By Megan Mayerle, PhD

July 8, 2019

Heart failure, the end result of many forms of cardiovascular disease, is the most common cause of death in the United States, accounting for approximately 800,000 deaths per year. One of the hallmarks of heart disease is interstitial fibrosis, which reduces tissue flexibility and increases the rate at which cardiovascular disease progresses to heart failure. Stopping fibrosis would decrease the incidence of heart failure significantly. However, despite the obvious need, currently there aren’t any anti-fibrotic drugs treating cardiac fibrosis available. This is due to a lack of understanding of how cardiac fibroblasts differ from other tissue’s fibroblasts, as well as an inability to generate sufficiently large populations of cardiac fibroblasts for experimental studies.

Stanford Cardiovascular Institute members Dr. Hao Zhang and Cardiovascular Institute Director Dr. Joseph C. Wu have recently published an innovative solution to this problem in Circulation Research. By analyzing the single-cell transcriptome profiles of fibroblasts from 10 different mouse tissues, the researchers were able to identify distinct tissue-specific signature genes for each fibroblast tissue subpopulation. Using these signature genes, the researchers were able to show that cardiac fibroblasts in large are of the epicardial lineage.

This key insight enabled the scientists to develop a robust, chemically-defined protocol that allows scientists to make large numbers of cardiac fibroblasts from human induced pluripotent stem cells (iPSCs). Zhang also showed that these iPSC-derived cardiac fibroblasts were sensitive to both pro- and anti-fibrosis drugs, and implicated crosstalk between cardiomyocytes and cardiac fibroblasts via the atrial/brain natriuretic peptide-natriuretic peptide receptor 1 pathway in suppressing fibrogenesis.

Stem-cell based advances such as this help doctors and scientists to gain a better understanding of the complexity of cardiac fibrosis, and to advance the development of more effective anti-fibrotic therapies.

Stanford researchers Hao Zhang, Lei Tian, Mengcheng Shen, Chengyi Tu, Haodi Wu, Mingxia Gu, David T. Paik, and Joseph C. Wu contributed to this study. Financial support came from research grants from National Institutes of Health (NIH) K99 HL135258 (M.G.), K99 HL133473 (H.W.), T32 EB009035 (D.T.P.), R01 HL141371, R01 HL145676, R01 HL146690, and UG3 TR002588 (J.C.W.).