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Updated: May 28, 2026
Ultrasound-Guided Induced Pluripotent Stem Cell-Derived Cardiomyocyte Implantation in Myocardial Infarcted Mice
Published on: March 30, 2022
Oxygen-generating Microparticles Enhance Viability and Functionality of Human Pluripotent Stem Cell-derived
Xingyu He1, Suchandrima Dutta1, Darshini Desai2
1Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.
Background:
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a promising therapy for myocardial infarction (MI), but their survival is severely limited by the hypoxic infarct environment. The optimal oxygen levels required to maintain the viability and functionality of hiPSC-CMs remain poorly defined. This study aimed to develop a controlled oxygen-delivery system to support engineered heart tissue (EHT) for cardiac regeneration.
Methods:
Oxygen-generating particles (OGPs) were engineered using peroxide (sodium percarbonate) and antioxidant (β-carotene (βCAR)) components encapsulated in PLGA microparticles. The effects of OGPs on hiPSC-CMs were evaluated through oxidative stress assays, cell viability analysis, and contractility measurements. RNA-seq was performed to investigate gene expression changes in hiPSC-CMs in response to OGPs and hypoxic stress. hiPSC-CMs combined with OGPs were encapsulated in a 3D hydrogel to generate oxygen-releasing engineered heart tissue (OR-EHT), which was implanted into infarcted hearts of immunodeficient mice. Cardiac function was assessed by echocardiography, and cell engraftment was evaluated using immunostaining.
Results:
OGPs provided controlled oxygen release for up to 22 days. Inclusion of βCAR minimized OGP-induced oxidative stress, preserved mitochondrial membrane potential, and maintained cell viability. OGP treatment enhanced calcium signaling and contractility in hiPSC-CMs. Transcriptomic analysis revealed that genes associated with CM maturation and contractile function were upregulated following OGP pretreatment. In addition, OGP pretreatment significantly reduced HIF-1α expression, decreased mitochondrial fragmentation, and improved survival. RNA-seq further demonstrated activation of oxygen-responsive metabolic pathways that facilitated cellular adaptation to hypoxic stress. In vivo, OR-EHT implantation for 6 weeks improved cardiac function, increased ejection fraction, reduced ventricular remodeling, and decreased infarct size compared with EHT without OGPs. Moreover, OGP incorporation significantly enhanced engraftment and survival of transplanted hiPSC-CMs and supported features consistent with early structural integration with host myocardium.
Conclusion:
OGP-mediated oxygen delivery offers a promising strategy for oxidative preconditioning and significantly improves the regenerative efficacy of hiPSC-CM-based cardiac therapies.
