The Future of Direct Cardiac Reprogramming: Any GMT Cocktail Variety?
Abstract
:1. Background
1.1. Cardiogenesis
- MEF2. MEF2 is a MAD-box containing transcription factor with a key role in heart morphogenesis and in the regulation of the CPC and CM gene program [4,18]. MEF2 is encoded by four genes, Mef2a, -b, -c, and -d. Mef2b and Mef2c are the first MEF2 isoforms expressed in the cardiac mesoderm at mouse E7.5, Mef2a and Mef2d are expressed in the linear heart tube between E8.0 and E8.5, and after E8.5, all four Mef2 genes are expressed throughout the developing heart [18]. Mef2c is required for activation of a subset of cardiac contractile protein genes, as well as for the development of cardiac structures derived from SHF [4]. In mice homozygous for a null mutation of Mef2c, the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed [19].
- HAND2. Hand1 and Hand2 encode basic helix-loop-helix transcription factors and are expressed in mesodermal and neural crest-derived structures of the developing heart. Hand2 is expressed in the outflow track, the epicardium, valve progenitors, and predominantly in the myocardial compartment of the right ventricle, while the related transcription factor Hand1 is predominantly expressed in the left ventricle [20,21]. Deletion of Hand2 results in severe hypoplasia of the right ventricle segment [22]. In fact, the absence of the right ventricular region of Mef2c mutant correlated with downregulation of the HAND2 [19]. HAND2 interacts with non-coding regions of many genes involved in cardiogenesis [21].
- GATA4. The Gata4 gene is expressed in CMs and their mesodermal precursors, as well as in the endocardium and the epicardium. GATA4 regulates expression of myocardium-related genes and is necessary for the proliferation of CMs, formation of the endocardial cushions, development of the right ventricle and septation of the outflow tract [23]. GATA4 binds and promotes deposition of H3K27ac, and subsequently, establish active chromatin regions, at multiple cardiac enhancers to stimulate transcription [24].
- BAF60c. Smarcd3 gene, encodes BAF60c, a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex. BAF60c is expressed specifically in the heart and somites in the early mouse embryo. Smarcd3 silencing in mouse embryos causes defects in heart morphogenesis that reflect impaired expansion of the AHF, and results in abnormal cardiac and skeletal muscle differentiation [25]. Baf60c regulates a gene expression program that regulates the main functional properties of CMs, including genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Interestingly, many of the genes deregulated in Baf60c null embryos are targets of the MYOCD, another important transcription factor in heart development [26], which can functionally interact with BAF60c [27].
- TBX5. Tbx5 gene is a T-box transcription factor, expressed early in development throughout the entire cardiac crescent. Lineage tracing of Tbx5 showed that this gene is expressed in the myocardium of the left ventricle, but not the right ventricle or outflow track, besides a population of the posterior SHF (contributing to the myocardium of the atria and the venous pole) [28]. TBX5 can have both positive and negative transcriptional activity depending on the transcription factors with which it interacts [29]. Interestingly, in 2009 Takeuchi et al. demonstrated the transdifferentiation of mouse mesoderm into beating CMs by the ectopic expression of GATA4, BAF60c, and TBX5. The authors described that BAF60c enabled binding of GATA4 to cardiac genes to initiate the cardiac expression program, whereas TBX5 repressed noncardiac mesodermal genes and promoted differentiation into CMs [30].
- NKX2.5. Nkx2.5 gene is a homeobox transcription factor essential for early heart formation. Nkx2.5 knockout mice die at E9.5-10.5 with severely underdeveloped heart [31]. NKX2.5 is expressed in the cardiac crescent stage and regulates CM differentiation [32]. Interestingly, NKX2.5 is expressed at lower levels in SHF progenitors than in FHF progenitors and CMs, and its expression level, combined with other factors, may trigger different outcomes. In SHF progenitors, NKX2.5 can promote proliferation and activate the expression of Fgf10 and Mef2c-AHF enhancer, together with FOXH1, whereas in the FHF, NKX2.5 reduces Fgf10 and Isl1 expression and induces differentiation [33].
- MESP1. Mesp1 is a basic helix-loop-helix transcription factor expressed in early mesoderm during gastrulation by the T-box transcription factor EOMES in response to low doses of NODAL/SMAD2/3 signaling [34]. MESP1 expressing cells migrate out from the primitive streak and are incorporated into the heart field to generate a single heart tube [35]. MESP1 acts as a master regulator of multipotent CPCs specification. It activates many genes that form the core cardiac transcriptional machinery and represses the expression of genes that control other early mesoderm and endoderm cell fates [36].
1.2. Regenerative Medicine to Treat Cardiac Diseases: Where Do We Stand?
1.3. The Current Progresses and Challenges to Cell Therapy For Heart Diseases
1.3.1. Cell Pre-Treatments
1.3.2. Genetically Modified Cells
1.3.3. Cells Encapsulated in Biomaterials
2. Direct Reprogramming for Heart Regeneration
2.1. Direct Cardiac Reprogramming In Vitro
2.1.1. Direct Reprogramming into Mouse iCMs
- First Discovery: the GMT cocktail
- Modifications to the GMT cocktail
Stoichiometric Optimization of GMT Factors
Inclusion of Additional Transcription Factors: The Relevance of Hand2 Transcription Factor
Addition of miRs
Regulation of Signaling Pathways
Inhibition of Epigenetic Barriers
- Other cocktails different from GMT
2.1.2. Direct Reprogramming Into Human iCMs
- Modifications to the GMT cocktail
- Other cocktails different from GMT
2.1.3. Direct Reprogramming Into iCPCs
- First Discovery: the ETS2 and MESP1 combination
- Modifications to the GMT cocktail
- Other cocktails different from GMT: expandable mouse iCPCs
2.2. Direct Cardiac Reprogramming In Vivo
- The GMT cocktail
- Modifications to the GMT cocktail
- Other cocktails different from GMT
3. Future Directions and Challenges
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
iCMs | induced Cardiomyocytes |
iCPCs | induced Cardiac Progenitor Cells |
iPSCs | induced Pluripotent Stem Cells |
AMI | Acute Myocardial Infarction |
MHC | Myosin Heavy Chain |
cTn | cardiac Troponin |
GMT | GATA4, MEF2C, TBX5 |
GHMT | GATA4, HAND2, MEF2C, TBX5 |
FHF | First Heart Field |
SHF | Second Heart Field |
AHF | Anterior Heart Field |
ReV | retrovirus |
LeV | lentivirus |
SeV | Sendai virus |
AV | Adenovirus |
miRs | microRNAs |
CFs | cardiac fibroblasts |
TTFs | tail-tip fibroblasts |
MEFs | mouse embryonic fibroblasts |
HDFs | human dermal fibroblasts |
HFFs | human foreskin fibroblasts |
hESC | human embryonic stem cell |
AP | action potentials |
CaT | calcium transients |
SB | spontaneous beating |
c-B | beating when co-cultured with murine CMs |
HF | heart function |
CS | cardiac tissue structure |
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Cell Origin | Reprogramming Cocktails | Efficiency | Functionality | References |
---|---|---|---|---|
Direct cardiac reprogramming into iCMs in vitro | ||||
GMT and modifications to GMT cocktail | ||||
Mouse | GATA4, MEF2C, TBX5 | 4-6% αMHC-GFP+/cTnT+ iCMs from CFs | AP,CaT, SB | [105] |
MEF2C, GATA4, TBX5 | ~10% αMHC-GFP+ and ~4.8% cTnT+ iCMs from CFs | AP,CaT, SB | [107] | |
GATA4, MEF2C, TBX5, HAND2 | 9.2% and 6.8% αMHC+/TnT+ iCMs from TTFs and CFs, respectively | CaT, SB | [108] | |
GATA4, MEF2C, TBX5, HAND2 | ~1.5% cTnT+ in pDox-GMT; 13% cTnT+ in pMX–GMT/pDox–Hand2 iCMs, from MEFs | CaT, SB | [109] | |
GATA4, MEF2C, TBX5, HAND2 | ~70–80% of cells expressing GMT(H) were Titin-eGFP+ or α-actinin+ iCMs from MEFs | CaT, SB | [113] | |
MEF2C, GATA4, TBX5, HAND2 | ~25% Titin-eGFP+/α-actinin+ iCMs from MEFs | CaT, SB | [114] | |
GATA4, MYOD-MEF2C, TBX5, HAND2 | 10-20% cTnT+ iCMs from embryonic head fibroblasts | CaT, SB | [110] | |
GATA4, MEF2C, TBX5, HAND2, NKX2.5 | 1.6% cTnT-GCaMP5+ iCMs from MEFs | CaT, SB | [111] | |
GATA4, MEF2C, TBX5, MYOCD, SRF, (MESP1, BAF60C) | 2.4% αMHC-GFP+ iCMs from MEFs | CaT, no SB | [112] | |
GATA4, MEF2C, TBX5, (miR-133 or MESP1, MYOCD) | 9.5% αMHC-GFP+/ cTnT+ and 19.9% α-actinin+ iCMs from MEFs | CaT, SB | [115] | |
GATA4, MEF2C, TBX5, HAND2, NKX2.5, SB431542 | 17% cTnT-GCaMP5+ iCMs from MEFs; 9.27% cTnT-GCaMP5+ iCMs from CFs | CaT, SB | [116] | |
GATA4, MEF2C, TBX5, HAND2, DAPT | ~38% cTnT+ and ~35% α-actinin+ iCMs from MEFs | CaT, SB | [118] | |
GATA4, MEF2C, TBX5, HAND2, miR-1, miR-133, A83-01, Y-27632 | 60% cTnT+ and 60% α-actinin+ iCMs from MEFs | AP, CaT, SB | [119] | |
GATA4, MEF2C, TBX5, HAND2, AKT1 | 23.3% αMHC-GFP+/cTnT+ iCMs from MEFs; 50% beating iCMs from MEFs at Day 21 | CaT, SB | [120] | |
GATA4, MEF2C, TBX5, (HAND2 or MESP1, MYOCD), FGF2, FGF10, VEGF | ~13% αMHC-GFP+ and ~2% cTnT+ iCMs from MEFs | CaT, SB | [121] | |
GATA4, MEF2C, TBX5, SB431542, XAV939 | ~30% αMHC-GFP+ iCMs from CFs | AP,CaT, SB | [122] | |
GATA4, MEF2C, TBX5, HAND2, Diclofenac | ~5% cTnT+/ αMHC+ iCMs from postnatal TTFs | CaT, SB | [123] | |
GATA4, MEF2C, TBX5, (HAND2), Bmi1 shRNA | 22% αMHC+/TnT+ iCMs from CFs | CaT, SB | [124] | |
Human | GATA4, MEF2C, TBX5, MESP1, MYOCD | 5.9% cTnT+ and 5.5% α-actinin+ iCMs from HCFs | AP, CaT, c-B | [129] |
GATA4, MEF2C, TBX5, ESRGG, MESP1, MYOCD, ZFPM2 | 13% αMHC-mCherry+/cTnT+ iCMs from hESC-derived fibroblasts | AP, CaT, no SB | [130] | |
GATA4, MEF2C, TBX5, MESP1, MYOCD, miR-133 | 27.8% cTnT+ and 8% α-actinin+ iCMs from HCFs | CaT, no SB | [115] | |
GATA4, MEF2C, TBX5, MYOCD, NKX2.5, mir-1, miR-133, JAK1i, GSK3βi or NRG | ~3.8% cTnT+ iCMs from HDFs | CaT, no SB | [132] | |
Human, rat, porcine | GATA4, MEF2C, TBX5, (HAND2, MYOCD or miR-590) | ~40% αMHC-GFP+ and ~5-6% cTnT+ iCMs from adult HCFs | No SB in human iCMs | [131] |
Other cocktails different from GMT | ||||
Mouse | TBX5, MEF2C, MYOCD | ~11% cTnT+ iCMs from CFs | AP | [125] |
miR-1, miR-133, miR-208, miR-499a, JI1 | ~28% αMHC-CFP+ iCMs from CFs | AP, CaT, SB | [117] | |
CHIR99021, RepSox, Forskolin, VPA, Parnate, TTNPB | 14.5% α-actinin+ and 9% α-MHC+ iCMs from MEFs | AP, CaT, SB | [127] | |
Human | GATA4, HAND2, TBX5, MYOCD, miR-1, miR-133 | ~35% cTnT+ and ~42% tropomyosin+ iCMs from HFFs | CaT, SB | [133] |
CHIR99021, A83-01, BIX01294, AS8351, SC1, Y27632, OAC2, SU16F, JNJ10198409 | 7% cTnT+ iCMs from HFFs | AP, CaT, SB | [134] | |
Direct reprogramming into iCPCs in vitro | ||||
Mouse | MESP1, TBX5, GATA4, NKX2.5, BAF60C, BIO, LIF | > 90% Nkx2.5-YFP+, Gata4+ and Irx4+ iCPCs from adult CFs | Expandable; Tri-lineage dif.; In vivo in AMI | [104] |
OCT4, SOX2, KLF4, C-MYC, BMP4, Activin A, CHIR99021, SU5402 | 70% Flk1+/Pdgfrα+ iCPCs from MEFs | Expandable; Tri-lineage dif.; In vivo in AMI | [139] | |
Human | ETS2, MESP1, Activin A, BMP2 | 9.3% NKX2.5-tdTomato+ iCPCs from HDFs | Not expandable; Unipotent (CM) | [135] |
GATA4, MEF2C, TBX5, HAND2 | 4.9% c-Kit+ iCPCs from adult HDFs | Not expandable; Unipotent (CM) | [136] | |
GATA4, MEF2C, TBX5, HAND2, BMP4, Activin A, bFGF | 81% Flk1+ and 83% Isl1+ iCPCs from HDFs | Not expandable; Tri-lineage dif.; In vivo in AMI | [137] | |
GATA4, MEF2C, TBX5, HAND2 | ~72% of GATA4+ cells were NKX2.5+; ~85% of HAND2+ cells were ISL1+, from HFFs | Not expandable; Tri-lineage dif. | [138] | |
Direct reprogramming into iCMs in vivo | ||||
GMT cocktail | ||||
Mouse | GATA4, MEF2C, TBX5, (ReV vector), Thymosin β4 (intramyocardial) | Periostin-Cre: R26R-lacZ mice: 35% β-Gal+ and α-actinin+ iCMs | Improvement in HF and CS | [142] |
TBX5, MEF2C, GATA4 (ReV vector) | 1% α-actinin+ iCMs derived from GMT transduced cells | Improvement in HF and CS | [143] | |
MEF2C, GATA4, TBX5 (ReV vector) | Periostin-Cre: R26R-lacZ mice: ~80 β-Gal+/α-actinin+ iCMs per section | Improvement in HF and CS | [144] | |
GATA4, MEF2C, TBX5 (SeV vector) | TCF21iCre/R26-tdTomato mice: ∼1.5% tdTomato+/cTnT+ iCMs | Improvement in HF and CS | [148] | |
GATA4, MEF2C, TBX5 (Nanoparticles) | In vitro: 22% αMHC-eGFP+ iCMs from MEFs; In vivo: ND | Improvement in HF and CS | [149] | |
Rat | GATA4, MEF2C, TBX5 (AV vector) | In vitro: ~6.5% cTnT+ iCMs from rat CFs; In vivo: ND | Improvement in HF and CS | [147] |
GATA4, TBX5, MEF2C (LeV vector), VEGF (AV vector) | ND | Improvement in HF and CS | [145,146] | |
Modifications to GMT cocktail | ||||
Mouse | GATA4, MEF2C, TBX5, HAND2 (ReV vector) | Fsp1-Cre x R26LacZ mice: ~6.5% β-Gal+ iCMs; TCF21-iCre x R26tdTomato mice: ~2.4% tdTomato+ iCMs | Improvement in HF and CS | [108] |
Other cocktails different from GMT | ||||
Mouse | miR-1, miR-133, miR-208, miR-499a (LeV vector) | Fsp1-Cre: R26R-tdTomato mice: 12% tdTomato+/cTnT+ iCMs | Improvement in HF and CS | [126] |
GATA4, MEF2C, TBX5 (ReV vector) SB431542, XAV939 (intraperitoneal) | ROSA-YFP/Periostin-Cre mice: 150-200 YFP+/cTnT+ iCMs per section | Improvement in HF and CS | [122] | |
CHIR99021, RepSox, Forskolin, TTNPB, Rolipram (oral) VPA, Parnate (intraperitoneal) | Fsp1-Cre: R26RtdTomato: 0.78% tdTomato+/α-actinin+ iCMs | Improvement in HF and CS | [150] |
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López-Muneta, L.; Miranda-Arrubla, J.; Carvajal-Vergara, X. The Future of Direct Cardiac Reprogramming: Any GMT Cocktail Variety? Int. J. Mol. Sci. 2020, 21, 7950. https://doi.org/10.3390/ijms21217950
López-Muneta L, Miranda-Arrubla J, Carvajal-Vergara X. The Future of Direct Cardiac Reprogramming: Any GMT Cocktail Variety? International Journal of Molecular Sciences. 2020; 21(21):7950. https://doi.org/10.3390/ijms21217950
Chicago/Turabian StyleLópez-Muneta, Leyre, Josu Miranda-Arrubla, and Xonia Carvajal-Vergara. 2020. "The Future of Direct Cardiac Reprogramming: Any GMT Cocktail Variety?" International Journal of Molecular Sciences 21, no. 21: 7950. https://doi.org/10.3390/ijms21217950