Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes
The sinoatrial node (SAN) initiates all heartbeats within the heart. The diseases of SAN result in catastrophic consequences from bradycardia to cardiac arrest. The sinoatrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. A complex interaction between PCs and their microenvironment (especially fibroblasts) critically determines SAN function. An altered microenvironment leads to rhythm failure. In the representative work, we explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in SANs. By the model of Tbx18-induced PCs and engineered tissue sheets, we found that fibroblasts induced metabolic reprogramming within PCs by specifically upregulating aldolase c (Aldoc) through integrin-dependent mitogen activated protein kinase-E2F1 (MAPK-E2F1) signals. This process enhanced aerobic glycolysis and regulated the rhythmicity of PCs. The interruption of fibroblast-PC interactions or Aldoc knockdown further nullified electrical activity. Similar machinery could be faithfully observed in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells. This work not only details the cellular machinery behind the complex milieu of vertebrate SANs but also gives new hope to reverse its dysfunction by targeting relevant pathways.
The study entitled “Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes” was published in Circulation Research and selected as the cover story with editorial (doi: 10.1161/CIRCRESAHA.121.320301). Dr. Yu-Feng Hu leads the research team (Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, and IBMS: Pei-Chun Chou, Chih-Min Liu, Ching-Hui Weng and Jin-Dian Liu). The work is a collaborative effort with Dr. Kai-Chien Yang, Yuh-Charn Lin, Ruey-Bing Yang, Bai-Chuang Shyu, Song-Kun Shyue, Michael Hsiao (Academia Sinica), Dr. Mei-Ling Cheng (Chang Gung University), and Dr. Shih-Pin Chen (Taipei Veterans General Hospital). Thanks to the Ministry of Science and Technology, Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, and Academia Sinica for research funding support.