Oxygen-generating Microparticles Enhance Viability and Functionality of Human Pluripotent Stem Cell-derived Cardiomyocytes for Myocardial Infarction Therapy.
Xingyu He, Suchandrima Dutta, Darshini Desai, Sheng Zhong, William Liu, Sophie Chen, Wei Huang, Waqas Ahmad, Jialiang Liang, Yigang Wang
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Abstract
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.
期刊介绍：
The purpose of Stem Cell Reviews and Reports is to cover contemporary and emerging areas in stem cell research and regenerative medicine. The journal will consider for publication:
i) solicited or unsolicited reviews of topical areas of stem cell biology that highlight, critique and synthesize recent important findings in the field.
ii) full length and short reports presenting original experimental work.
iii) translational stem cell studies describing results of clinical trials using stem cells as therapeutics.
iv) papers focused on diseases of stem cells.
v) hypothesis and commentary articles as opinion-based pieces in which authors can propose a new theory, interpretation of a controversial area in stem cell biology, or a stem cell biology question or paradigm. These articles contain more speculation than reviews, but they should be based on solid rationale.
vi) protocols as peer-reviewed procedures that provide step-by-step descriptions, outlined in sufficient detail, so that both experts and novices can apply them to their own research.
vii) letters to the editor and correspondence.
In order to facilitate this exchange of scientific information and exciting novel ideas, the journal has created five thematic sections, focusing on:
i) the role of adult stem cells in tissue regeneration;
ii) progress in research on induced pluripotent stem cells, embryonic stem cells and mechanism governing embryogenesis and tissue development;
iii) the role of microenvironment and extracellular microvesicles in directing the fate of stem cells;
iv) mechanisms of stem cell trafficking, stem cell mobilization and homing with special emphasis on hematopoiesis;
v) the role of stem cells in aging processes and cancerogenesis.
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