Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine

Abstract

The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2 .

Keywords: preclinical research; regeneration; rejuvenation; repair.

Figure 1.

Different targets of the cardiac regenerative process. Although quantitative and qualitative restoration of cardiomyocytes has an important role in cardiac regeneration, other constitutive cardiac components are required to reach an optimal recovery of cardiac architecture and functionality after an injury. Pro-(green) and anti-regenerative (red) factors influencing different heart components are shown. CCR2 indicates C-C chemokine receptor type 2; HIF-1α, hypoxia-inducible factor 1α; IL, interleukin; MAPK, mitogen-activated protein kinase; nAG, newt anterior gradient protein; SDF1, C-X-C motif chemokine 12; STAT3, signal transducer and activator of transcription 3; Tbx, T-box protein; and VEGF, vascular endothelial growth factor.

Figure 2.

Regenerative therapies. Classification of different type of therapies in cell-based, cell-free or tissue engineering is done mostly from an academic perspective. In reality many of them converge and the combined use of different strategies may lead to better results. CPC indicates cardiac progenitor cell; CRISPR-Cas9, clustered regularly interspaced short palindromic repeats-associated 9; ECS, embryonic stem cell; and iPSC, induced pluripotent stem cell.