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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

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

OriginalspracheEnglisch
Aufsatznummer6499
Seitenumfang22
FachzeitschriftNature Communications
Jahrgang2022
Ausgabenummer13
PublikationsstatusVeröffentlicht - 22 Okt. 2022
Peer-Review-StatusJa

Externe IDs

Scopus 85140956201
ORCID /0000-0002-1270-7885/work/142250323

Schlagworte

Schlagwörter

  • mathematical modeling, Bioinformatics analysis