IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling.
Jamila H SiamwalaFrancesco S PaganoPatrycja M DubieleckaMalina J IveyJose Pedro Guirao-AbadAlexander ZhaoSonja ChenHaley GranstonJae Yun JeongSharon RoundsOnur KanisicakSakthivel SadayappanRichard J GilbertPublished in: Communications biology (2023)
The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfrα CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1β increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1β also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1β induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1β induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling.
Keyphrases
- endothelial cells
- single cell
- left ventricular
- extracellular matrix
- pulmonary arterial hypertension
- induced pluripotent stem cells
- stem cells
- induced apoptosis
- high glucose
- pluripotent stem cells
- mycobacterium tuberculosis
- pulmonary hypertension
- rna seq
- oxidative stress
- dendritic cells
- regulatory t cells
- type diabetes
- idiopathic pulmonary fibrosis
- heart failure
- metabolic syndrome
- immune response
- transforming growth factor
- polycyclic aromatic hydrocarbons
- high throughput
- endoplasmic reticulum stress
- mesenchymal stem cells
- pet imaging
- cancer stem cells