Human induced pluripotent stem cell derived nanovesicles for cardiomyocyte protection and proliferation

作者：Yuhua Wei, Xiaoxiao Geng, Qing You, Yu Zhang, Fangfang Cao, Gunaseelan Narayanan, Thanh Nguyen, Xiaoyuan Chen, Jianyi Zhang, Lei Ye · 发表于：Bioactive Materials · 年份：2025 · DOI：10.1016/j.bioactmat.2025.04.017 · 被引用次数：7 · 研究领域：Congenital heart defects research、Pluripotent Stem Cells Research、Hippo pathway signaling and YAP/TAZ

It remains a significant challenge to reactivate the cell cycle activity of adult mammalian cardiomyocytes (CMs). This study created a hypo-immunogenic human induced pluripotent stem cell (hiPSC) line using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing to knockout β2-microglobulin in hiPSCs ( B2MKO hiPSCs) for manufacturing nanovesicles ( B2MKO hiPSC-NVs). Approximately 9500 B2MKO hiPSC-NVs were produced from a single B2MKO hiPSC. Proteomic analyses indicated that, compared to B2MKO hiPSCs, the cargos of B2MKO hiPSC-NVs were enriched in spindle and chromosomal proteins, as well as proteins that regulate the cell cycle and scavenge reactive oxygen species (ROS). When administrated to hiPSCs derived CMs (hiPSC-CMs), B2MKO hiPSC-NVs reduced lactate dehydrogenase leakage and apoptosis in hypoxia-cultured hiPSC-CMs through activating the AKT pathway, protected hiPSC-CMs from H 2 O 2 -induced damage by ROS scavengers in the NV cargo, increased hiPSC-CM proliferation via the YAP pathway, and were hypoimmunogenic when co-cultured with human CD8 + T cells or delivered to mice. Furthermore, when B2MKO hiPSC-NVs or 0.9 % NaCl were intramyocardially injected into mice after cardiac ischemia/reperfusion injury, cardiac function and infarct size, assessed 4 weeks later, were significantly improved in the B2MKO hiPSC-NV group, with increased mouse CM survival and cell cycle activity. Thus, the proteins in the B2MKO hiPSC-NV cargos convergently activated the ...