911勛圖

Suspension-derived organoid models of human development

Human induced pluripotent stem cells (hiPSCs) have proven invaluable for human disease modeling and translation. Additionally, Self-assembling human organoid models promise to enable studies of human organogenesis in unprecedented detail. Up to date, several groups generated self-assembling human organoids such as neural, liver, intestinal, thymic and cardiac organoids. These novel human in vitro systems are critical to overcome current limitations of widely used animal models, which do not reproduce human organ development and fail in validation of molecular drug targets. In fact, only 8% of clinical cancer trials successfully translate from animals to humans. However, challenges with quality, cellular specification and maturity, inter-batch consistency, cryopreservation and scale remain, reducing experimental reproducibility and clinical translation of currently used cell and organoid models. Additionally, these organoids do not fully recapitulate multilineage development and cellular crosstalk present in human organs. The goal of my research group is to advance the state-of-the-art in modeling human organ development and disease. Thus, we recently reported using 3D suspension systems to enhance quality, reproducibility, and yield of hiPSC-derived cardiomyocytes (hiPSC-CMs). In the same study, I showed that this approach also generated the first reported fully suspension-derived cardiac organoid. My current unpublished data shows that with further refinement I am able to use suspension culture to induce formation of multilineage cardiac, neural, gastric and intestinal organoids. Further, using the same methodology and chemical cues I can generate mixed-lineage organoids (e.g. cardiac-neural, intestinal-neuronal) and multi-organ organoids, resembling ���organs on a string���. These studies will provide the necessary framework and first steps for generating new human in vitro models reproducing the complex cellular interactions that are necessary to guide human organ development, function and disease, while providing a more relevant testbed for future human medicine focused on regenerative approaches.