YAP-Induced Glycolysis Drives Fibroinflammation and Disrupts Fibroblast Fidelity

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Fibrosis Research

Background:

• Mammalian cardiac chambers possess specialized structures and functions, yet the mechanisms behind chamber-specific transcriptomic and metabolic differences are poorly understood.
• The Hippo/Yes-associated protein (YAP) pathway regulates cellular processes, with Hippo kinases inhibiting YAP in cardiac fibroblasts (CFs) to limit fibrosis and inflammation.
• The precise role of YAP in regulating the metabolic microenvironment during homeostasis and fibroinflammation remains unclear.

Purpose of the Study:

• To investigate the activity of YAP and glycolysis in the four cardiac chambers.
• To understand the role of YAP in cardiac fibroblasts (CFs) and its impact on the metabolic microenvironment.
• To elucidate the mechanisms driving chamber-specific transcriptomic and metabolic differences in the heart.

Main Methods:

• Scored expression of YAP target and glycolysis genes in human single-nucleus RNA sequencing data.
• Measured isotope-labeled glucose uptake in isolated mouse atria to compare glucose uptake between left and right atria.
• Inactivated Hippo kinases (Lats1/Lats2) in mouse CFs to perform metabolic studies, snRNA-seq, single-nucleus assay for transposase-accessible chromatin with sequencing, and spatial transcriptomics.

Main Results:

• Hippo-deficient CFs activated glycolysis, promoting fibroinflammation, and inhibition of glycolysis suppressed fibrosis.
• Elevated YAP activity disrupted fibroblast lineage fidelity, inducing an osteochondroprogenitor cell state.
• Macrophages secreted insulin-like growth factor 1 (IGF1) to activate IGF1 signaling in Hippo-deficient CFs, increasing proliferation and fibrosis.

Conclusions:

• Right atrial CFs exhibit higher glycolysis and YAP activity, with YAP activation driving fibrosis and inducing an osteochondroprogenitor cell state.
• YAP promotes macrophage expansion via CSF1 secretion, and macrophages reciprocally signal via IGF1 to enhance CF proliferation and fibrosis.
• Upregulated IGF1 receptor in Hippo-deficient CFs mediates enhanced proliferation and fibrosis in response to macrophage-secreted IGF1.