Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. Non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, has become the leading indication for liver transplantation in both Europe and the USA. Liver fibrosis is the consequence of sustained, iterative liver injury, and the main determinant of outcomes in NASH. The liver possesses remarkable inherent plasticity, and liver fibrosis can regress when the injurious agent is removed, thus providing opportunities to alter long-term outcomes through therapeutic interventions. Although hepatocyte injury is a key driver of NASH, multiple other cell lineages within the hepatic fibrotic niche play major roles in the perpetuation of inflammation, mesenchymal cell activation, extracellular matrix accumulation as well as fibrosis resolution. The constituents of this cellular interactome, and how the various subpopulations within the fibrotic niche interact to drive fibrogenesis is an area of active research. Important cellular components of the fibrotic niche include endothelial cells, macrophages, passaging immune cell populations and myofibroblasts. In this review, we will describe how rapidly evolving technologies such as single-cell genomics, spatial transcriptomics and single-cell ligand-receptor analyses are transforming our understanding of the cellular interactome in NAFLD/NASH, and how this new, high-resolution information is being leveraged to develop rational new therapies for patients with NASH.

Heart failure (HF) is characterized by progressive fibrosis. Both fibroblasts and mesenchymal stem cells (MSCs) can differentiate into pro-fibrotic myofibroblasts. MSCs secrete and express platelet-derived growth factor (PDGF) and its receptors. We hypothesized that PDGF signaling in cardiac MSCs (cMSCs) promotes their myofibroblast differentiation and aggravates post-myocardial infarction left ventricular remodeling and fibrosis. We show that cMSCs from failing hearts post-myocardial infarction exhibit an altered phenotype. Inhibition of PDGF signaling in vitro inhibited cMSC-myofibroblast differentiation, whereas in vivo inhibition during established ischemic HF alleviated left ventricular remodeling and function, and decreased myocardial fibrosis, hypertrophy, and inflammation. Modulating cMSC PDGF receptor expression may thus represent a novel approach to limit pathologic cardiac fibrosis in HF.

Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti-IL-6 antibodies (Abs) result in panantagonism. In a rat model of reperfused MI, sgp130Fc, but not anti-IL-6-Ab, attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI. These data demonstrate the efficacy of exclusive IL-6 trans-signaling blockade and support further investigation of sgp130Fc as a potential novel therapy in MI.

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Although chronic inflammation is a central feature of heart failure (HF), the immune cell profiles differ with different underlying causes. This suggests that for immunomodulatory therapy in HF to be successful, it needs to be tailored to the specific etiology. Here, the authors demonstrate that monocyte-derived C-C chemokine receptor 2 (CCR2)+ macrophages infiltrate the heart early during pressure overload in mice, and that blocking this response either pharmacologically or with antibody-mediated CCR2+ monocyte depletion alleviates late pathological left ventricular remodeling and dysfunction, T-cell expansion, and cardiac fibrosis. Hence, suppression of CCR2+ monocytes/macrophages may be an important immunomodulatory therapeutic target to ameliorate pressure-overload HF.