scholarly journals Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 449 ◽  
Author(s):  
Stefania Raimondo ◽  
Ornella Urzì ◽  
Alice Conigliaro ◽  
Giosuè Lo Bosco ◽  
Sofia Parisi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Mesenchymal Stem Cells ◽  
Bone Disease ◽  
Human Mesenchymal Stem Cells ◽  
Major Complication ◽  
Extracellular Vesicle ◽  
Osteoblastic Differentiation ◽  
Differentiation Markers ◽  
Osteolytic Bone Disease

Osteolytic bone disease is the major complication associated with the progression of multiple myeloma (MM). Recently, extracellular vesicles (EVs) have emerged as mediators of MM-associated bone disease by inhibiting the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Here, we investigated a correlation between the EV-mediated osteogenic inhibition and MM vesicle content, focusing on miRNAs. By the use of a MicroRNA Card, we identified a pool of miRNAs, highly expressed in EVs, from MM cell line (MM1.S EVs), expression of which was confirmed in EVs from bone marrow (BM) plasma of patients affected by smoldering myeloma (SMM) and MM. Notably,we found that miR-129-5p, which targets different osteoblast (OBs) differentiation markers, is enriched in MM-EVs compared to SMM-EVs, thus suggesting a selective packaging correlated with pathological grade. We found that miR-129-5p can be transported to hMSCs by MM-EVs and, by the use of miRNA mimics, we investigated its role in recipient cells. Our data demonstrated that the increase of miR-129-5p levels in hMSCs under osteoblastic differentiation stimuli inhibited the expression of the transcription factor Sp1, previously described as a positive modulator of osteoblastic differentiation, and of its target the Alkaline phosphatase (ALPL), thus identifying miR-129-5p among the players of vesicle-mediated bone disease.

Intranuclear mesoscale viscoelastic changes during osteoblastic differentiation of human mesenchymal stem cells

2021 ◽  
Vol 35 (12) ◽  
Author(s):  
Kojiro Matsushita ◽  
Chiharu Nakahara ◽  
Shun Kimura ◽  
Naoya Sakamoto ◽  
Satoshi Ii ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Human Mesenchymal Stem Cells ◽  
Osteoblastic Differentiation

scholarly journals Insulin-Like Growth Factor Binding Protein-6 Alters Skeletal Muscle Differentiation of Human Mesenchymal Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Doaa Aboalola ◽  
Victor K. M. Han
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Human Mesenchymal Stem Cells ◽  
Muscle Cells ◽  
Muscle Differentiation ◽  
Insulin Like Growth Factor ◽  
Differentiation Markers ◽  
Time Points ◽  
Factor Binding

Insulin-like growth factor binding protein-6 (IGFBP-6), the main regulator of insulin-like growth factor-2 (IGF-2), is a component of the stem cell niche in developing muscle cells. However, its role in muscle development has not been clearly defined. In this study, we investigated the role of IGFBP-6 in muscle commitment and differentiation of human mesenchymal stem cells derived from the placenta. We showed that placental mesenchymal stem cells (PMSCs) have the ability to differentiate into muscle cells when exposed to a specific culture medium by expressing muscle markers Pax3/7, MyoD, myogenin, and myosin heavy chain in a stage-dependent manner with the ultimate formation of multinucleated fibers and losing pluripotency-associated markers, OCT4 and SOX2. The addition of IGFBP-6 significantly increased pluripotency-associated markers as well as muscle differentiation markers at earlier time points, but the latter decreased with time. On the other hand, silencing IGFBP-6 decreased both pluripotent and differentiation markers at early time points. The levels of these markers increased as IGFBP-6 levels were restored. These findings indicate that IGFBP-6 influences MSC pluripotency and myogenic differentiation, with more prominent effects observed at the beginning of the differentiation process before muscle commitment.

A Transgenic Model Of Multiple Myeloma Bone Disease Shows Profound Mesenchymal Stem Cell Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 130-130 ◽  
Author(s):  
Monica Gomez-Palou ◽  
Huang Fang ◽  
Richard Kremer ◽  
Michael Sebag
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Mesenchymal Stem Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Bone Disease ◽  
Ex Vivo ◽  
Wild Type ◽  
Lytic Lesions ◽  
Msc Differentiation

Abstract Bone disease affects 70% of Multiple Myeloma (MM) patients during the course of their illness. While new treatments for the MM itself have prolonged their survival, patients are living longer with their bone disease. Bisphophonates have been shown to reduce skeletal related events in MM, but they neither eliminate these events nor reverse skeletal damage. The transgenic mouse model of MM (vk*myc) is the only mouse model that has been shown to faithfully recapitulate the clinical disease, including its bony abnormalities. The original publication of the model showed principally a decrease in bone mineral density of affected animals but scant lytic lesions. We have cross bred this model with a substrain of C56/BL6 mice, KaLwRiJ, that is the basis of a competing model of MM and its bone disease the 5T33 model. This new transgenic substrain shows significant number bony lesions on x-ray and microCT analyses. Immunohistochemistry of the femurs and spines of these animals show an increased number of osteoclast and a decreased number of osteoblasts as compared to non-transgenic wild type mice of the same substrain. Dynamic labeling of bone shows a decreased mineral apposition rate (1.21mm/day ±0.03 vs 2.05mm/day ±0.04) in mice with MM vs wild type mice. In addition to the demineralization associated with MM bone disease and unique to this model, we show a dramatic decrease in the formation of osteoblasts from cultured mesenchymal stem cells (MSCs). These are grown ex-vivo from affected transgenic mice and induced to differentiate into osteoblasts in culture. We demonstrate a close to 90% reduction in observed and quantified mineralized colonies indicating a dramatic impairment in MSC differentiation in these mice, similar to what is seen in human MM. Gene expression profiling analyses using mRNA from ex-vivo mesenchymal stem cells derived from transgenic and wild type mice reveal a number of pathways and genes that can potentially play a role in the inhibition of MSC differentiation in this model. These include the wnt signaling pathway as well as genes involved in histone acetyltransferase activity. The latter suggests that MSCs are ‘permanently’ affected by the presence of MM cells in vivo and that this inhibition does not improve even when they are separated from MM cells for a prolonged period of time. Bortezomib has been shown in MM patients to improve the appearance of MM lytic lesions radiographically as well as to improve serum markers of osteoblastic activity. This improvement is thought to be due to a reversal of MSC differentiation impairment. Wild type and transgenic mice with MM and bone disease were treated with bortezomib (0.5mg/Kg twice per week) for two weeks. CT analyses of mice pre and post bortezomib treatment showed a 28% improvement in the treated transgenic mice. We also show a concomitant improvement in the ex-vivo ability of MSCs to differentiate into osteoblasts. In summary, we present a unique animal model to study MM bone disease that shows profound MSC impairment. This model responds to a treatment strategy that has been shown to work in the human disease and opens itself to further study and use for future developments targeting MM bone disease. Disclosures: No relevant conflicts of interest to declare.

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