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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE42914 | GEO | 2012/12/15

SECONDARY ACCESSION(S): PRJNA183879

REPOSITORIES: GEO

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Gene expression profiling for 2 cell samples

Project description: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.

2012-12-15 | E-GEOD-42914 | biostudies-arrayexpress

MIF-CXCR4 as a novel axis for Mesenchymal Stem Cells recruitment to tumours in vivo.

Project description:MSCs are inherently tumor-homing and immunosuppressive and can be isolated, cultured, expanded, and transduced, making them viable candidates for cell therapy. MSCs can also be useful in allogeneic transplantation because of their immunocompatibility. MSCs have the capacity to home specifically to tumors including gliomas and breast, colon, ovarian, and lung carcinomas, among many other primary and metastatic tumors. Some discrepancies are however present regarding the mechanism and the involvement of molecules/receptors in MSC homing to tumours. We have used in this study a combination of genome expression profiling and cytokine arrays to screen for candidates mediating MSC homing to two different cancer cell lines: A549 and MDAMB231. We found a variety of interleukines and cytokines already described as players in the process, such as IL6, IL8, CCL2. Additionally, from in vitro migration and invasion assays, we show that CXCR4 is a major player in this mechanism being the essential MSC receptor for the process to occur. For the first time, we have identified in this study a novel axis: MIF-CXCR4, showing a physical interaction between them and validating their essential role in vitro and in vivo. A better understanding of MSC homing players towards tumours will help the development of novel strategies in their use as vehicles in cancer cell therapy.

2015-02-01 | GSE46156 | GEO

Extra-hematopoietic immunomodulatory role of the guanine exchange factor DOCK-2 [MethylCap-Seq]

Project description:The molecular basis of stromal immunomodulation is still unresolved. Here, we show a novel function for dedicator of cytokinesis 2 (DOCK2) in regulating extra-hematopoietic immune function of three independent stromal cell sources: induced pluripotent stem cells (iPSC)-derived mesodermal stromal cell (iPS-MSC), severe combined immunodeficiency (SCID) patient-derived fibroblasts and CRISPR/Cas9 knockout cells (iPS-MSCDOCK2KO). We first reprogrammed human mesenchymal stromal cells (MSC) into iPSC before differentiating the iPSCs back into MSC. Immature iPS-MSCs lacked immunosuppressive potential. Successive phenotypic maturation facilitated immunomodulatory function, while maintaining clonogenicity, comparable to parental MSCs. Sequential RNA-seq displayed time-dependent immune-related gene expression eventually resembling parental MSCs. SCID patient-derived fibroblasts harboring bi-allelic DOCK2 mutations also showed significantly reduced immunomodulatory capacity compared to non-mutated fibroblasts. CRISPR/Cas9-mediated DOCK2 knockout in healthy iPSCs resulted in significantly reduced immunomodulatory capacity, reduced F-actin stress-fibers, and a disturbed subcellular localization of CDC42 activation. We provide first evidence for extra-hematopoietic immunomodulation by the guanin exchange factor DOCK2. This suggests that persisting immune disease after successful blood stem cell transplantation in SCID patients could in part be due to loss-of-function DOCK2 mutations.

2022-11-11 | GSE189896 | GEO

Extra-hematopoietic immunomodulatory role of the guanine exchange factor DOCK-2 [RNA-Seq]

2022-11-11 | GSE189895 | GEO

miR-146a-5p circuitry uncouples cell proliferation and migration, but not differentiation, in human mesenchymal stem cells

Project description:Administration of mesenchymal stem cells (MSCs) has the potential to ameliorate degenerative disorders and to repair damaged tissues. The homing of transplanted MSCs to injured sites is a critical property of engraftment. Our aim was to identify microRNAs involved in controlling MSC proliferation and migration. MSCs can be isolated from bone marrow and umbilical cord Wharton's jelly (BM-MSCs and WJ-MSCs, respectively), and WJ-MSCs show poorer motility yet have a better amplification rate compared to BM-MSCs. One human BM-MSC (pooled sample of 4 independent donors), one human WJ-MSC (pooled sample of 3 independent donors), and differentiated osteocytes and adipocytes derived from BM-MSCs after 2 weeks induction.

2013-09-05 | E-GEOD-46989 | biostudies-arrayexpress

Whole transcript expression profiling of umbilical cord- and bone marrow-derived stem cells

Project description:Mesenchymal stromal cells (MSCs) are multipotent stem cells with potent immunosuppressive and trophic support functions. Although bone marrow is considered the golden standard to isolate classical MSCs (BM-MSC), MSC-like cells are currently also derived from other, more easily accessible extra-embryonic tissues such as the umbilical cord. In this study we compared the gene expression profile of human Wharton's jelly explant-derived MSC cultures with two adult MSC populations derived from bone marrow, namely BM-MSC and multipotent adult progenitor cells (MAPC). Here we demonstrate, by using genome wide gene expression analysis, that WJ-MSCs intrinsically have a differential gene expression profile compared to the adult MSCs. Gene ontology analysis revealed an increased expression of genes associated with cell-adhesion, proliferation, and immune system functioning. Furthermore, in comparison to adult MSC, stem cells from the Wharton’s jelly highly express genes involved in neurotrophic support (e.g. LIF, BDNF, NTF3). Such enhanced signatures make WJ-MSC an attractive candidate for cell-based therapy in neurodegenerative and immune-mediated CNS disorders such as multiple sclerosis or amyotrophic lateral sclerosis.

2017-12-28 | GSE77685 | GEO

Mesenchymal stem cell integrin-associated complexes

Project description:The composition and stiffness of the extracellular matrix (ECM) environment that surrounds Multipotent mesenchymal stem cells (MSCs) stem cells dictates transcriptional programming, thereby affecting stem cell lineage decision-making. Cells sense force between themselves and their microenvironment controlling the capability of MSCs to differentiate into adipocytes, osteocytes and chondrocytes. Force sensing is transmitted by integrin receptors and their associated adhesion signalling complexes. To identify regulators of MSC force sensing we sought to catalogue MSC adhesion complex composition. Therefore we isolated integrin-associated adhesion complexes formed in MSCs plated on the ECM ligand fibronectin. We identifed proteins using mass spectrometry that define a MSC specific subset of adhesion complex proteins consisting of key linkages to the actin cytoskeleton together with integrin signalling and force sensing components.

2016-07-20 | MSV000079956 | MassIVE

Analysis of gene expression in human adipose tissue-derived multipotent mesenchymal stromal cells lacking GARP/LRRC32

Project description:Multipotent mesenchymal stromal cells (MSCs) have been shown to promote tissue repair and inhibit inflammatory/autoimmune responses in preclinical and human clinical trials A major problem for MSC-based therapies is the need to expand MSCs in vitro due to the low frequency of MSCs in tissues and the large numbers of cells needed/patient (1-10 x 10^6 cells/kg). The expansion of MSCs is associated with several problems including loss of homing capacity, onset of cellular senescence, decrease in differentiation capacityand susceptibility to genomic instability and malignant transformation, limiting the utility of MSCs as a cell-based therapy. We have recently reported that murine adipose tissue-derived MSCs (mASCs) and human ASCs (hASCs) express glycoprotein A repetitions predominant (GARP)/leucine-rich repeat-containing 32 (LRRC32). GARP binds LAP/TGF-β1 to the surface of mASCs and hASCs, regulating their secretion and activation of TGF-β1 and promoting their immunomodulatory capacity. Interestingly, silencing of GARP in ASCs significantly decreased their proliferative capacity but the mechanisms remain unknown. As the proliferative capacity of MSCs is fundamental for their success in therapy, we have aimed at understanding how GARP modulates the expansion of MSC.

2019-06-05 | GSE104254 | GEO

Large-scale secretome analyses unveil a superior immunosuppressive phenotype from umbilical cord stromal cells compared to other adult mesenchymal stromal cells

Project description:Mesenchymal stromal cells (MSCs) with regenerative and immunomodulatory potential are being investigated as a potential therapeutic tool for cartilage lesions. MSCs express a wide variety of bioactive molecules including cytokines, trophic factors, and proteases, which act in a paracrine fashion to modulate the tissue microenvironment. Yet, little is known about the divergence of these signalling molecules between MSCs populations from adult or young tissues. This makes it challenging to decide the optimal source of MSCs for a specific clinical application. In this study, we investigated cell secretomes from cultured human stromal cells harvested from Hoffa’s fat pad (HFPSCs), synovial membrane (SMSCs), umbilical cord (UCSCs) and cartilage (ACs) by quantitative LC-MS/MS proteomics. We also performed multiplex protein arrays and functional assays to compare the constitutive immunomodulatory capabilities of different MSCs. Proteins involved in extracellular matrix degradation and inflammation such as MMPs, IL-17, and complement factors were significantly downregulated in UCSCs compared to other cell types. Additionally, we found enhanced expression of TGF-β1 and PGE2 in UCSCs supernatants. UCSCs were superior in inhibiting peripheral blood mononuclear cells proliferation, migration and TNF-α and IFN-γ secretion compared to ACs, HFPSCs and SMSCs. Although all cell types could repress HLA-DR surface expression and cytokine release by activated macrophages, only UCSCs significantly blocked IL-6 and IL-12 production. Our data demonstrate that stromal cells from umbilical cords display superior anti-inflammatory and immunosuppressive properties than stromal cells from adult tissues. This Allogeneic cell source could potentially be considered as an adjuvant therapy for articular cartilage repair.

2019-01-29 | PXD011762 | Pride

Uncovering the secretome of mesenchymal stromal cells exposed to healthy, traumatic and 1 degenerative intervertebral discs: A proteomic analysis

Project description:Mesenchymal stromal cells (MSCs) have been introduced as promising cell source for regenerative medicine. Besides their multilineage differentiation capacity, MSCs release a wide spectrum of bioactive factors. This secretome holds immunomodulatory and regenerative capacities. In intervertebral disc (IVD) cells, application of MSC secretome has been shown to decrease the apoptosis rate, induce proliferation and promote production of extracellular matrix (ECM). For clinical translation of secretome-based treatment, characterization of the secretome composition is needed to better understand the induced biological processes and identify potentially effective secretomes. Methods: This study aimed to investigate the proteome released by bone marrow derived MSCs following exposure to a healthy, traumatic, or degenerative human IVD environment by mass spectroscopy and quantitative immunoassay analyses. Exposure of MSCs to the proinflammatory stimulus interleukin 1β (IL-1b) was used as control.

2021-09-09 | PXD021281 | Pride

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