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

Cornelia Scharler, Rodolphe Poupardin, Patricia Ebner-Peking, Martin Wolf, Christina Schreck, Gabriele Brachtl, Andre Cronemberger Andrade, Linda Krisch, Laurence Daheron, Katharina Schallmoser, Karsten Jürchott, Judit Küchler, Harald Stachelscheid, Hans Dieter Volk, Robert A.J. Oostendorp, Dirk Strunk

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

1 Zitat (Scopus)

Abstract

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.

OriginalspracheEnglisch
Aufsatznummer1246
FachzeitschriftCommunications Biology
Jahrgang5
Ausgabenummer1
DOIs
PublikationsstatusVeröffentlicht - Dez. 2022
Extern publiziertJa

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