PubMed · 14910549
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H FRANKE. 1951-11-23. [Endocrinology].. https://pubmed.ncbi.nlm.nih.gov/14910549/
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MOTIVATION: Algorithms for ligand-receptor network inference have emerged as commonly used tools to estimate cell-cell communication from reference single-cell data. Many studies employ these algorithms to compare signaling between conditions and lack methods to statistically identify signals that are significantly different. We previously developed the cell communication inference algorithm Domino, which considers ligand and receptor gene expression in association with downstream transcription factor activity scoring. We developed the dominoSignal software to innovate upon Domino and extend its functionality to test statistically differential cellular signaling. RESULTS: This new functionality includes the compilation of active signals as linkages from multiple subjects in a single-cell data set and testing condition-dependent signaling linkage. The software is applicable for analysis of single-cell data sets with multiple subjects as biological replicates as well as with bootstrapped replicates from data sets with few or pooled subjects. We use simulation studies to benchmark the number of subjects in compared groups and cells within an annotated cell type sufficient to accurately identify differential linkages. We demonstrate the application of the Differential Cell Signaling Test (DCST) in the dominoSignal software to investigate consequences of cancer cell phenotypes and immunotherapy on cell-cell communication in tumor microenvironments. These applications in cancer studies demonstrate the ability of differential cell signaling analysis to infer changes to cell communication networks from therapeutic or experimental perturbations, which is broadly applicable across biological systems. AVAILABILITY: dominoSignal is available through Bioconductor at https://www.bioconductor.org/packages/release/bioc/html/dominoSignal.html.
Mesenchymal stem cells (MSCs) are multipotent cells found in several adult tissues. Transplanted allogeneic MSCs can be detected in recipients at extended time points, indicating a lack of immune recognition and clearance. As well, a role for bone marrow-derived MSCs in reducing the incidence and severity of graft-versus-host disease (GVHD) during allogeneic transplantation has recently been reported; however, the mechanisms remain to be investigated. We examined the immunomodulatory functions of human MSCs (hMSCs) by coculturing them with purified subpopulations of immune cells and report here that hMSCs altered the cytokine secretion profile of dendritic cells (DCs), naive and effector T cells (T helper 1 [T(H)1] and T(H)2), and natural killer (NK) cells to induce a more anti-inflammatory or tolerant phenotype. Specifically, the hMSCs caused mature DCs type 1 (DC1) to decrease tumor necrosis factor alpha (TNF-alpha) secretion and mature DC2 to increase interleukin-10 (IL-10) secretion; hMSCs caused T(H)1 cells to decrease interferon gamma (IFN-gamma) and caused the T(H)2 cells to increase secretion of IL-4; hMSCs caused an increase in the proportion of regulatory T cells (T(Regs)) present; and hMSCs decreased secretion of IFN-gamma from the NK cells. Mechanistically, the hMSCs produced elevated prostaglandin E2 (PGE(2)) in co-cultures, and inhibitors of PGE(2) production mitigated hMSC-mediated immune modulation. These data offer insight into the interactions between allogeneic MSCs and immune cells and provide mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that could be therapeutic for reduction of GVHD, rejection, and modulation of inflammation.
There is a symbiotic relationship between continued growth and proliferation of myeloma cells and the bone destructive process. It has been shown in animal models that blocking bone destruction can result in decreased myeloma tumor burden. Osteoclasts are bone destroying cells found in the bone marrow, and their significance in myeloma is supported by recent findings that osteoclasts alone can support sustained survival and proliferation of purified primary myeloma cells in ex vivo co-cultures. However, molecular mechanisms associated with interactions between myeloma cells and osteoclasts remain unclear. Here, we show that when myeloma plasma cells are co-cultured with osteoclasts, chondroitin synthase 1 (CHSY1) is the most significantly altered soluble, secreted protein present in the conditioned medium. RNA interference experiments with CHSY1 small interfering RNA (siRNA) reduced the amount of CHSY1 in the co-culture conditioned medium, and this was associated with a 6.25-fold increase in apoptotic myeloma cells over control co-cultures. CHSY1 contains a Fringe domain, and Fringe is well known for its regulation of Notch signaling via its DDD motif. And interestingly, Fringe domain in CHSY1 has this DDD motif. Shortly after co-culture with osteoclasts, we found that the Notch2 receptor was activated in myeloma cells but Notch1 was not. Activation of Notch2 was down-regulated by CHSY1 siRNA treatment. Modulating Notch signaling by CHSY1 via its DDD motif provides new insight into mechanisms of the interactions between myeloma cells and their bone marrow microenvironment. Targeting this interaction could shed light on treatment of myeloma, which is currently incurable.