Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling for 2 cell samples

ABSTRACT: Mesenchymal stem cells (MSCs) exhibit immunosuppressive properties. However the homing mechanisms underlying MSC trafficking to target tissues remain elusive. Here we report that skin-derived MSCs (S-MSCs) secrete high levels of interleukin-6 (IL-6), inhibit T helper (Th)1- and Th17-cell differentiation, and possess IL-6-dependent immunomodulatory capacity in inflammatory microenvironment. Disruption of the il6 locus or its signaling transducer gp130 blocks voltage-operated calcium (Ca2+) channels (VOCC) critically required for cell contraction involved in the sequential adhesion and de-adhesion events during S-MSC migration. IL-6 directly regulates CaV2.3 encoded by cacna1e of R-type Ca2+ channels through the JAK3/STAT3 signaling pathway. Deletion of il6 or silencing CaV2.3 gene expression leads to a severe defect in S-MSC’s homing and immunosuppressive function in vivo. Thus, this unexpected requirement of autocrine IL-6 for activating CaV2.3 Ca2+ channels uncovers a previously unrecognized link between IL-6 signaling and the VOCC, and provides novel mechanistic insights for the immunomodulatory activities of S-MSCs. A two chip study using total RNA recovered from three mixed S-MSCs derived from WT mice and three mixed S-MSCs derived from IL6KO mice.

ORGANISM(S): Mus musculus

SUBMITTER: fang ke

PROVIDER: E-GEOD-42914 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Intervertebral disc (IVD) degeneration is a common pathological condition associated with low back pain. Recent evidence suggests that MSCs promote IVD regeneration, but underlying mechanisms remain poorly defined. One postulated mechanism is via modulation of macrophage phenotypes. MSCs encounter drastic declines in oxygen tension when injected into the avascular IVD; thus, understanding how oxygen tension affects interactions between MSCs and macrophages may offer clues as to how MSCs act therapeutically. We investigated how conditioned medium (CM) derived from MSCs cultured in hypoxia altered macrophage subsets. We cultured human, bone marrow-derived STRO3+ MSCs in hypoxia or normoxia, and collected CM. We then cultured human bone marrow-derived macrophages with IFN-y, followed by either hypoxic or normoxic STRO3+ MSC CM. We also cultured macrophages in hypoxic MSC CM in the presence of IL-4 and collected cells for scRNA-seq analyses. Bioinformatic analyses confirmed multiple macrophage subpopulations. We first performed comparative analyses between macrophages cultured in hypoxic and normoxic MSC CM. Integration of these data sets showed large overlap between macrophage subsets; however, we identified a unique hypoxic MSC CM-induced macrophage cluster. Gene Ontogeny (GO) analyses revealed enrichment in IL-10, Ccl5/Ccr5, G alpha (i) Signaling, and Rho GTPases within this unique cluster. To determine if factors from MSC CM simulated effects of the anti-inflammatory cytokine IL-4, we integrated the data from macrophages cultured in hypoxic MSC CM with and without IL-4 addition. Integration of these data sets showed considerable overlap, demonstrating that hypoxic MSC CM simulates the effects of IL-4. Interestingly, macrophages cultured in normoxic MSC CM in the absence of IL-4 did not significantly contribute to the unique cluster within our comparison analyses and showed differential TGF-β signaling; thus, normoxic conditions did not approximate IL-4. In addition, TGF-β neutralization partially limited the effects of MSC CM. Our study identifies a unique macrophage subset induced by MSCs within hypoxic conditions, and supports that MSCs alter macrophage phenotypes through TGF-β-dependent mechanisms

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Gene expression profiling for 2 cell samples

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