scholarly journals Characterization of freshly isolated bone marrow mesenchymal stromal cells from healthy donors and patients with multiple myeloma: transcriptional modulation of the microenvironment

Haematologica ◽  
2020 ◽  
Vol 105 (9) ◽  
pp. e470-473 ◽  
Author(s):  
Daniel Alameda ◽  
Borja Saez ◽  
David Lara-Astiaso ◽  
Sarai Sarvide ◽  
Marta Lasa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Healthy Donors ◽  
Transcriptional Modulation

scholarly journals Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2542
Author(s):  
Patricia Maiso ◽  
Pedro Mogollón ◽  
Enrique M. Ocio ◽  
Mercedes Garayoa
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Myeloma Cells ◽  
Growth And Survival ◽  
Myeloma Bone Disease ◽  
Healthy Donors ◽  
Immunosuppressive Microenvironment

Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment.

Lenalidomide Modulates the Phenotype and Function of Human Mesenchymal Stromal Cells From Healthy Donors and MDS Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3816-3816
Author(s):  
Manja Wobus ◽  
Gwendolin Dünnebier ◽  
Silvia Feldmann ◽  
Gerhard Ehninger ◽  
Martin Bornhauser ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Osteogenic Differentiation ◽  
Clinical Efficacy ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Morphological Changes ◽  
Adipogenic Differentiation ◽  
Healthy Controls ◽  
Healthy Donors

Abstract Abstract 3816 Poster Board III-752 Introduction Recent studies in patients with MDS have clearly demonstrated the clinical efficacy of lenalidomide. However, its exact mechanisms of action have not been elucidated yet. Myelosuppression is the most common adverse event and seems to be dependent on dose as well MDS subtype, being rather infrequent in patients other than del5q. The aim of this study was to investigate whether lenalidomide affects the bone marrow microenvironment. Therefore, we analyzed in-vitro characteristics of isolated mesenchymal stromal cells (MSCs) from MDS patients and from healthy controls. Methods Bone marrow samples were collected from healthy donors (n=5) and patients with MDS (del5q MDS n=3, RA n=2, RAEB1/2 n=3). MSCs were isolated according to the standard adhesion protocol and cultured in the presence or absence of lenalidomide. Results Lenalidomide treatment of MSCs caused no morphological changes but proliferation was slightly increased. Typical surface molecules as CD73, CD90, CD105 and CD166 were expressed in MSCs from MDS patients at comparable levels to healthy controls. Lenalidomide treatment caused an upregulation of CD29 by 17.8 ± 4.4% and of CD73 by 24 ± 5.7% (mean fluorescence intensity). Investigating the cytokine production, we found lower IL-8 mRNA and protein levels in MSCs from MDS patients (mean in MDS MSC: 138.1 pg/ml vs. mean in healthy MSC: 1177 pg/ml). Interestingly, the IL-8 production can be increased by approximately 40% under lenalidomide treatment. MDS MSCs retained the capacity for adipogenic and osteogenic differentiation as well as their supportive function towards hematopoietic cells in long term culture-initiating assays (LTC-IC). However, the LTC-IC frequency was lower on MSC which had been preincubated with lenalidomide compared to controls. Lenalidomide also slightly accelerated osteogenic differentiation because mineralization started as early as on day 5 with lenalidomide whereas in the control cells first calcium deposits were visible after 7 days. Other samples showed augmented lipid vacuoles after adipogenic differentiation under lenalidomide treatment. Conclusion In conclusion, lenalidomide modulates the phenotype of MSC and leads to an increase of their IL-8 secretion by a yet unknown mechanism. Whether these in-vitro effects are associated with the clinical efficacy of this compound in patients with MDS remains to be investigated. Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Comparative characterization of bone marrow-derived mesenchymal stromal cells from four different rat strains

Cytotherapy ◽  
2009 ◽  
Vol 11 (4) ◽  
pp. 435-442 ◽  
Author(s):  
Ran Barzilay ◽  
Ofer Sadan ◽  
Eldad Melamed ◽  
Daniel Offen
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Rat Strains ◽  
Comparative Characterization

Immune impairments in multiple myeloma bone marrow mesenchymal stromal cells

2014 ◽  
Vol 64 (2) ◽  
pp. 213-224 ◽  
Author(s):  
Thibaud André ◽  
Mehdi Najar ◽  
Basile Stamatopoulos ◽  
Karlien Pieters ◽  
Olivier Pradier ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells

Cell-cycle phases and genetic profile of bone marrow-derived mesenchymal stromal cells expanded in vitro from healthy donors

2011 ◽  
Vol 112 (7) ◽  
pp. 1817-1821 ◽  
Author(s):  
Valentina Achille ◽  
Melissa Mantelli ◽  
Giulia Arrigo ◽  
Francesca Novara ◽  
Maria Antonietta Avanzini ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Genetic Profile ◽  
Healthy Donors ◽  
Cell Cycle Phases

Characterization of bone marrow stromal cells from multiple myeloma

1994 ◽  
Vol 18 (9) ◽  
pp. 675-682 ◽  
Author(s):  
Maria Grazia Gregoretti ◽  
Daniela Gottardi ◽  
Paolo Ghia ◽  
Luciana Bergui ◽  
Franca Merico ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells

scholarly journals Dual Activation of NRF2 in Multiple Myeloma and Bone Marrow Mesenchymal Stromal Cells Regulates Chemotherapy Resistance

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3287-3287 ◽  
Author(s):  
Yu Sun ◽  
Lyubov Zaitseva ◽  
Manar S Shafat ◽  
Kristian M Bowles ◽  
Stuart A Rushworth
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Transcriptional Activation ◽  
Proteasome Inhibitors ◽  
Heme Oxygenase 1 ◽  
Antioxidant Genes ◽  
Pharmacological Inhibition

Abstract Background The cornerstone treatments of multiple myeloma (MM) are proteasome inhibitors bortezomib (BZ) and carfilzomib (CFZ). However, MM still remains incurable for that MM cells rapidly develop resistance to chemotherapy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathways have been shown to contribute to the malignant phenotypes of several cancers through effects on proliferation and drug sensitivity. NRF2 functions to rapidly change the sensitivity of the cells environment to oxidants and electrophiles by stimulating the transcriptional activation of drug metabolism and antioxidant genes. NRF2 is negatively regulated by proteasome degradation through its inhibitor KEAP1. The aim of this study was to determine if proteasome inhibitor induced NRF2 signalling orchestrates survival of MM in the bone marrow (BM) microenvironment. Methods To investigate the role of NRF2 in the MM microenvironment primary human MM and BM mesenchymal stromal cells (MSC) were obtained under UK ethical approval (LREC ref 07/H0310/146). NRF2 activity in MM and BM-MSC was measured by NRF2 protein expression, target genes expression and using promoter assays. Lentiviral mediated shRNA knockdown of NRF2 in the MM and BM-MSC. The NRF2 inhibitor, brusatol was used to verify the knockdown experiments. Results Results show that primary MM and MM cell lines have increased NRF2 activity in response to the proteasome inhibitors BZ and CFZ as measured by increased nuclear NRF2, increased NRF2 regulated genes and increased ARE activity in the promoter of heme oxygenase-1. Expression of basal NRF2 was high in the majority of primary MM cells and cell lines tested. Pharmacological inhibition and shRNA mediated knock-down of NRF2 showed a significant reduction in survival of MM cells, when treated alone and in combination with BZ or CFZ. Investigations also revealed that BM-MSC had increased NRF2 activity in response to BZ and CFZ. Moreover, knockdown of NRF2 in BM-MSC or pharmacological inhibition of NRF2 in BM-MSC/MM co-cultures reverses the protection conferred to MM by BM-MSC in response to BZ and CFZ. Conclusion: Here we show the first description of NRF2 driven cytoprotective responses in MM. We show that NRF2 in MM is activated by both BZ and CFZ which subsequently activates pro-survival mechanisms in response to proteasome inhibition. Furthermore, NRF2 is also activated in the BM microenvironment by BZ and CFZ, which also confers protection to MM. This highlights the importance of NRF2 in regulating MM drug resistance within the BM microenvironment through independent actions in both the tumour and the non-malignant BM-MSC which support it. Disclosures Rushworth: Infinity Pharmaceuticals: Research Funding.

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