Humanized hiPSC Platforms for I/R Injury: Advancing Toward Precision Cardioprotection

Figures

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  Figure 1. Pathological sequence of myocardial I/R injury and rationale for hiPSC‐based modeling. The figure separates the ischemic and reperfusion phases and annotates ATP depletion, acidosis, ionic imbalance, Ca2+ overload, ROS burst, mPTP opening, endothelial dysfunction, microvascular impairment, inflammatory activation, regulated cell death, infarct expansion, and adverse remodeling. It also highlights why conventional animal and simplified in vitro models incompletely capture human comorbidities, immune biology, and patient heterogeneity, thereby motivating human‐relevant hiPSC‐based platforms.

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  Figure 2. Systematic comparison of hiPSC‐CM maturation strategies for myocardial I/R modeling. The figure compares electrical stimulation, mechanical loading, metabolic reprogramming, endocrine maturation, 3D tissue architecture, and microfluidic perfusion. For each strategy, it indicates major maturation targets, advantages, limitations, and translational relevance to I/R injury modeling, including electrophysiology, calcium handling, mitochondrial oxidative metabolism, sarcomere organization, contractile force, and tissue‐level functional stability. FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation.

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  Figure 3. Integrated mechanisms and feedback loops in hiPSC‐based myocardial I/R models. The figure depicts mitochondrial ROS burst, Ca2+ overload, Drp1‐dependent fission, impaired mitophagy, ER stress, MAM remodeling, ferroptosis, lipid peroxidation, cGAS–STING activation, NLRP3 inflammasome signaling, pyroptosis, apoptosis, necroptosis, and PANoptosis as an interconnected network. It also illustrates how single‐cell/spatial omics, CRISPR perturbation, AI‐assisted phenotyping, and integrated functional readouts can interrogate these mechanisms in hiPSC‐based platforms. Some PANoptosis‐related mechanisms are inferred from myocardial I/R studies and remain to be systematically validated in hiPSC‐based platforms. DAMPs, damage‐associated molecular patterns; AI, artificial intelligence; ROS, reactive oxygen species; MAMs, mitochondria‐associated endoplasmic reticulum membranes.

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  Figure 4. Current limitations, emerging solutions, and future translational workflow for hiPSC‐based myocardial I/R platforms. The figure presents a future‐oriented workflow that moves beyond maturation alone by integrating multicellular cardiac tissues, vascularization, immune competence, disease modeling, multiomics, CRISPR‐based functional genomics, AI‐assisted analysis, integrated electrophysiology–contractility–calcium–metabolism assessment, and patient‐specific preclinical modeling. Immature and mature cardiomyocytes are represented as cells rather than small and large hearts.