Therapeutic approaches for cardiac regeneration and repair

• Published in: Nature reviews cardiology Vol. 15; no. 10; pp. 585 - 600
• Main Authors: Hashimoto, Hisayuki, Olson, Eric N., Bassel-Duby, Rhonda
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2018; Nature Publishing Group
• Subjects: 13; 13/100; 631/154/51/1844; 631/61/490; 692/4019/592/2725; 692/4019/592/75/2/1674; 692/700/565/1331; Animals; Cardiac Imaging; Cardiac Surgery; Cardiology; Cardiomyocytes; Cardiovascular disease; Care and treatment; Cell cycle; Cellular therapy; Clinical trials; Gene therapy; Genetic Therapy - methods; Genome editing; Heart; Heart Diseases - genetics; Heart Diseases - pathology; Heart Diseases - physiopathology; Heart Diseases - therapy; Heart failure; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Humans; Medicine; Medicine & Public Health; Methods; Myocardial ischemia; Myocardium - pathology; Physiological aspects; Recovery of Function; Regeneration; Regenerative medicine; Review Article; Stem Cell Transplantation - methods; Tissue engineering; Treatment Outcome; Ventricular Remodeling; United States
• ISSN: 1759-5002; 1759-5010
• DOI: 10.1038/s41569-018-0036-6

Ischaemic heart disease is a leading cause of death worldwide. Injury to the heart is followed by loss of the damaged cardiomyocytes, which are replaced with fibrotic scar tissue. Depletion of cardiomyocytes results in decreased cardiac contraction, which leads to pathological cardiac dilatation, additional cardiomyocyte loss, and mechanical dysfunction, culminating in heart failure. This sequential reaction is defined as cardiac remodelling. Many therapies have focused on preventing the progressive process of cardiac remodelling to heart failure. However, after patients have developed end-stage heart failure, intervention is limited to heart transplantation. One of the main reasons for the dramatic injurious effect of cardiomyocyte loss is that the adult human heart has minimal regenerative capacity. In the past 2 decades, several strategies to repair the injured heart and improve heart function have been pursued, including cellular and noncellular therapies. In this Review, we discuss current therapeutic approaches for cardiac repair and regeneration, describing outcomes, limitations, and future prospects of preclinical and clinical trials of heart regeneration. Substantial progress has been made towards understanding the cellular and molecular mechanisms regulating heart regeneration, offering the potential to control cardiac remodelling and redirect the adult heart to a regenerative state. This Review discusses the advances in therapeutic approaches for cardiac repair and regeneration, including cell-based therapies as well as the use of secretory factors, such as microRNAs and exosomes, direct reprogramming strategies, and gene editing to control cardiac remodelling and redirect the adult heart to a regenerative state, and highlights the future prospects of preclinical and clinical trials of heart regeneration. Key points Preclinical outcomes of cardiac regenerative therapy approaches have not translated effectively to clinical trials. Transplantation of induced pluripotent stem cell-derived cardiomyocytes for cardiac repair has encountered problems related to safety and low engraftment rates. Cell-free-based approaches for heart repair and regeneration involve cardioprotective secretory factors or direct reprogramming of resident cardiac fibroblasts to cardiomyocyte-like cells. Endogenous cardiomyocyte proliferation can be evoked by modulating cell cycle regulators, the Hippo signalling pathway, and the cardiac microenvironment. Genome editing can correct underlying mutations causing heart disease in animals and offers a state-of-the-art therapeutic approach for cardiac repair. The therapeutic potential of cardiac regeneration approaches can be improved by optimizing the delivery method of the therapeutic factors.