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Liu, L. Cardiac Reprogramming. Encyclopedia. Available online: https://encyclopedia.pub/entry/16797 (accessed on 02 July 2024).
Liu L. Cardiac Reprogramming. Encyclopedia. Available at: https://encyclopedia.pub/entry/16797. Accessed July 02, 2024.
Liu, Liu. "Cardiac Reprogramming" Encyclopedia, https://encyclopedia.pub/entry/16797 (accessed July 02, 2024).
Liu, L. (2021, December 06). Cardiac Reprogramming. In Encyclopedia. https://encyclopedia.pub/entry/16797
Liu, Liu. "Cardiac Reprogramming." Encyclopedia. Web. 06 December, 2021.
Cardiac Reprogramming
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This entry is adapted from the peer-reviewed paper 10.3390/cells10123297

Direct reprogramming of fibroblasts into CM-like cells has emerged as an attractive strategy to generate induced CMs (iCMs) in heart regeneration. However, low conversion rate, poor purity, and the lack of precise conversion of iCMs are still present as significant challenges. In this review, we summarize the recent development in understanding the molecular mechanisms of cardiac reprogramming with various strategies to achieve more efficient iCMs. reprogramming. Specifically, we focus on the identified critical roles of transcriptional regulation, epigenetic modification, signaling pathways from the cellular microenvironment, and cell cycling regulation in cardiac reprogramming. We also discuss the progress in delivery system optimization and cardiac reprogramming in human cells related to preclinical applications. We anticipate that this will translate cardiac reprogramming-based heart therapy into clinical applications. In addition to optimizing the cardiogenesis related transcriptional regulation and signaling pathways, an important strategy is to modulate the pathological microenvironment associated with heart injury, including inflammation, pro-fibrotic signaling pathways, and the mechanical properties of the damaged myocardium. We are optimistic that cardiac reprogramming will provide a powerful therapy in heart regenerative medicine.

cardiac reprogramming heart regeneration cardiogenesis pathological microenvironment inflammation pro-fibrotic signaling nanoparticle

1. Transcriptional Regulation in Cardiac Reprogramming

1.1. Additional Transcriptional Factors Screening

Different transcriptional factor combinations or additional transcriptional factors based on GMT, have been examined to improve cardiac reprogramming efficiency. In one transcription factor screen experiment, iCMs induced by the combination of Tbx5, Mef2c and Myocd show higher cardiomyocyte marker gene expression than GMT-induced iCMs by Q-PCR assay [1]. It has also been identified that GMT and Hand2 (GHMT) can cooperatively reprogram adult mouse tail-tips and cardiac fibroblasts into iCMs, which show a higher percentage of α-MHC-GFP+, cTnT+, and α-MHC-GFP/cTnT+ cells compared to GMT-induced iCMs [2]. Another study shows that the overexpression of transcription factors MYOCD and SRF, alone or in conjunction with Mesp1 and SMARCD3, enhances the cardio-inducing effect of GMT in cardiac reprogramming by improving global cardiac related gene expression and corresponding cardiac specific functions including Ca2+ transient oscillations [3]. Apart from α-MHC-GFP+ fibroblasts, a screening platform that uses calcium transient as the major measurement of reprogramming has been established [4]. In this study, the combination of Hand2, Nkx2.5, Gata4, Mef2c, and Tbx5 (HNGMT) is >50-fold more efficient than GMT alone, with higher cardiac related gene expression and more cells exhibiting calcium transient and spontaneous beating. Focusing on cardiac fibroblasts isolated from adult mice with myocardial infarction (MICFs), a five factor combination, GMTMS (GMT plus Myocd and Sall4), induces more iCMs expressing the cardiac structural and functional proteins [5].

1.2. Transcriptional Factors Optimization

Aside from screening additional transcriptional factors for cardiac reprogramming, there are other findings related to transcriptional factors themselves. The fusion of the powerful transactivation domain (TAD) derived from MyoD (the M3 domain), firstly used in iPSCs, improves the reprogramming efficiency of iPSCs [6][7][8]. Thus, Hirai et al. have applied the same strategy in cardiac reprogramming and show that fused Mef2c with wild-type Gata4, Hand2, and Tbx5 reaches the highest reprogramming efficiency. Additionally, different isoforms of Mef2c also affect the conversion rate of fibroblasts into iCMs [9].
Due to the fact that fibroblasts should be infected by each of the three transgene vectors, a “Triplet” polycistronic vectors encoding Gata4, Mef2c, and Tbx5 which has ensured infected cells overexpressing three transcriptional factors simultaneously is constructed [10]. Subsequently, the stoichiometry of Gata4, Mef2c, and Tbx5 has been found to play a significant role in cardiac reprogramming [11]. After comparing all six possible splicing orders of Gata4, Mef2c, and Tbx5, researchers found that MGT vectors result in a more than 10-fold increase in the number of beating iCMs, which is caused by different protein expression levels of the three transcriptional factors. Similarly, stoichiometric optimization of Gata4, Hand2, Mef2c, and Tbx5 also further enhances the efficiency of cardiac reprogramming [12].
Recently, Zhang et al. indicated that ensuring the expression of all transcription factors enhances cardiac reprogramming [13]. By selectively analyzing subpopulations of reprogrammed cells, they showed that iCMs with all transcriptional factor overexpression possess higher cardiac related gene expression levels and contractile cardiac structure formations. Their research emphasizes the significance of all transcriptional factors’ co-expression in the system, which has provided an important guideline for future studies.

1.3. Mechanisms of the Transcriptional Network in Cardiac Reprogramming

Though researchers have worked out numerous strategies for manipulating transcription networks in cardiac reprogramming, the underlying mechanisms remain largely unknown. Therefore, a deep understanding of the conversion process should provide us with new insights and inspiration for future studies and applications.
Gata4, one of three cardiac reprogramming factors, is a master transcriptional factor in heart development. Gata4 has been identified to downregulate pro-fibrotic factors and mediators, including Snai1, during the process of GMT-induced reprogramming [14]. Moreover, Fernandez-Perez et al. have identified the function of Hand2 in the induction of pacemaker-like myocytes (iPMs) [15]. As a subtype of cardiac reprogramming, they find that Hand2 plays a vital role in the combination of GHMT. Hand2 augments chromatin accessibility at loci involved in sarcomere formation, electrical coupling, and membrane depolarization. Selective reorganization of chromatin accessibility by Hand2 provides possibilities for pacemaker specific gene expression, thus completing the reprogramming of iPMs. Further study reveals that all transcription factors in GHMT synergistically activate genome-wide cardiogenic specific enhancers, which has helped us reach a deeper understanding of the transcription network in cardiac reprogramming [16].
Single-cell technology was first reported in 2009, which has provided excellent opportunities to study individual cells in different biological stages [17]. Liu et al. have delineated the antagonistic relationship between cell proliferation and iCM induction by analyzing single-cell transcriptomes during cardiac reprogramming [18]. Intriguingly, they have also revealed the unexpected downregulation of factors involved in mRNA processing and splicing. Focusing on this finding, they have identified several splicing factors as barriers of cardiac reprogramming including Sf3a1, Sf3b1, and Zrsr2 through loss-of-function experiments [19]. Continued studies of the mechanisms of the transcriptional network related to combinations of TFs direct cardiac lineage conversion are required for revealing the nature of the conversion process [20], which may provide more potential targets for future research and clinical translation.

2. Epigenetic Regulations in Reprogramming

2.1. MicroRNAs

MicroRNAs have been uncovered in directing cardiac reprogramming due to their unique roles in cell fate changes [21]. A screen of candidate miRNAs based on their roles in cardiac muscle development and differentiation has allowed Jayawardena et al. to identify a combination of microRNAs (miRNA) 1, 133, 208, and 499 that can reprogram mouse cardiac fibroblasts into iCMs. In their in vitro study, calcium oscillations are observed in a miRNA treated group but with only a few exhibited spontaneous contraction. Mechanistically, these miRNAs likely target Nanog to induce early cardiac reprogramming. These miRNAs can also directly repress Snai1 and silence pro-fibrotic signatures. The same group also identified that the addition of an RNA-sensing receptor ligand, called ICR2, further enhances the ability of reprogramming factors to produce iCMs by targeting the RNA-sensing receptors Rig-I and TLR3 [22].
Interestingly, miR-1 and miR-133a can also enhance MGT-based reprogramming by silencing pro-fibrotic signatures [23]. Although it has been shown that miR-133a can be used to enhance cardiac reprogramming in human cells, whether the combination of reprogramming factors with miRNAs could further improve heart function and cardiac reprogramming efficiency in vivo, remains to be explored.

2.2. Chromatin Remodeling Factors

Chromatin remodeling factors also affect reprogramming. BAF60c, a cardiac-specific subunit of ATP-dependent chromatin remodeling SWI/SNF complexes, can increase cardiac reprogramming with MGT [3], which is consistent with a previous finding that Baf60c can initiate ectopic cardiac gene expression in mouse mesoderm with Gata4 [24][25].
Another chromatin remodeling factor HELLS, has also been identified to increase reprogramming by screening, although the mechanism is unknown [26].

2.3. Epigenetic Factors Related to Methylation

The epigenetic factors related to methylation have also been found to regulate cardiac reprogramming. By screening 35 selected components of chromatin modifying or remodeling complexes, researchers have identified the polycomb complex gene Bmi1 as a major barrier for cardiac reprogramming [26]. Bmi1 directly binds to a set of key cardiogenic loci that are co-occupied by other PRC components. Reduced Bmi1 expression corresponds with increased levels of the active histone mark H3K4me3 and reduced levels of repressive H2AK119ub at cardiogenic loci. More importantly, Testa and colleagues showed that the Bmi1 inhibitor PTC-209 promotes the chemically-induced direct cardiac reprogramming of cardiac fibroblasts into cardiomyocytes [27]. Our group has identified H3K4 methyltransferase Mll1 in inhibiting iCM reprogramming based on a screen of 47 cardiac development-related epigenetic and transcription factors [28]. Inhibiting Mll1 activity with small molecules improves efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. Since Bmi1 and Mll1 belong to two complexes with opposite functions for methylation, it is rather intriguing that both can enhance reprogramming. More interestingly, both Bmi1 and Mll1 are involved in not only cardiac reprogramming, but also iPSC [29] and pluripotent stem cell reprogramming [30]. These results imply that Bmi1 and Mll1 might have more general targets instead of the specific cardiogenic loci.
Along with methylation writers and erasers, histone readers, such as PHF7, which directly bind to histone H3K4me3 and H3K4me2 marks, also play a significant role in cardiac reprogramming [31][32]. Mechanistically, PHF7 can bind to cardiac super enhancers and increase chromatin accessibility by interacting with the SWI/SNF complex. More interestingly, Phf7 plus Mef2c and Tbx5 can achieve efficient cardiac reprogramming without Gata4, as confirmed by immunocytochemistry, flow cytometry, and quantitative PCR (qPCR).
The current body of work regarding the epigenetic regulation of cardiac reprogramming represents only the tip of the iceberg. Although chromatin remodeling and histone methylation related epigenetic regulation have been studied, very few studies have pursued other epigenetic regulations in cardiac reprogramming, such as histone acetylation and phosphorylation.

3. Cellular Microenvironment in Cardiac Reprogramming

3.1. Growth Factor Regulation

One earlier investigation showed that pre conditioning infarcted myocardium with vascular endothelial growth factor enhances cardiac reprogramming and heart function [33]. Subsequently, another study showed that a combination of FGF2, FGF10, and VEGF (FFV medium), significantly enhances cardiac reprogramming, including, most importantly, a 100-fold increase in beating iCMs [34]. Notably, these growth factors have also been used in cardiomyocyte differentiation protocols. Moreover, Gata4 is not required when using FFV medium, enabling the induction of functional cardiomyocytes via only Mef2c and Tbx5.

3.2. Signaling Pathways

Signaling pathways always lead to the activation of certain kinases. The importance of kinase regulation has been shown in cell fate change. One such study screened a constitutively activated protein kinase library and identified Akt1/protein kinase B as an enhancer for reprogramming [35]. Akt1 induces spontaneous beating in approximately 50% of reprogrammed mouse embryo fibroblasts after 3-week induction with GATA4, HAND2, MEF2C, and Tbx5 (GHMT). Furthermore, the addition of Akt1 to GHMT results in a more mature cardiac phenotype for iCMs [35]. A follow up study indicates that Akt1 acts synergistically with Hand2 to recruit other TFs to enhancer elements [16]. Based on these studies, a cardiac reprogramming gene regulatory network has been established and within this network, repressing EGFR signaling and JAK pathways can enhance reprogramming.
Another important pathway identified to regulate cardiac reprogramming is the TGF beta pathway [36]. Researchers utilized calcium indicator GCaMP driven by the cardiac Troponin T promoter to quantify iCM yield and identified the TGF β inhibitor, SB431542 (SB), as a small molecule capable of increasing the conversion of both mouse embryonic fibroblasts and adult cardiac fibroblasts to iCMs up to 5-fold [36]. It has been revealed that the TGF β pathway is activated during the early stage of reprogramming, whereas overactivation of pro-fibrotic signaling networks by TGF β attenuates cardiac reprogramming [23]. TGF β inhibitor is not the only molecule shown to enhance cardiac reprogramming in vitro. Another study screened 5500 compounds in primary cardiac fibroblasts and found that transforming growth factor-β inhibitor SB431542 and the WNT inhibitor XAV939, increase reprogramming efficiency 8-fold when added to GMT-overexpressing cardiac fibroblasts. More importantly, SB431542 and XAV939 also enhance in vivo reprogramming with GMT [37].

3.3. Inflammation Regulation

Our laboratory has identified four agents, insulin-like growth factor-1 (IGF1), Mll1 inhibitor MM589, that transform growth factor-β inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed IMAP, coordinately enhancing reprogramming efficiency. IMAP treatment represses many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways [38]. Therefore, we investigated the roles of C-C motif chemokine ligand 3 (CCL3), CCL6, and CCL17 in cardiac reprogramming and observed that these ligands inhibit iCM formation, whereas inhibitors of C-C motif chemokine receptor 1 (CCR1), CCR4, and CCR5 have the opposite effect. This is not the only example of the role of inflammation signaling for cardiac reprogramming. Another study screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming [39]. The major effect of diclofenac is silencing the inflammatory effect by targeting cyclooxygenase-2, prostaglandin E2/prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1β signaling. Interestingly, for the microRNA mediated cardiac reprogramming, JAK inhibitor I treatment also enhances reprogramming efficiency [21]. Notably, the JAK-STAT pathway plays an important role in inflammation [40].
Olson and colleagues screened 1052 ORF cDNAs, which led to the discovery of 49 activators and 129 inhibitors of cardiac reprogramming. They found that one of the most potent activators, ZNF281, stimulates cardiac reprogramming by genome-wide association with GATA4 on cardiac enhancers and the recruitment of a NuRD complex. The Nucleosome Remodeling Deacetylase (NuRD) complex is a group of associated proteins related to chromatin remodeling and histone deacetylase activities. The major effect of the NuRD complex is attributed to its anti-inflammatory function, which is consistent with the finding that anti-inflammatory drugs dexamethasone and nabumetone also promote cardiac reprogramming [41]. Interestingly, ZNF281 have important functions in somatic reprogramming and the maintenance of pluripotent states [42][43].

3.4. Cellular Matrix Regulation

Mechanical properties represent another important element of the cellular microenvironment. Given that the tissue elasticity of the myocardium is much softer than that of culture dishes, Shotaet al. studied the effect of matrix stiffness on cardiac reprogramming [44]. They found that the soft matrix was comparable with native myocardium, promoting the efficiency and quality of cardiac reprogramming. Mechanistically, this is due to the inhibition of integrin, Rho/ROCK, actomyosin, and YAP/TAZ signaling, as well as the suppression of fibroblast programs. However, as the infarcted myocardium stiffens during the first 1 to 2 weeks [45], studies to specifically understand the effect of mechanical propertiesof cardiac reprogramming in the infarcted heart are required.
In summary, studies of the cellular microenvironment in cardiac reprogramming have identified cardiogenesis signaling (FFV and Akt1), inflammation signaling, pro-fibrotic signaling, and mechanical properties as important regulators for reprogramming. Since cardiac lineage differentiation and immune lineage differentiation are highly related during development [46], inhibition of inflammation signaling during cardiac reprogramming might also reflect the requirement of inhibition immune lineage cells during cardiac lineage development.

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