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Global Translational Medicine Advancements in cardiac regenerative therapy

Table 1. (Continued)
Method Approach Maturation Mature CM features Recent Findings
duration (day) (2018 – 2024)
Metabolic/ Media+ Thyroid 7 Enhanced cellular alignment Microtissue formats
biochemical/physical hormone- Lengthened sarcomere structure improve cellular
dexamethasone-IGF-1 Elevated expression of ATP2A2, MYH7, alignment and
(TDI) formed in SLCBA1, PLN, PPARG, ADRB1, CHRM2, contractility. 57
microtissue and p-AKT
Reduced level of MYH6, TNNI1
Boosted contractile strength
Prolonged time to peak
Extended relaxation phase
Metabolic/biochemical EHT-based media 3 – 5 × 7 Elevated fatty acid oxidation EHT Formats enhance
culture Greater sensitivity to tetrodotoxin metabolic activity
Enhanced aerobic metabolic activity and functional
Mitochondria aligned in sarcomere maturation. 58
structure
Improved calcium regulation
Increased density of l
k1
Reduced diastolic membrane potential
3D Bioprinting 3D printing of cardiac 2 – 4 × 7 Vascularization of tissues 3D bioprinting
tissue Enhanced cell alignment advances functional
Mimics native heart structure and function cardiac tissue
engineering. 59
Genetic Modification CRISPR/Cas9 and Editing: 2 × 7 Enhanced expression of cardiac markers Genetic modifications
other gene editing Further iPSC Improved metabolic functions using CRISPR
technologies maturation: 2 – 4 Enhanced cell survival enhance cardiac
× 7 differentiation. 60,61
ECM Engineering Modifications to ECM ~30 Improved cell-matrix interactions ECM engineering
properties Enhanced mechanical properties improves cardiac
Mimics native ECM composition patch integration 62
Integration with Connection with As early as 48 h Real-time monitoring of cardiac activity Device integration
Devices electronic and sensing Enhanced integration with engineered enhances functionality
devices tissues of engineered cardiac
Feedback mechanisms for stimulation tissues 63,64
Note: This table is adapted and updated from Thomas et al. 49
Abbreviations: MHC-α: Alpha-myosin heavy chain; SERCA2a: Sarcoplasmic reticulum Ca [2]+ ATPase; β-MHC: Beta-myosin heavy chain;
HCN1: Hyperpolarization activated cyclic nucleotide-gate potassium channel 1; SCN5A: Sodium voltage-gated channel alpha subunit 5; GATA4: GATA
binding protein 4; TNNT: Troponin T; CM: Cardiomyocyte; FB: Fibroblast; MSC: Mesenchymal stem cell; MLCV: iPSC: Induced pluripotent
stem cell; MYL: Myosin light chain; MYH: Myosin heavy chain; CACNA1C: Calcium voltage-gated channel subunit alpha 1C; NPPA: Natriuretic
peptide precursor A; ATP2A2: ATPase sarcoplasmic/endoplasmic reticulum Ca [2]+ transporting 2; PLN: Phospholamban; PPARG: Peroxisome
proliferator-activated receptor gamma; ADRB1: Adrenoceptor beta 1; CHRM2: Cholinergic receptor muscarinic 2; EHT: Engineered heart tissue;
ECM: Extracellular matrix.

One of the methods used to further mature CPCs is cell function and protect CMs from hypoxia-induced cell
electrical stimulation (ES). ES promotes cardiac repair by death, aiding tissue repair and regeneration. 64,65 Neutral
recruiting stem cells to injury sites through cardioprotective sphingomyelinase 2 (nSMase2) assists in ceramide
extracellular vesicles (EVs) and exosomes released from formation, further promoting EV biogenesis under ES and
CPCs. These EVs carry bioactive molecules, including enhancing cell survival. In addition, cAMP is involved in
VEGF, cytokines (such as interleukin [IL]-6, IL-8, and signaling to support stem cell survival. 66,67
tumor necrosis factor-alpha), matrix metalloproteinases, In cell culture, ES promotes the differentiation of CPCs
tissue inhibitors of metalloproteinases, stromal cell- into mature CMs by driving calcium ion (Ca² ) influx
+
derived factor 1, and heat shock proteins, which support through voltage-gated channels. This influx activates
angiogenesis, remodeling, and inflammation resolution, calmodulin and calcineurin, leading to the nuclear
including in Q-waves denervation. 64,65 EVs also contain translocation of transcription factors. Key pathways, such
peptides, mRNA, and miRNAs that modulate recipient as AKT and GSK3β phosphorylation, along with focal

Volume 4 Issue 1 (2025) 6 doi: 10.36922/gtm.5745