Huaxiao Yang1,2,3,4, Ningyi Shao1,2,3, Alexandra Holmström1,2,3, Xin Zhao1,2,3, Tony Chour1,2,3, Haodong Chen1,2,3, Ilanit Itzhaki1,2,3, Haodi Wu1,2,3, Mohamed Ameen1,2,3, Nathan J Cunningham1,2,3, Chengyi Tu1,2,3, Ming-Tao Zhao1,2,3, Alice F Tarantal5,6,7, Oscar J Abilez1,2,3, Joseph C Wu1,2,3. 1. Stanford Cardiovascular Institute, 265 Campus Drive G1120B, Stanford, CA 94305-5454, USA. 2. Division of Cardiology, Department of Medicine, 265 Campus Drive G1120B, Stanford, CA 94305-5454, USA. 3. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive G1120B, Stanford, CA 94305-5454, USA. 4. Department of Biomedical Engineering, University of North Texas, 390 N. Elm Street K240B, Denton, TX 76207-7102, USA. 5. Department of Pediatrics, School of Medicine, One Shields Avenue, Davis, CA 95616-8542, USA. 6. Department Cell Biology and Human Anatomy, School of Medicine, One Shields Avenue, Davis, CA 95616-8542, USA. 7. California National Primate Research Center, UC Davis, One Shields Avenue, Davis, CA 95616-8542, USA.
Abstract
AIMS: Stem cell therapy has shown promise for treating myocardial infarction via re-muscularization and paracrine signalling in both small and large animals. Non-human primates (NHPs), such as rhesus macaques (Macaca mulatta), are primarily utilized in preclinical trials due to their similarity to humans, both genetically and physiologically. Currently, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are delivered into the infarcted myocardium by either direct cell injection or an engineered tissue patch. Although both approaches have advantages in terms of sample preparation, cell-host interaction, and engraftment, how the iPSC-CMs respond to ischaemic conditions in the infarcted heart under these two different delivery approaches remains unclear. Here, we aim to gain a better understanding of the effects of hypoxia on iPSC-CMs at the transcriptome level. METHODS AND RESULTS: NHP iPSC-CMs in both monolayer culture (2D) and engineered heart tissue (EHT) (3D) format were exposed to hypoxic conditions to serve as surrogates of direct cell injection and tissue implantation in vivo, respectively. Outcomes were compared at the transcriptome level. We found the 3D EHT model was more sensitive to ischaemic conditions and similar to the native in vivo myocardium in terms of cell-extracellular matrix/cell-cell interactions, energy metabolism, and paracrine signalling. CONCLUSION: By exposing NHP iPSC-CMs to different culture conditions, transcriptome profiling improves our understanding of the mechanism of ischaemic injury. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Stem cell therapy has shown promise for treating myocardial infarction via re-muscularization and paracrine signalling in both small and large animals. Non-human primates (NHPs), such as rhesus macaques (Macaca mulatta), are primarily utilized in preclinical trials due to their similarity to humans, both genetically and physiologically. Currently, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are delivered into the infarcted myocardium by either direct cell injection or an engineered tissue patch. Although both approaches have advantages in terms of sample preparation, cell-host interaction, and engraftment, how the iPSC-CMs respond to ischaemic conditions in the infarcted heart under these two different delivery approaches remains unclear. Here, we aim to gain a better understanding of the effects of hypoxia on iPSC-CMs at the transcriptome level. METHODS AND RESULTS: NHP iPSC-CMs in both monolayer culture (2D) and engineered heart tissue (EHT) (3D) format were exposed to hypoxic conditions to serve as surrogates of direct cell injection and tissue implantation in vivo, respectively. Outcomes were compared at the transcriptome level. We found the 3D EHT model was more sensitive to ischaemic conditions and similar to the native in vivo myocardium in terms of cell-extracellular matrix/cell-cell interactions, energy metabolism, and paracrine signalling. CONCLUSION: By exposing NHP iPSC-CMs to different culture conditions, transcriptome profiling improves our understanding of the mechanism of ischaemic injury. Published on behalf of the European Society of Cardiology. All rights reserved.
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