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

Autor: Scharler C; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria., Poupardin R; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria., Ebner-Peking P; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria., Wolf M; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria., Schreck C; Technical University of Munich, School of Medicine, Internal Medicine III, Munich, Germany., Brachtl G; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria., Cronemberger Andrade A; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria., Krisch L; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria.; Department of Transfusion Medicine and SCI-TReCS, PMU, Salzburg, Austria., Daheron L; HSCI iPS Core Facility, Harvard University, Cambridge, USA., Schallmoser K; Department of Transfusion Medicine and SCI-TReCS, PMU, Salzburg, Austria., Jürchott K; BCRT & Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Küchler J; BCRT & Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Stachelscheid H; BCRT & Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Volk HD; BCRT & Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Oostendorp RAJ; Technical University of Munich, School of Medicine, Internal Medicine III, Munich, Germany., Strunk D; Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria. dirk.strunk@pmu.ac.at.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2022 Nov 15; Vol. 5 (1), pp. 1246. Date of Electronic Publication: 2022 Nov 15.
DOI: 10.1038/s42003-022-04078-1
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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