Associate Professor Tsinghua University Beijing, Beijing, China
Abstract: Human pluripotent stem cells (hPSCs) serve as a powerful platform for disease modeling and regenerative medicine. We developed efficient protocols for differentiating cardiovascular cells and macrophages (MACs) from hPSCs under chemically defined conditions. Using hPSC-derived cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs), we constructed 3D mini-cardiac organoids (MCOs). Single-cell transcriptome analysis revealed that the 3D microenvironment enhanced CM maturation and led to the emergence of DLK1+ fibroblasts with immunomodulatory potential. Transplantation of MCOs into a rat model of myocardial infarction significantly improved cardiac function and reduced fibrosis, demonstrating their therapeutic promise.
In addition, hPSC-derived ECs expressed markers of choroidal endothelial cells (CECs) and could integrate into the choriocapillaris. In a rat model of choroidal ischemia, transplanted hPSC-ECs restored choroid thickness and vasculature. Remarkably, EC transplantation improves the visual function of CI rats, highlighting their potential for treating ocular diseases such as age-related macular degeneration.
We also demonstrated the potential of hPSC-derived macrophages as a powerful model for investigating immune interactions between pathogens and human tissues. hPSC-MAC responded to human pathogens, including hepatitis C virus (HCV), SARS-CoV-2, and Streptococcus pneumoniae, by activating distinct inflammatory and immune pathways. RNA sequencing identified pathogen-specific gene networks, and image-based analysis of iMACs interacting with HCV demonstrated their utility in evaluating infection and therapeutic strategies.
Our study highlights the versatility of hPSC-derived cells in advancing disease modeling, uncovering molecular mechanisms, and developing regenerative therapies for tissue repair and regeneration.
