Description

Single-cell gene expression analysis of cardiac progenitor cells’ paracrine impact on human iPS-derived cardiomyocytes and target macrophages

M. Noseda, C. Constantinou, S. Samari, P. Chaves Guerrero, K. Cheng, C. Beretta, T. Rito, M. S. Abreu Paiva, A. Pombo, M. D. Schneider

National Heart and Lung Institute, Imperial College London, UK; Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Germany

Ischemic heart disease remains the foremost cause of death globally, with many patients still evolving to heart failure, in proportion to infarct size. Thus, preventing cardiomyocyte loss at time of injury and stimulating self-repair are fruitful approaches to counteract the severity of cardiac damage. Intramyocardial injection of cardiac progenitor cells (CPCs) at time of ischemia improves cardiac function 12 weeks later. Given poor long-term engraftment, early paracrine effects are the consensus likely cause of the benefits observed, including potential effects on cardiac macrophages as key players in the response to injury.

Here, we show how single-cell gene expression analysis enabled us to: (1) Define a homogenous population of clonogenic adult CPCs with tri-lineage potential after grafting and a distinct paracrine gene signature; and (2) Resolve the specific benefits in macrophage phenotypes conferred by CPCs. CPC-conditioned medium markedly reduced oxidative stress-dependent cell death in hiPSC-derived cardiomyocytes. Moreover, CPC-conditioned medium affected macrophage differentiation and polarization, driving a protective (M2-like) phenotype. By single-cell gene expression profiling in protective versus non-protective cells, we defined 6-8 candidates as mediators of cardiomyocyte protection and M2 macrophage induction.

Funding:

British Heart Foundation (MN: PG/16/47/32156; MDS: CH/08/002/29257, RE/13/4/30184, RG/08/007, RG/15/1/31165, RM/13/1/30157)