Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis

Anne L Fletcher, Jessica S Elman, Jillian Astarita, Ryan Murray, Nima Saeidi, Joshua D'Rozario, Konstantin Knoblich, Flavian D Brown, Frank A Schildberg, Janice M Nieves, Tracy S P Heng, Richard L Boyd, Shannon J Turley, Biju Parekkadan

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Sepsis is an aggressive inflammatory syndrome and a global health burden estimated to kill 7.3 million people annually. Single-target molecular therapies have not addressed the multiple disease pathways triggered by septic injury. Cell therapies might offer a broader set of mechanisms of action that benefit complex, multifocal disease processes. We describe a population of immune-specialized myofibroblasts derived from lymph node tissue, termed fibroblastic reticular cells (FRCs). Because FRCs have an immunoregulatory function in lymph nodes, we hypothesized that ex vivo-expanded FRCs would control inflammation when administered therapeutically. Indeed, a single injection of ex vivo-expanded allogeneic FRCs reduced mortality in mouse models of sepsis when administered at early or late time points after septic onset. Mice treated with FRCs exhibited lower local and systemic concentrations of proinflammatory cytokines and reduced bacteremia. When administered 4 hours after induction of lipopolysaccharide endotoxemia, or cecal ligation and puncture (CLP) sepsis in mice, FRCs reduced deaths by at least 70%. When administered late in disease (16 hours after CLP), FRCs still conveyed a robust survival advantage (44% survival compared to 0% for controls). FRC therapy was dependent on the metabolic activity of nitric oxide synthase 2 (NOS2) as the primary molecular mechanism of drug action in the mice. Together, these data describe a new anti-inflammatory cell type and provide preclinical evidence for therapeutic efficacy in severe sepsis that warrants further translational study.

Original languageEnglish
Pages (from-to)249ra109
JournalScience Translational Medicine
Volume6
Issue number249
DOIs
Publication statusPublished - 13 Aug 2014

Bibliographical note

Copyright © 2014, American Association for the Advancement of Science.

Keywords

  • Animals
  • Bacteremia
  • Cecum
  • Cell Movement
  • Cytokines
  • Disease Models, Animal
  • Endotoxemia
  • Female
  • Fibroblasts
  • Ligation
  • Lipopolysaccharides
  • Lymph Nodes
  • Mice
  • Nitric Oxide Synthase Type II
  • Peritoneum
  • Punctures
  • Sepsis
  • Spleen
  • Survival Analysis

Fingerprint

Dive into the research topics of 'Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis'. Together they form a unique fingerprint.

Cite this