studies

Introduction: As a part of our drug discovery program for anti-tubercular agents, dihydroartemisinin (DHA-1) was screened against Mtb H37Rv, which showed moderate anti-tubercular activity (>25.0 µg/mL). These results prompted us to carry out the chemical transformation of DHA-1 into various derivatives and study their antitubercular potential. Materials and Methods: DHA-1 was semi-synthetically converted into four new acyl derivatives (DHA-1A – DHA-1D) and in-vitro evaluated for their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. The derivatives, DHA-1C (12-O-(4-nitro) benzoyl; MIC 12.5 µg/mL) and DHA-1D (12-O-chloro acetyl; MIC 3.12µg/mL) showed significant activity against the pathogen. Results: In silico studies of the most active derivative (DHA-1D) showed interaction with ARG448 inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages. Conclusion: DHA-1D killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. To the best of our knowledge, this is the first-ever report on the antitubercular potential of dihydroartemisinin and its derivatives. Since dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non-toxic natural product.

scholarly journals Prognostic significance of bone marrow FDG uptake in patients with gynecological cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kotaro Shimura ◽  
Seiji Mabuchi ◽  
Naoko Komura ◽  
Eriko Yokoi ◽  
Katsumi Kozasa ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Bone Marrow ◽  
Poor Prognosis ◽  
Gynecological Cancer ◽  
Prognostic Significance ◽  
Standardized Uptake Value ◽  
Suppressor Cells ◽  
Underlying Mechanism ◽  
Fdg Uptake

AbstractWe investigated the prognostic significance and the underlying mechanism of increased bone marrow (BM) 2-(18F) fluoro-2-deoxy-D-glucose as a tracer (FDG)-uptake in patients with gynecological cancer. A list of patients diagnosed with cervical, endometrial, and ovarian cancer from January 2008 to December 2014 were identified. Then, through chart reviews, 559 patients who underwent staging by FDG-positron emission tomography (PET)/computed tomography (CT) and subsequent surgical resection were identified, and their clinical data were reviewed retrospectively. BM FDG-uptake was evaluated using maximum standardized uptake value (SUVmax) and BM-to-aorta uptake ratio (BAR). As a result, we have found that increased BAR was observed in 20 (8.7%), 21 (13.0%), 21 (12.6%) of cervical, endometrial, and ovarian cancer, respectively, and was associated with significantly shorter survival. Increased BAR was also closely associated with increased granulopoiesis. In vitro and in vivo experiments revealed that tumor-derived granulocyte colony-stimulating factor (G-CSF) was involved in the underlying causative mechanism of increased BM FDG-uptake, and that immune suppression mediated by G-CSF-induced myeloid-derived suppressor cells (MDSCs) is responsible for the poor prognosis of this type of cancer. In conclusion, increased BM FDG-uptake, as represented by increased BAR, is an indicator of poor prognosis in patients with gynecological cancer.

scholarly journals Reprogramming of bone marrow myeloid progenitor cells in patients with severe coronary artery disease

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Marlies P Noz ◽  
Siroon Bekkering ◽  
Laszlo Groh ◽  
Tim MJ Nielen ◽  
Evert JP Lamfers ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Bone Marrow ◽  
Coronary Artery ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Peripheral Blood Mononuclear ◽  
Artery Disease ◽  
Myeloid Progenitors

Atherosclerosis is the major cause of cardiovascular disease (CVD). Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. In patients with atherosclerotic CVD, leukocytes have a hyperinflammatory phenotype. We hypothesize that immune cell reprogramming in these patients occurs at the level of myeloid progenitors. We included 13 patients with coronary artery disease due to severe atherosclerosis and 13 subjects without atherosclerosis in an exploratory study. Cytokine production capacity after ex vivo stimulation of peripheral blood mononuclear cells (MNCs) and bone marrow MNCs was higher in patients with atherosclerosis. In BM-MNCs this was associated with increased glycolysis and oxidative phosphorylation. The BM composition was skewed towards myelopoiesis and transcriptome analysis of HSC/GMP cell populations revealed enrichment of neutrophil- and monocyte-related pathways. These results show that in patients with atherosclerosis, activation of innate immune cells occurs at the level of myeloid progenitors, which adds exciting opportunities for novel treatment strategies.

scholarly journals A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

Leukemia ◽  
2016 ◽  
Vol 31 (8) ◽  
pp. 1743-1751 ◽  
Author(s):  
S Hipp ◽  
Y-T Tai ◽  
D Blanset ◽  
P Deegen ◽  
J Wahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Selective Lysis ◽  
Bispecific T Cell Engager

Abstract B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

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