Cardiac regeneration by direct reprogramming in this decade and beyond

Abstract

Japan faces an increasing incidence of heart disease, owing to a shift towards a westernized lifestyle and an aging demographic. In cases where conventional interventions are not appropriate, regenerative medicine offers a promising therapeutic option. However, the use of stem cells has limitations, and therefore, "direct cardiac reprogramming" is emerging as an alternative treatment. Myocardial regeneration transdifferentiates cardiac fibroblasts into cardiomyocytes in situ.Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 (GMT) can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. The three main approaches to improving reprogramming efficiency are (1) improving direct cardiac reprogramming factors, (2) improving cell culture conditions, and (3) regulating epigenetic factors. miR-133 is a potential candidate for the first approach. For the second approach, inhibitors of TGF-β and Wnt signals, Akt1 overexpression, Notch signaling pathway inhibitors, such as DAPT ((S)-tert-butyl 2-((S)-2-(2-(3,5-difluorophenyl) acetamido) propanamido)-2-phenylacetate), fibroblast growth factor (FGF)-2, FGF-10, and vascular endothelial growth factor (VEGF: FFV) can influence reprogramming. Reducing the expression of Bmi1, which regulates the mono-ubiquitination of histone H2A, alters histone modification, and subsequently the reprogramming efficiency, in the third approach. In addition, diclofenac, a non-steroidal anti-inflammatory drug, and high level of Mef2c overexpression could improve direct cardiac reprogramming.Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.

Keywords: Cardiac fibroblast; Direct cardiac reprogramming; Induced cardiomyocytes (iCMs); Micro RNAs; Sendai virus; Transcription factors; iPS cells.

Fig. 1

Three pathways for deriving cardiomyocytes for myocardial regeneration [4]. There are (1) full reprogramming approaches (purple line), (2) partial reprogramming approaches (orange line), and (3) direct reprogramming approaches (green line). For the treatment of myocardial infarction and heart failure, (1) iPS-derived cardiomyocytes are about to be clinically studied for myocardial transplantation experiments. (3) Direct cardiac reprogramming does not require cardiomyocyte transplantation and may be feasible through a direct reprogramming approach. (2) Partial reprogramming may offer the advantages of (1) and (3). Further research is desirable in the future

Fig. 2

Schema of future heart regenerative medicine. The outline of heart regenerative medicine in the case of myocardial infarction is shown. When the heart is damaged due to myocardial infarction, heart failure, and so on, cardiomyocytes are preferentially lost. The fibroblasts of the heart remain and replace the lost cardiomyocytes. Currently, a method of transplanting iPS-derived cardiomyocytes is becoming a reality (upper side). Another method is the transduction of the cardiomyocytes based on the remaining fibroblasts. This is the direct cardiac reprogramming (lower side)

Fig. 3

Age-related inflammation and fibrosis are barriers to direct cardiac reprogramming [29]. With aging, fibroblasts activate the COX-2/PGE2/EP4/IL-1β/IL-1R1 pathway. These signaling pathways suppress myocardial induction via expression of fibrosis-related genes (left and middle panels). Diclofenac promotes myocardial induction by suppressing this pathway (right panel)

Fig. 4

Soft matrix promotes the efficiency and maturation of direct cardiac reprogramming [38]. Soft matrix enhanced cardiac reprogramming via YAP/TAZ suppression. As a result, this can increase the efficiency of induction and maturation of iCMs