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Updated: May 10, 2025
Assessment of the Immunomodulatory Properties of Human Mesenchymal Stem Cells MSCs
Published on: December 24, 2015
Age-related mesenchymal stromal cell senescence is associated with progression from MGUS to multiple myeloma
Natalya Plakhova1,2, Vasilios Panagopoulos1,2, Melissa D Cantley1,2
1Myeloma Research Laboratory, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.
Abstract:
The risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) increases with advancing age, suggesting that progression may be influenced by age-related changes within the bone marrow (BM) microenvironment. We hypothesise that senescent mesenchymal stromal cells (MSCs), which accumulate in the BM with age, may contribute to MGUS progression to MM. Here, we show that, like BM MSCs from aged non-cancer controls, BM MSCs from both MM and MGUS patients exhibit a senescent phenotype characterised by enlarged, flattened morphology, increased β-galactosidase activity and CDKN2A expression, and decreased proliferation rate compared with BM MSCs from healthy young individuals. While coculture with BM MSCs suppresses the proliferative capacity of MM cell lines in vitro, induction of senescence via irradiation or replicative exhaustion in healthy MSCs relieves this suppression, compared with non-senescent MSCs. This may, in part, be attributable to upregulated expression of the BMP antagonist Gremlin1 in senescent MSCs, which facillitates MM cell proliferation. Notably, the risk of progression to MM was significantly elevated in MGUS patients with increased MSC senescence. Collectively, our data provide evidence that age-related accumulation of senescent MSCs may be a driver of MGUS to MM progression.
Insights
Age-related senescent mesenchymal stromal cells (MSCs) in the bone marrow microenvironment may drive the progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). Increased MSC senescence is linked to a higher risk of MGUS progressing to MM.
Area of Science:
- Hematology
- Oncology
- Cell Biology
Background:
- Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM).
- Age is a risk factor for MGUS progression to MM.
- Bone marrow microenvironment changes with age and may influence disease progression.
Purpose of the Study:
- To investigate the role of senescent mesenchymal stromal cells (MSCs) in the bone marrow (BM) microenvironment in the progression of MGUS to MM.
- To determine if MSC senescence is a contributing factor to the age-related increase in MGUS progression risk.
Main Methods:
- Characterization of BM MSCs from MGUS, MM patients, and healthy young/aged individuals.
- Assessment of MSC senescence markers (morphology, β-galactosidase activity, CDKN2A expression, proliferation rate).
- In vitro co-culture experiments of MSCs with MM cell lines to evaluate effects on proliferation.
- Analysis of Gremlin1 expression in senescent MSCs.
- Correlation of MSC senescence levels with MGUS progression risk in patients.
Main Results:
- BM MSCs from MGUS and MM patients, as well as aged healthy individuals, exhibit a senescent phenotype compared to young healthy individuals.
- Senescent MSCs, unlike non-senescent MSCs, do not suppress MM cell line proliferation in vitro.
- Upregulated Gremlin1 in senescent MSCs may promote MM cell proliferation.
- Increased MSC senescence in MGUS patients is associated with a significantly elevated risk of progression to MM.
Conclusions:
- Age-related accumulation of senescent MSCs in the bone marrow microenvironment is implicated in the progression of MGUS to MM.
- Senescent MSCs may promote MM development by altering the BM microenvironment and facilitating MM cell proliferation.
- Targeting MSC senescence could be a potential therapeutic strategy for preventing MGUS progression to MM.
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