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Extra-hematopoietic immunomodulatory role of the guanine exchange factor DOCK-2

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189898 | GEO | 2022/11/11

REPOSITORIES: GEO

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Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2.

Project description:Stromal cells interact with immune cells during initiation and resolution of immune responses, though the precise underlying mechanisms remain to be resolved. Lessons learned from stromal cell-based therapies indicate that environmental signals instruct their immunomodulatory action contributing to immune response control. Here, to the best of our knowledge, we show a novel function for the guanine-exchange factor DOCK2 in regulating immunosuppressive function in three human stromal cell models and by siRNA-mediated DOCK2 knockdown. To identify immune function-related stromal cell molecular signatures, we first reprogrammed mesenchymal stem/progenitor cells (MSPCs) into induced pluripotent stem cells (iPSCs) before differentiating these iPSCs in a back-loop into MSPCs. The iPSCs and immature iPS-MSPCs lacked immunosuppressive potential. Successive maturation facilitated immunomodulation, while maintaining clonogenicity, comparable to their parental MSPCs. Sequential transcriptomics and methylomics displayed time-dependent immune-related gene expression trajectories, including DOCK2, eventually resembling parental MSPCs. Severe combined immunodeficiency (SCID) patient-derived fibroblasts harboring bi-allelic DOCK2 mutations showed significantly reduced immunomodulatory capacity compared to non-mutated fibroblasts. Conditional DOCK2 siRNA knockdown in iPS-MSPCs and fibroblasts also immediately reduced immunomodulatory capacity. Conclusively, CRISPR/Cas9-mediated DOCK2 knockout in iPS-MSPCs also resulted in significantly reduced immunomodulation, reduced CDC42 Rho family GTPase activation and blunted filopodia formation. These data identify G protein signaling as key element devising stromal cell immunomodulation.

| S-EPMC9666545 | biostudies-literature

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

Extra-hematopoietic immunomodulatory role of the guanine exchange factor DOCK-2

Project description:Extra-hematopoietic immunomodulatory role of the guanine exchange factor DOCK-2

| PRJNA784966 | ENA

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

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

| PRJNA784965 | ENA

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

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

| PRJNA784968 | ENA

A crucial role of the ubiquitously expressed transcription factor Sp1 at early stages of hematopoietic specification

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-12 | E-GEOD-52499 | biostudies-arrayexpress

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-06-21 | E-GEOD-43174 | biostudies-arrayexpress

Role of de novo DNA methyltransferases in hematopoietic stem cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-08-19 | E-GEOD-50793 | biostudies-arrayexpress

Role of the histone demethylase KDM2B in hematopoietic homeostasis and malignancies

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-02-22 | E-GEOD-70729 | biostudies-arrayexpress

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