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A worm gel-based 3D model to elucidate the paracrine interaction between multiple myeloma and mesenchymal stem cells
Renza Spelat1, Federico Ferro1, Paolo Contessotto1
1CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway-H91 TK33, Ireland.
Abstract:
Multiple myeloma (MM) is a malignancy of terminally-differentiated plasma cells that develops mainly inside the bone marrow (BM) microenvironment. It is well known that autocrine and paracrine signals are responsible for the progression of this disease but the precise mechanism and contributions from single cell remain largely unknown. Mesenchymal stem cells (MSC) are an important cellular component of the BM: they support MM growth by increasing its survival and chemo-resistance, but little is known about the paracrine signaling pathways. Three-dimensional (3D) models of MM-MSC paracrine interactions are much more biologically-relevant than simple 2D models and are considered essential for detailed studies of MM pathogenesis. Herein we present a novel 3D co-culture model designed to mimic the paracrine interaction between MSC and MM cells. MSC were embedded within a previously characterized thermoresponsive block copolymer worm gel that can induce stasis in human pluripotent stem cells (hPSC) and then co-cultured with MM cells. Transcriptional phenotyping of co-cultured cells indicated the dysregulation of genes that code for known disease-relevant factors, and also revealed IL-6 and IL-10 as upstream regulators. Importantly, we have identified a synergistic paracrine signaling pathway between IL-6 and IL-10 that plays a critical role in sustaining MM cell proliferation. Our findings indicate that this 3D co-culture system is a useful model to investigate the paracrine interaction between MM cells and the BM microenvironment in vitro. This approach has revealed a new mechanism that promotes the proliferation of MM cells and suggested a new therapeutic target.
Insights
A new 3D model reveals that Interleukin-6 and Interleukin-10 synergistically promote multiple myeloma cell growth. This finding identifies a novel therapeutic target for this bone marrow malignancy.
Area of Science:
- Cancer Biology
- Stem Cell Biology
- Biomaterials
Background:
- Multiple myeloma (MM) is a plasma cell malignancy originating in the bone marrow (BM) microenvironment.
- Autocrine and paracrine signaling drive MM progression, but mechanisms and cellular contributions remain unclear.
- Mesenchymal stem cells (MSCs) in the BM support MM growth, survival, and chemo-resistance, yet their paracrine signaling role is poorly understood.
Purpose of the Study:
- To develop and validate a novel 3D co-culture model simulating paracrine interactions between MM cells and MSCs.
- To investigate the molecular mechanisms underlying MM-MSC paracrine communication within a biomaterial-based system.
- To identify novel therapeutic targets for multiple myeloma by elucidating key signaling pathways.
Main Methods:
- Development of a 3D co-culture system using a thermoresponsive block copolymer worm gel to embed MSCs.
- Co-culture of MSCs within the gel matrix with multiple myeloma cells.
- Transcriptional phenotyping to analyze gene expression changes and identify upstream regulators in the co-culture system.
Main Results:
- The 3D co-culture model successfully mimicked MM-MSC paracrine interactions.
- Transcriptional analysis revealed dysregulation of disease-relevant genes and identified IL-6 and IL-10 as key upstream regulators.
- A synergistic paracrine signaling pathway involving IL-6 and IL-10 was identified as critical for sustaining MM cell proliferation.
Conclusions:
- The developed 3D co-culture system is an effective tool for studying MM-MSC interactions in vitro.
- A novel synergistic IL-6/IL-10 signaling pathway promotes multiple myeloma cell proliferation.
- This pathway represents a potential new therapeutic target for multiple myeloma treatment.
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