KLF4 in Smooth Muscle Cell-Derived Progenitor Cells Is Essential for Angiotensin II-Induced Cardiac Inflammation and Fibrosis
Abstract
Background: Cardiac fibrosis is defined by the excessive accumulation of ECM (extracellular matrix) material resulting in cardiac tissue scarring and dysfunction. Although it is commonly accepted that myofibroblasts are the major contributors to ECM deposition in cardiac fibrosis, their origin remains controversial. Our group discovered that a subpopulation of resident vascular stem cells residing within the artery adventitia (termed adventitial Sca1+ smooth muscle-derived progenitor cells [AdvSca1-SM]) originates from mature vascular smooth muscle cells through a KLF4 (Kruppel-like factor 4)-dependent in situ reprogramming process. However, the molecular mechanism(s) whereby KLF4 regulates the AdvSca1-SM phenotype remain unclear.
Methods: We leveraged a highly specific AdvSca1-SM cell reporter system, single-cell RNA-sequencing, and spatial transcriptomic approaches to examine the spatiotemporal differentiation trajectory of AdvSca1-SM cells in AngII (angiotensin II) challenged cardiac tissues. To examine the function of KLF4, we compared the cardiac inflammation and fibrotic response of wild-type and AdvSca1-SM-specific Klf4 knockout mice.
Results: We demonstrate the profibrotic differentiation trajectory of coronary artery-associated AdvSca1-SM cells in cardiac fibrosis, characterized by loss of stemness-related genes, including Klf4, but gain of expression of a profibrotic phenotype. Importantly, these changes were recapitulated in human cardiac hypertrophic tissue,…
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