2021 New Initiative Grant
Nathan Lord, Ph.D. (PI) Assistant Professor, Department of Computational and Systems Biology
Mo Ebrahimkhani, Ph.D. (Co-PI) Associate Professor, Department of Pathology and member of the Pittsburgh Liver Research Center at the McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine
Spatially guided morphogenesis in human liver organoids
Human embryos use an elaborate language of signals to tell each of their cells when and where to divide, migrate and differentiate. Learning to translate this language—to read and write precise instructions that stem cells understand—is a defining aim of modern developmental biology. This ability would have broad implications for regenerative medicine by making it possible to guide the development of replacement tissues in the laboratory. Recent advances in stem cell culture make this goal feel within reach. With carefully chosen conditions, it is now possible to grow miniaturized tissues, or ‘organoids,’ that mimic the structure and function of adult organs. Organoids promise to transform our understanding of our own biology by providing a unique, human-based testbed to decode the complex rules of development. However, organoid development suffers from limited reproducibility and is failure prone. A key reason for these limitations is that unlike a developing embryo, we cannot issue individualized instructions to each cell in an organoid. In this new initiative, we will use cutting-edge optical and genetic techniques to guide liver organoid development with light. Our proposal combines a new class of self-vascularizing human liver organoids developed by the Ebrahimkhani lab with a platform for spatially-resolved light stimulation established in the Lord lab. Our unique approach will enable us to independently and specifically guide the development of every cell of a developing organoid using light-sensitive gene expression. Our platform creates an opportunity to carry out these experiments at unprecedented scale. By initiating organoids with of thousands of distinct sets of cellular instructions in parallel, we will systematically decode the molecular language that enables the embryo to control organ development. This initiative will establish a new path to rational engineering of complex tissues by decoding the principles of our own development.