Human iPSC intestine mimetics with integrated mesenchymal, endothelial and enteric nervous tissue

In this proposal, we present exciting preliminary data showing that we have generated an iPSC-derived human intestinal organoid (HIO) model that co-differentiates a complex multilineage tissue that possesses epithelium, a mesenchymal/stromal layer that includes organized smooth muscle, endothelial cells and enteric neurons. This is the first complex HIO model from iPSCs to spontaneously co-differentiate tissues from all 3 embryonic germ layers, which is a prerequisite for a fully formed and functional organ, and the phenotype is driven by specific members of the EGF-family of grow factors that are supplied as niche factors in the HIO growth medium. The goals of this proposal is to interrogate the development of the complex lineages present in complex HIOs (Aim 1), to further enhance the organization and complexity of HIOs by using a novel suspension culture method and via in vivo transplantation (Aim 2), and to functionally interrogate the vascular and neuronal cells present complex HIOs using microfluidics and in vivo transplantation (Aim 3).