Mesenchymal stem cells gene signature in high‐risk myeloma bone marrow linked to suppression of distinct IGFBP2‐expressing small adipocytes

Abstract

Summary Recent studies suggest that multiple myeloma (MM) induces proliferation and expansion of bone marrow (BM) mesenchymal stem cells (MSCs), but others showed that MM cells induce MSC senescence. To clarify the interaction between MM and MSCs, we exploited our established MSC gene signature to identify gene expression changes in myeloma MSCs and associated functional differences. Single MSCs from patients with MM had changes in expression of genes associated with cellular proliferation and senescence and a higher proportion of senescent cells and lower proliferative potential than those from age‐matched healthy donors. Single MSCs from both sources heterogeneously express MSC genes associated with adipogenesis and osteoblastogenesis. We identified the gene encoding insulin‐like growth factor‐binding protein 2 (IGFBP2), an MSC gene commonly altered in high risk MM, as under‐expressed. Morphologically, IGFBP2+ cells are underrepresented in MM BM compared to smouldering MM. Strong IGFBP2 and adiponectin co‐expression was detected in a subset of small adipocytes. Co‐culturing normal MSCs with myeloma cells suppressed MSC differentiation to adipocytes and osteoblasts, and reduced expression of IGFBP2 and adiponectin. Recombinant IGFBP2 blocked IGF1‐mediated myeloma cell growth. Our data demonstrate that myeloma MSCs are less proliferative and that IGFBP2+ small adipocytes are a distinct mesenchymal cell population suppressed by myeloma.

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

“…Our findings are consistent with previous reports of myeloma “primed” MSCs differentiated into adipocytes such as the Mehdi et al study that demonstrated MSC-MM co-culture for 3 days suppressed adipogenic differentiation and reduced the overall size and lipid content of those adipocytes ( 26 ). In patient samples, the authors suggest that production of small, immature IGFBP2+ adipocytes is negatively correlated with disease progression- suggesting that myeloma inhibits the formation of these cells, or that these cells are somehow utilized during MM progression ( 26 ). In 3T3-L1 adipocytes, we observed a slight, non-significant increase in Igfbp2 expression after a two-day exposure to MM cells by indirect co-culture.…”

“…Our data suggest that while these genes can be turned on in MM-MSCs during in vitro differentiation, traditional adipogenic differentiation is inhibited. Our findings are consistent with single cell qRT-PCR analysis of normal MSCs exposed to myeloma cells, which exhibit trends for suppression of LEPR and PPARG ( 26 ). In addition, a second dataset comparing gene expression in MM- to NBM-MSCs demonstrated significant reductions in CEBPA , SOX9 , MEIS1, ZFP36 , and SAV1 —all of which have been linked to the promotion of adipogenic differentiation ( 40 ), supporting our hypothesis that adipogenesis is likely suppressed in MM-MSCs.…”

“…Adipocyte-derived factors such as MCP-1/ CCL2 and SDF1α/ CXCL12 are chemotactic factors for myeloma cells ( 8 , 15 ), while other adipokines promote myeloma proliferation (e.g., leptin/LEP) ( 18 ) and resistance to chemotherapies (e.g., leptin/LEP, adipsin/CFD) ( 9 , 23 ). Recent studies have demonstrated that BMAds are modulated by MM cells ( 22 , 24 – 26 ) and that MM-reprogrammed BMAds contribute to myeloma-induced bone disease ( 27 ). Myeloma patient-derived MSCs (MM-MSCs) also have alterations in the expression of transcripts involved in MM disease pathogenesis (IL-6) ( 28 ) as well as impaired osteogenic capabilities ( 7 , 28 – 30 ).…”

Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma

“…Although MDS‐MSCs and MM‐MSCs underwent similar changes, there existed some differences depending on disease category. MM‐MSCs showed decreased adipogenic potential while MDS‐MSCs did not 44 . Besides, gene expression profile utilizing microarray analysis revealed significant enrichment of neuron development and cardiogenic differentiation in MDS‐MSCs and MM‐MSCs, respectively.…”

Current Understanding of Myelomatous Mesenchymal Stromal Cells Extended through Advances in Experimental Methods

“…MM-MSCs derived from patients with bone lesions showed distinct gene expression profiles, compared to those from patient without bone complications [86]. The differentiation capacity of MM-MSCs to adipocytes and osteoblasts is suppressed [78,79,100]. Circulating cytokines, such as transforming growth factor (TGF)β, TNFα, interferon (IFN)γ, IL-1β, and IL-6, as well as the direct interaction with MM cells, promote the apoptosis of osteoprogenitors [89,[101][102][103].…”