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Defining the origin of lymph node and Peyer's patch fibroblastic reticular cells at single cell resolution

English title Defining the origin of lymph node and Peyer's patch fibroblastic reticular cells at single cell resolution
Applicant Ludewig Burkhard
Number 166500
Funding scheme Project funding (Div. I-III)
Research institution Institut für Immunbiologie Kantonsspital St. Gallen
Institution of higher education Cantonal hospital of St.Gallen - KSPSG
Main discipline Immunology, Immunopathology
Start/End 01.04.2016 - 31.03.2019
Approved amount 525'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Embryology, Developmental Biology

Keywords (4)

Peyer's patch; Lymph node; development; fibroblastic reticular cells

Lay Summary (German)

Lead
Fibroblastische Stromazellen bilden das strukturelle Grundgerüst der sekundären lymphatischen Organe wie Lymphknoten und der Peyerschen Platten im Dünndarm und steuern wichtige Immunprozesse. Die Entwicklung dieser Zellen im Embryo und die molekularen Mechanismen ihrer Differenzierung sind nur ungenügend untersucht. In diesem Projekt werden diese Fragen mit neuen genetischen Methoden bearbeitet.
Lay summary

Sekundäre lymphatische Organe wie Lymphknoten und Peyersche Platten sind die Schaltzentralen des Immunsystems. Die Struktur dieser Organe und ihre Unterteilung in unterschiedliche Funktionsräume wird durch fibroblastische Stromazellen gewährleistet. Unter anderem steuern diese spezialisierten Fibroblasten die Wanderung und Positionierung der Lymphozyten innerhalb dieser Organe und stellen kritische Wachstumsfaktoren für Lymphozyten und Makrophagen zur Verfügung. Bisher ist allerdings weitgehend unbekannt, wie sich diese wichtigen nicht hämatopoetischen Zellen entwickeln und welche molekularen Mechanismen ihre funktionelle Spezifizierung regulieren.

In diesem Projekt werden neue genetische Modelle genutzt, um die embryonale Entwicklung der fibroblastischen Stromazellen in Lymphknoten und Peyerschen Platten in Mäusen auf Einzelzellniveau zu untersuchen. Zu Klärung der molekularen Mechanismen und der Differenzierungswege werden Methoden wie genetische Zellmarkierung, Einzelzellsortierung und RNA-Sequenzierung genutzt.

Fibroblastische Stromazellen regulieren kritische Prozesse in der Entwicklung von Immunantworten gegen Tumorzellen und Infektionserreger. Daher können neue Erkenntnisse aus diesem Projekt zu einem besseren Verständnis der Biologie dieser Zellen beitragen und die Entwicklung von neuen Ansätzen zur Behandlung und Prävention von Krebserkrankungen und Infektionskrankheiten unterstützen.

Direct link to Lay Summary Last update: 30.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp
Cheng Hung-Wei, Onder Lucas, Novkovic Mario, Soneson Charlotte, Lütge Mechthild, Pikor Natalia, Scandella Elke, Robinson Mark D., Miyazaki Jun-ichi, Tersteegen Anne, Sorg Ursula, Pfeffer Klaus, Rülicke Thomas, Hehlgans Thomas, Ludewig Burkhard (2019), Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp, in Nature Communications, 10(1), 1739-1739.
Fibroblastic reticular cells at the nexus of innate and adaptive immune responses
Perez‐Shibayama Christian, Gil‐Cruz Cristina, Ludewig Burkhard (2019), Fibroblastic reticular cells at the nexus of innate and adaptive immune responses, in Immunological Reviews, 289(1), 31-41.
Fibroblastic reticular cells initiate immune responses in visceral adipose tissues and secure peritoneal immunity
Perez-Shibayama Christian, Gil-Cruz Cristina, Cheng Hung-Wei, Onder Lucas, Printz Andrea, Mörbe Urs, Novkovic Mario, Li Conglei, Lopez-Macias Constantino, Buechler Matthew B., Turley Shannon J., Mack Matthias, Soneson Charlotte, Robinson Mark D., Scandella Elke, Gommerman Jennifer, Ludewig Burkhard (2018), Fibroblastic reticular cells initiate immune responses in visceral adipose tissues and secure peritoneal immunity, in Science Immunology, 3(26), eaar4539-eaar4539.

Collaboration

Group / person Country
Types of collaboration
Prof. Thomas Hehlgans, University of Regensburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Thomas Rülicke, Veterinary University Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Mark Robinson, University of Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
146133 Selection and education of heart-specific Th cells by thymic and lymph node stromal cells 01.04.2013 Project funding (Div. I-III)
182583 Stromal Cell Niches at the Nexus of the Innate Lymphoid Cell Interactome 01.01.2019 Project funding (Div. I-III)
159188 Ontogeny and functional characterization of splenic fibroblastic reticular cells (FRCs) and their mesenchymal precursors during homeostasis and infection 01.09.2015 Project funding (Div. I-III)

Abstract

Secondary lymphoid organs such as lymph nodes (LNs) and Peyer’s patches (PPs) sample antigens from the body’s inner and outer surfaces and mediate optimal interaction of immune cells. These functions rely on the presence of specialized microenvironments that are built and maintained by fibroblastic reticular cells (FRCs). In addition to their scaffold-building function, FRCs impact on inducing and shaping innate and adaptive immune responses. However, we do not know the embryonic origin of these important cells and the molecular mechanisms underlying FRC differentiation in LNs or PPs. Our laboratory has generated the appropriate lineage-tracing and fate-mapping approach to address these questions. Accordingly, the work program of this project has been designed on the basis of two main hypotheses: (i) LN and PP FRCs originate from an organ-specific pluripotent embryonic precursor cell, and (ii) committed embryonic LN FRC progenitors descend from fat pad fibroblasts.We have generated an inducible Ccl19-iEYFP fate-mapping model that permits in vivo fate mapping of both LN and PP FRCs. Utilizing this novel tool, we will clarify whether LN FRC diversity is programmed in embryonic precursors. Next, we will assess to which extent critical molecular pathways such as lymphotoxin-beta receptor (LTbR) or alternative NF-kappaB signaling impact FRC subtype diversification. In order to determine clonal expansion and differentiation pattern during FRC subtype specification, a stochastic multicolor Cre-reporter strain will be utilized. Finally, we will provide a molecular systems biology analysis of FRC development and subtype differentiation using RNA expression analysis (RNAseq) from defined cell cohorts. Since the nature of PP FRCs is still unexplored, we will first categorize PP FRC subsets and define transgene activity in developing and adult PPs. Next, we will dissect in detail how LTbR and alternative NF-kappaB signaling govern the differentiation of PP FRC subsets. Moreover, we aim to resolve the relationship between PP FRC progenitors in the PP anlage and their contribution to the formation of PP FRC subsets in the adult.Only in recent years, has the importance of secondary lymphoid organ stromal cells for induction and regulation of immune responsiveness been appreciated. The field is now rapidly moving forward exploring functions and exploiting the potential of these cells as therapeutic targets in autoimmune diseases, cancer and infection. We anticipate that defining the origin of fibroblastic stromal cells and elaborating the mechanisms that govern subset differentiation in LNs and PPs will provide critical knowledge to further elaborate diagnostic and therapeutic avenues for various diseases.
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