In vitro 3D organoid cultures are emerging as novel systems to study tissue development, organogenesis, and stem cell behavior ex-vivo. Organoids are multicellular structures that (1) self-assemble and can be clonally expanded, (2) resemble the corresponding tissues-of-origin, and (3) allow the study of some aspects of tissue development and tissue physiology in a dish.
Over the past decade, we have developed organoid cultures from healthy and diseased, human and mouse, adult and embryonic tissues for a range of organs including stomach, liver and pancreas. These, have allowed, for the first time, the long-term expansion of adult (stomach, liver and pancreas) tissues in a dish, thus defying the Hayflick limit, by which only cancer cells with aberrant ploidy and unstable genomes would expand in culture.
Here, I will present our organoid work and summarize our findings on how this culture system is amenable for the study of adult tissue regeneration and disease across different biological scales. At the cellular scale, we have recently found that heterotypic cellular interactions between stromal and epithelial cells dictate the behavior of the liver epithelia, thus reconciling the apparent dichotomy between a pro-regenerative and a pro-quiescent stromal niche. At the molecular scale, we have found that a transient, genome-wide remodeling, of the cells’ epigenome (DNA methylome/hydroxymethylome), licenses adult differentiated liver cells to reprogram into bi-potent liver progenitors, both during organoid initiation and in vivo, following tissue damage. Our results indicate that adult tissue derived organoid cultures represent novel, reductionist in vitro models, that enable gaining mechanistic understanding of basic biological principles of human tissue regeneration and cancer.