Direct Cardiac Reprogramming: A Novel Approach for Heart Regeneration.

Hidenori Tani,Taketaro Sadahiro,Masaki Ieda

doi:10.3390/ijms19092629

Hidenori Tani, Taketaro Sadahiro + Show 1 more

Open Access

https://doi.org/10.3390/ijms19092629

Copy DOI

Abstract

Cardiac diseases are among the most common causes of death globally. Cardiac muscle has limited proliferative capacity, and regenerative therapies are highly in demand as a new treatment strategy. Although pluripotent reprogramming has been developed, it has obstacles, such as a potential risk of tumor formation, poor survival of the transplanted cells, and high cost. We previously reported that fibroblasts can be directly reprogrammed to cardiomyocytes by overexpressing a combination of three cardiac-specific transcription factors (Gata4, Mef2c, Tbx5 (together, GMT)). We and other groups have promoted cardiac reprogramming by the addition of certain miRNAs, cytokines, and epigenetic factors, and unraveled new molecular mechanisms of cardiac reprogramming. More recently, we discovered that Sendai virus (SeV) vector expressing GMT could efficiently and rapidly reprogram fibroblasts into integration-free cardiomyocytes in vitro via robust transgene expression. Gene delivery of SeV-GMT also improves cardiac function and reduces fibrosis after myocardial infarction in mice. Through direct cardiac reprogramming, new cardiomyocytes can be generated and scar tissue reduced to restore cardiac function, and, thus, direct cardiac reprogramming may serve as a powerful strategy for cardiac regeneration. Here, we provide an overview of the previous reports and current challenges in this field.

Highlights

Cardiac diseases still represent a leading cause of mortality globally, despite decades of development of medical technologies for treating such diseases
We developed a new approach for heart regeneration—direct cardiac reprogramming—in which fibroblasts are converted to induced cardiomyocyte-like cells, without first reverting them to stem cells, through the transduction of cardiac-specific factors [11]
Direct cardiac reprogramming in vivo can induce the conversion of resident cardiac fibroblasts (CFs) into functional induced cardiomyocyte-like cells (iCMs) in situ and improve cardiac function after myocardial infarction (MI)

Summary

Introduction

Cardiac diseases still represent a leading cause of mortality globally, despite decades of development of medical technologies for treating such diseases. IPSC-based regenerative medicine needs further refinement as it is associated with obstacles, such as a potential risk of tumor formation, poor survival of the transplanted cells, and the high cost related with large-scale CM production To overcome such obstacles, we developed a new approach for heart regeneration—direct cardiac reprogramming—in which fibroblasts are converted to induced cardiomyocyte-like cells (iCMs), without first reverting them to stem cells, through the transduction of cardiac-specific factors [11]. Addis et al developed a unique screening system to determine optimal combinations of reprogramming factors to generate functional iCMs. many groups have measured reprogramming efficiency by analyzing the expression of cardiac markers or a fluorescent reporter driven by a CM-specific gene promoter, Addis et al measured quantifiable functions, such as the percentage of cells that show calcium transients. This study provided new insights into the molecular mechanisms of cardiac reprogramming; maintenance of residual fibroblast identity is the major roadblock during reprogramming toward functional iCMs

Modification of Signaling Pathways and Environmental Cues

Epigenetic Factors

Cardiac Reprogramming In Vivo

Findings

Conclusions