Induced regeneration--the progress and promise of direct reprogramming for heart repair

Abstract

Regeneration of cardiac tissue has the potential to transform cardiovascular medicine. Recent advances in stem cell biology and direct reprogramming, or transdifferentiation, have produced powerful new tools to advance this goal. In this Review we examine key developments in the generation of new cardiomyocytes in vitro as well as the exciting progress that has been made toward in vivo reprogramming of cardiac tissue. We also address controversies and hurdles that challenge the field.

Figure 1

Therapeutic approaches to regenerate cardiac tissue. A schematic representation of the various approaches under investigation to produce new cardiac muscle is shown.

Figure 2

Development of cardiac muscle. The progression of lineage restriction and specification of cardiac muscle is depicted moving from the pluripotent inner cell mass (from which ESCs are derived) on the left to mature myocardial tissue on the right, with some of the key signaling pathways (top) and gene expression characteristics (bottom) shown. The factors that are listed represent examples that are discussed in the text and are not intended to be inclusive.

Figure 3

Defining cardiomyocyte identity. A wide range of phenotypic features can be assayed to determine whether a reprogrammed cell is an iCM. These range from expression of a panel of genes or the activation of a reporter transgene (such as α-MHC–GFP) to more complex functional characteristics, such as the ability to fire action potentials and show calcium oscillation. As functional attributes require the orchestration of a complex collection of parts, they are probably more reliable indicators of successful transdifferentiation to iCMs. Other testable characteristics include the presence of cardiomyocyte-specific epigenetic marks, the ability of iCMs to generate force, the ability of in vitro–generated iCMs to form gap junctions and electrically couple with host cardiomyocytes after transplantation and genetic or lineage tracing to show that iCMs are derived from fibroblasts or another starting cell type. T tubule, transverse tubule; RyR, ryanodine receptor; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; NCX, sodium-calcium exchanger; PLN, phospholamban; GCaMP, a genetically encoded calcium indicator consisting of a fusion of GFP and calmodulin (CaM).