Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Elisa Setten - , IRCCS Istituto Clinico Humanitas - Rozzano (Milano), University of Milan (Author)
  • Alessandra Castagna - , IRCCS Istituto Clinico Humanitas - Rozzano (Milano) (Author)
  • Josué Manik Nava-Sedeño - , Universidad Nacional Autónoma de México (Author)
  • Jonathan Weber - , University of Upper Alsace (Author)
  • Roberta Carriero - , IRCCS Istituto Clinico Humanitas - Rozzano (Milano) (Author)
  • Andreas Reppas - , Charité – Universitätsmedizin Berlin (Author)
  • Valery Volk - , Hannover Medical School (MHH) (Author)
  • Jessica Schmitz - , Hannover Medical School (MHH) (Author)
  • Wilfried Gwinner - , Hannover Medical School (MHH) (Author)
  • Haralampos Hatzikirou - , Department of Innovative Methods of Computing (IMC), Khalifa University of Science and Technology (Author)
  • Friedrich Feuerhake - , Hannover Medical School (MHH), University Medical Center Freiburg (Author)
  • Massimo Locati - , IRCCS Istituto Clinico Humanitas - Rozzano (Milano), University of Milan (Author)

Abstract

Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical settings. Although fibroblasts and macrophages are known as key cellular players for fibrosis development, a comprehensive functional model that considers their interaction in the metabolic/immunologic context of fibrotic tissue has not been set up. Here we show, by transcriptome-based mathematical modeling in an in vitro system that represents macrophage-fibroblast interplay and reflects the functional effects of inflammation, hypoxia and the adaptive immune context, that irreversible fibrosis development is associated with specific combinations of metabolic and inflammatory cues. The in vitro signatures are in good alignment with transcriptomic profiles generated on laser captured glomeruli and cortical tubule-interstitial area, isolated from human transplanted kidneys with advanced stages of glomerulosclerosis and interstitial fibrosis/tubular atrophy, two clinically relevant conditions associated with organ failure in renal allografts. The model we describe here is validated on tissue based quantitative immune-phenotyping of biopsies from transplanted kidneys, demonstrating its feasibility. We conclude that the combination of in vitro and in silico modeling represents a powerful systems medicine approach to dissect fibrosis pathogenesis, applicable to specific pathological conditions, and develop coordinated targeted approaches.

Details

Original languageEnglish
Article number6499
Number of pages22
JournalNature Communications
Volume13
Issue number1
Publication statusPublished - 30 Oct 2022
Peer-reviewedYes

External IDs

ORCID /0000-0002-1270-7885/work/142250323
PubMed 36310236

Keywords